HIGHLY ACTIVE POLYPEPTIDES AND METHODS OF MAKING AND USING THE SAME

Abstract

This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an -amino acid and at least one -amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived.

Claims

1. A composition comprising a vasoactive intestinal peptide (VIP) analog, wherein said analog comprises an -amino acid and at least one -amino acid.

2.-52. (canceled)

53. A composition comprising a peptide or a pharmaceutical salt thereof comprising a repetitive pattern of and amino acids from the amino-terminus to the carboxy-terminus chosen from: ; ; ; ; ; ; and , wherein the peptide comprises between about 7% to about 50% amino acids.

54. The composition of claim 53, wherein the peptide or pharmaceutical salt thereof comprises between about 10 and about 100 residues.

55. The composition of claim 53, wherein at least one amino acid is a cyclic amino acid.

56. The composition of claim 55, wherein the cyclic amino acid is APC or ACPC.

57. The composition of claim 53, wherein the pattern of and amino acids repeats at least once.

58. The composition of claim 53, wherein the peptide or pharmaceutical salt thereof comprises an amino acid sequence from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO. 10.

59. The composition of claim 53, further comprising at least one other active agent.

60. A method of manufacturing the composition of claim 53 or a pharmaceutical salt derived therefrom comprising catalyzing a reaction between at least one -amino acid with at least one -amino acid.

61. A kit comprising the composition of claim 53.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0220] FIG. 1 shows MALDI-TOF data of a purified VIP analogue which illustrates the expected mass (within a reasonable tolerance) of both singly charged and doubly charged species of the analogue after chemical synthesis, cleavage from resin, and subsequent purification of the analogue through a C18 HPLC column.

[0221] FIG. 2 presents circular dichroism data of a VIP analogue diluted in a 10 mM sodium phosphate buffer at pH of 7.5. The signal exhibited for the structure of the VIP analogue is similar to previously characterized -amino acid/ amino acid peptides of similar backbone length and concentration, which indicates a substantial helical content (Home et. al., J. Am. Chem. Soc., 2007, 129 (14), pp 4178-4180; Home et. al. PNAS, Sep. 1, 2009, vol. 106, no. 35, 14751-14756).

[0222] FIG. 3 illustrates in vitro functional EC.sub.50 data of a VIP analogue tested in the presence of VIPR1 (VPAC.sub.1) or VIPR2 (VPAC.sub.2) receptors as compared to the binding of wild-type VIP protein to the same receptors. The data show that the analogue achieves full activation of VIPR1 (100%, relative to maximum activation), but has an EC.sub.50 at a concentration higher than the EC.sub.50 of wild-type VIP protein.

[0223] FIG. 4 illustrates data from an in vitro antagonist inhibition assay in which competition for VIPR1 (VPAC.sub.1) or VIPR2 (VPAC.sub.2) was measured by the amount of VIP analogue capable of inhibiting the association of wild-type VIP to its receptors.

[0224] FIG. 5 illustrates helical wheel diagrams of repeating patterns of - or -amino acids residues in alignment along one longitudinal axis of a folded molecular structure from N-terminus to C-terminus when the unnatural polypeptides adopt a helical conformation, where the position of -amino acids are represented by solid dots.

[0225] FIG. 6 illustrates a helical wheel diagram of the predicted -helical portion of VIP polypeptide, positions 10-28.

[0226] FIG. 7 illustrates multiple VIP analog sequences and their corresponding helical wheel diagrams, where the position of -amino acids are represented by solid dots.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0227] Various terms relating to the methods and other aspects of the present invention are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definition provided herein.

[0228] As used in this specification and the appended claims, the singular forms a, an. and the include plural referents unless the content clearly dictates otherwise.

[0229] The term about as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, or 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0230] The term active state refers to the conformation or set of conformations of a polypeptide that allows functional domain or domains of the polypeptide to associate or disassociate with another compound, macromolecule, or ligand. In some embodiments, the association or disassociation of the polypeptide with another compound, macromolecule, or ligand may propagate or inhibit a biologic signal.

[0231] The terms amino acid refer to a molecule containing both an amino group and a carboxyl group bound to a carbon which is designated the -carbon. Suitable amino acids include, without limitation, both the D- and L-isomers of the naturally-occurring amino acids, as well as non-naturally occurring amino acids prepared by organic synthesis or other metabolic routes, in some embodiments, a single amino acid might have multiple sidechain moieties, as available per an extended aliphatic or aromatic backbone scaffold. Unless the context specifically indicates otherwise, the term amino acid, as used herein, is intended to include amino acid analogs.

[0232] The term analog refers to any polypeptide comprising at least one -amino acid and at least one -amino acid residue, wherein the polypeptide is structurally similar to a naturally occurring full-length protein and shares the biochemical or biological activity of the naturally occurring full-length protein upon which the analog is based. In some embodiments, an analog is any polypeptide comprising at least one -amino acid residue, wherein the polypeptide is structurally similar to a naturally occurring full-length protein and shares the biochemical or biological activity of the naturally occurring full-length protein upon which the analog is based and wherein the addition of one or more -amino acid residues constrains an alpha helical structure in the polypeptide. In some embodiments, an analog is any polypeptide comprising at least one -amino acid residue, wherein the polypeptide is structurally similar to a naturally occurring full-length protein and shares the biochemical or biological activity of the naturally occurring full-length protein upon which the analog is based. In some embodiments, the non-natural amino acid residue is a monomer of an aliphatic polypeptide. In some embodiments the aliphatic analogs are chosen from oligoureas, azapeptides, pyrrolinones, -aminoxy-peptides, and sugar-based peptides. In some embodiments, the composition comprises a non-natural -amino acid. In some embodiments, the analog is a fragment of the full-length protein upon which the analog is based. In some embodiments, fragments are from about 5 to about 75 amino acids in length as compared to the naturally occurring, fully translated and fully processed protein sequences. In some embodiments, the analogs comprise a fragment of a naturally translated full-length protein that induces the biochemical or biological activity of a biological pathway of a subject at a level equivalent to or increased as compared to the activity induced by a naturally occurring full-length protein upon which the analog is derived. In some embodiments, the analog is a truncated polypeptide as compared to the full-length, naturally translated or naturally occurring polypeptide upon which the truncated polypeptide is derived. In some embodiments, the analog is a synthetic polypeptide, wherein at least one of the amino acid residues of the polypeptide comprises at least one non-natural side chain. In some embodiments, the analogs of the invention comprise at least one non-natural amino acid chosen from one of the following structures: aminoisobutyric acid. 3-Aminobutyric acid, and 2-hydroxy-4-(4-nitrophenyl)butyric acid. In some embodiments, the analog has a polypeptide backbone of identical length and similar homology to the polypeptides disclosed in Tables 1, 2, 3, and/or 4. In some embodiments, the analog is about 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% homolgous to at least one of the polypeptides disclosed in Tables 1, 2, 3, and/or 4. In some embodiments, the analog is an agonist or antagonist of one or more of the following receptors: VPAC1, VPAC2, or PAC1. In some embodiments, the analog is a fragment of one of the polypeptides disclosed in Tables 1, 2, 3, and 4 and shares the same or improved biological or biochemical activity as compared to the biological or biochemical activity of the polypeptides disclosed in Tables 1, 2, 3, and/or 4 upon which the analog amino acid sequence is derived. In some embodiments, the analog is an agonist or antagonist of the receptor of the full-length, naturally translated or naturally occurring polypeptide upon which the amino acid sequence of the agonist or antagonist is derived. In some embodiments, the analog is an agonist or antagonist of the receptor of the polypeptides disclosed in Tables 1, 2, 3, and/or 4. In such embodiments, the amino acid sequence of the agonists or antagonists are derived from the amino acid sequence of the polypeptides disclosed in Tables 1, 2, 3, and/or 4. In some embodiments the analog of the present invention is modified by a bioactive lipid moiety on at least one amino acid residue of the analog. In such embodiments, the lipid moieties may be chosen from the following lipid molecules: LPA, progesterone, prostanoids, SIP, LPA, cannabinoids, 2-arachidonylglycerol. In some embodiments, the side chain or terminal end of the amino acid residues of the polypeptides disclosed in Tables 1, 2, 3, and/or 4 may be modified with the bioreactive lipid moieties. In some embodiments, the analogs of the present invention are derived from one of the following sequences:

TABLE-US-00002 (SEQIDNO:6) HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK-NH.sub.2; (SEQIDNO:5) HSDGIFTDSYSRYRKQMAVKKYLAAVL-NH.sub.2; (SEQIDNO:9) HSDGTFTSELSRLRDSARLQRLLQGLV-NH.sub.2; (SEQIDNO:1335) HSDGTFTSDYSKYLDSRRAQDFVQWLMNT-NH.sub.2; (SEQIDNO:7) HADGVFTSDFSKLLGQLSAKKYLESLM-NH.sub.2

[0233] The term -amino acid refers to any and all natural and unnatural -amino acids and their respective residues (i.e., the form of the amino acid when incorporated into a polypeptide molecule), without limitation. In some embodiments, -amino acid explicitly encompasses the conventional and well-known naturally occurring amino acids, as well as all synthetic variations, derivatives, and analogs thereof. In some embodiments. -amino acid means alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and/or valine. In some embodiments, -amino acids also include analogs such as N-methylated -amino acids, hydroxylated -amino acids, and aminoxy acids. In some embodiments, -amino refers to include N-alkyl -amino acids (such as N-methyl glycine), hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, nor-valine, nor-leucine, and omithine.

[0234] The terms -amino acid and -amino acid residue refer to any and all -amino acids and their respective residues (i.e., the form of the amino acid when incorporated into a polypeptide molecule), without limitation. In some embodiments, the terms -amino acid refers to those -amino acids described in U.S. Pat. No. 6,060,585, issued May 9, 2000, incorporated herein by reference, and those described in allowed U.S. Pat. No. 6,683,154, issued Jan. 27, 2004; U.S. Pat. No. 6,710,186, issued Mar. 23, 2004; and U.S. Pat. No. 6,727,368, issued Apr. 27, 2004, all of which are incorporated herein by reference. Further still, cyclic imino carboxylic acids and gem-di-substituted cyclic imino carboxylic acids (both of which are a type of cyclically-constrained -amino acid) may also be used in the invention. In some embodiments, the term -amino acid refers to residues disclosed in U.S. Pat. No. 6,958,384, issued Oct. 25, 2005, incorporated herein by reference. Further still, these -residues may also take the form of the gem-di-substituted cyclic amino acids disclosed in U.S. Pat. No. 6,710,186, incorporated herein by reference. In some embodiments, the terms -amino acid refers to -homo amino acids. In some embodiments the R-amino acids refers to the selection of an amino acid chosen from the following:

##STR00001##

R.sup.1 is selected from the group consisting hydrogen and an amino protecting group; R.sup.2 is selected from the group consisting of hydrogen and a carboxy protecting group; and when R.sup.3 is bonded to a carbon atom. R.sup.3 is selected from the group consisting of hydrogen, hydroxy, linear or branched C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic heteroaryl-C.sub.1-C.sub.6-alkyl, (CH.sub.2).sub.n+1, OR.sup.4, (CH.sub.2).sub.n+1SR.sup.4, (CH.sub.2).sub.n+1S(O)CH.sub.2R.sup.4, (CH.sub.2).sub.n+1S(O).sub.2CH.sub.2R.sup.4, (CH.sub.2).sub.n+1NR.sup.4R, (CH.sub.2).sub.n+1NHC(O)R.sup.4, (CH.sub.2).sub.n+1NHS(O).sub.2CH.sub.2R.sup.4, (CH.sub.2).sub.n+1O(CH.sub.2).sub.mR.sup.5, (CH.sub.2).sub.n+1S(CH.sub.2).sub.mR.sup.5, (CH.sub.2).sub.n+1S(O)(CH.sub.2).sub.mR.sup.5, (CH.sub.2).sub.n+1S(O).sub.2(CH.sub.2).sub.mR.sup.5, (CH.sub.2).sub.n+1NH(CH.sub.2).sub.mR.sup.3, (CH.sub.2).sub.n+1N{(CH.sub.2).sub.mR.sup.5}.sub.2, (CH.sub.2).sub.n+1NHC(O).sub.n+1CH.sub.2).sub.n+1R.sup.5, and (CH.sub.2).sub.n+1NHS(O).sub.2(CH.sub.2).sub.mR.sup.5; wherein each R.sup.4 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to S heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C.sub.1-C.sub.6alkyl, mono- or bicyclic heteroaryl-C.sub.1-C.sub.6alkyl; and wherein R.sup.5 is selected from the group consisting of hydroxy, C.sub.1-C.sub.6alkyloxy, aryloxy, heteroaryloxy, thio, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C.sub.1-C.sub.6alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C.sub.1-C.sub.6alkylamino, carboxylic acid, carboxamide, mono- or di-C.sub.1-C.sub.6alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C.sub.1-C.sub.6alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea: mono- di- or tri-substituted urea, wherein the subsitutent(s) is selected from the group consisting of C.sub.1-C.sub.6alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane; and m is an integer of from 2-6 and n is an integer of from 0-6; and when R.sup.3 is bonded to a nitrogen atom, R.sup.3 is independently selected from the group consisting of those listed above for when R; is attached to a carbon atom, and further selected from the group consisting of S(O).sub.2CH.sub.2R.sup.4, C(O)R.sup.4S(O).sub.2(CH.sub.2).sub.mR.sup.5, and C(O)(CH.sub.2).sub.n+1R.sup.5; wherein R.sup.4 and R.sup.5 are as defined hereinabove, and m is an integer of from 2-6 and n is an integer of from 0-6; provided that when the -amino acid is of formula R.sup.3 is not hydrogen: racemic mixtures thereof, isolated or enriched enantiomers thereof; isolated or enriched diastereomers thereof, and salts thereof. In some embodiments the -amino acids refers to the selection of an amino acid chosen from the following:

##STR00002##

[0235] In some embodiments the -amino acids refers to the following formula:

##STR00003##

[0236] In some embodiments the -amino acids refers to the following formula:

##STR00004## [0237] An APC residue within an undefined peptide chain, under neutral aqueous conditions (the ring N is protonated).
wherein the NH.sub.2 and/or COOH groups are replaced with functional peptide bonds.

[0238] In some embodiments the term -amino acid refers to:

##STR00005## [0239] wherein X and Y combined, together with the carbon atoms to which they are bonded, define a substituted or unsubstituted C.sub.4-C.sub.8cycloalkyl, cycloalkenyl or heterocyclic ring having one or more nitrogen atoms as the sole heteroatom; the substituents on carbon atoms of the rings being independently selected from the group consisting of linear or branched C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic heteroaryl-C.sub.1-C.sub.6-alkyl, (CH.sub.2).sub.n+1OR.sup.4, (CH.sub.2).sub.n+1SR.sup.4, (CH.sub.2).sub.n+1S(O)CH.sub.2R.sup.4, (CH.sub.2).sub.n+1S(O).sub.2CH.sub.2R.sup.4, (CH.sub.2).sub.n+1NR.sup.4R.sup.4, (CH.sub.2).sub.n+1NHC(O)R.sup.4, (CH.sub.2).sub.n+1NHS(O).sub.2CH.sub.2R.sup.4, (CH.sub.2).sub.n+1O(CH.sub.2).sub.n+1R, (CH.sub.2).sub.n+1S(CH.sub.2).sub.mR.sup.5, (CH.sub.2).sub.n+1S(O)CH.sub.2).sub.mR.sup.5, (CH.sub.2).sub.n+1S(O).sub.2(CH.sub.2).sub.mR.sup.5, (CH.sub.2).sub.n+1NH(CH.sub.2).sub.mR.sup.5, (CH.sub.2).sub.n+1N{(CH.sub.2).sub.mR.sup.5}.sub.2, (CH.sub.2).sub.n+1NHC(O)(CH.sub.2).sub.n+1R.sup.5, and (CH.sub.2).sub.n+1NHS(O).sub.2(CH.sub.2).sub.mR.sup.5, [0240] wherein R.sup.4 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl: mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic heteroaryl-C.sub.1-C.sub.6-alkyl; and [0241] wherein R.sup.5 is selected from the group consisting of hydroxyl, C.sub.1-C.sub.6-alkyloxy, aryloxy, heteroarylocy, thio, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heterarylsulfonyl, amino, mino- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C.sub.1-C.sub.6-alkylamino, carboxylic acid, carboxamide, mono- or di-C.sub.1-C.sub.6-alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-Narylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C.sub.1-C.sub.6-alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheterarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heterarylsulfonamide, urea, mono- or di- or tri-substituted urea, wherein the substitutent(s) is selected from the group consisting of C.sub.1-C.sub.6-alkyl, aryl, heteraryl, O-alkylurethane, O-arylurethane, and O-heterarylurethane; and m is an integer from 2-6 and n is an integer from 0-6; [0242] the substituents on heteroatoms of the ring being independently selected from the group consisting of S(O).sub.2CH.sub.2R, C(O)R.sup.4S(O).sub.2(CH.sub.2).sub.mR.sup.5, and C(O)(CH.sub.2).sub.n+1R.sup.5, wherein R.sup.4 and R.sup.5 are as defined hereinabove, and m is an integer from 2-6 and n is an integer from 0-6; [0243] provided that when X and Y together with the carbons to which they are bonded define a five- or six-membered cycloalkyl or a five-membered heterocyclic ring having one nitrogen as the sole heteroatom, and the nitrogen is bonded to a carbon atom adjacent to the carboxy carbon of Formula I, the cycloalkyl or heterocyclic ring is substituted; [0244] R.sup.1 is selected from the group consisting of hydrogen and an amino protecting group: R.sup.2 is selected from the group consisting of hydrogen and a carboxy protecting group; Racemic mixtures thereof, isolated or enriched enantiomers thereof: isolated or enriched diasteromers thereof; and salts thereof.

[0245] In some embodiments the term -amino acid refers to selection of an amino acid chosen from the following: .sup.3 or .sup.2. In some embodiments the term -amino acid refers to selection of an amino acid chosen from the following:

##STR00006##

wherein R, R, R, and R are any substituent.

[0246] In some embodiments the term -amino acid refers to selection of an amino acid chosen from the following:

##STR00007##

wherein R, R, R, and R is an amine, hydroxy, hydroxyl, carbonyl, H, O, OH, COOH, N, CH.sub.3, CH.sub.2X, halo, aryl, arylalkoxy, arylalkyl, alkynyl, alkenyl, alkylene, alkyl, alkyl-halo, arylamido, alkylheterocycle, alkylamino, alkylguanidino, alkanol, alkylcarboxy, cycloalkyl, heteroaryl, heteroarylalkyl, heteroarylalkoxy, or heterocyclyl; wherein X is any substituent.

[0247] In some embodiments the term -amino acid refers to selection of an amino acid chosen from the following:

##STR00008##

wherein R, R, R, and R are any substituent, provided that: (i) R is not O, N, or halo when the R is in a .sup.3-residue, (ii) R and R are not O, N, or halo when the R and R are in a .sup.3,3-residue; (iii) R is not O, N, or halo when the R is in a .sup.2,3-residue; (iv) R and R are not O, N, or halo when the R and R are in a .sup.2,3,3-residue; (v) R is not O, N, or halo when the R is in a .sup.2,2,3-residue; (vi) R and R are not O, N, or halo when the R and R are in a .sup.2,2,3,3-residue.

[0248] In some embodiments the term -amino acid refers to selection of an amino acid chosen from the following:

##STR00009##

wherein R, R, R, and R is an amine, hydroxy, hydroxyl, carbonyl, H, O, OH, COOH, N, CH.sub.3, CH.sub.2X, halo, aryl, arylalkoxy, arylalkyl, alkynyl, alkenyl, alkylene, alkyl, alkyl-halo, arylamido, alkylheterocycle, alkylamino, alkylguanidino, alkanol, alkylcarboxy, cycloalkyl, heteroaryl, heteroarylalkyl, heteroarylalkoxy, or heterocyclyl; wherein X is any substituent; provided that: (i) R is not O, N, or halo when the R is in a .sup.3-residue, (ii) R and R are not O, N, or halo when the R and R are in a .sup.3,3-residue: (iii) R is not O, N, or halo when the R is in a .sup.2,3-residue: (iv) R and R are not O, N, or halo when the R and R are in a .sup.2,3,3-residue; (v) R is not O, N, or halo when the R is in a .sup.2,2,3-residue: (vi) R and R are not O, N, or halo when the R and R are in a .sup.2,2,3,3-residue.

[0249] A cyclic beta- amino acid is acid is an amino acid of the following formula I:

##STR00010##

wherein X and Y combined, together with the carbon atoms to which they are bonded, define a substituted or unsubstituted C.sub.4-C.sub.8 cycloalkyl or cycloalkenyl group; wherein substituents on carbon atoms of the rings being independently selected from the group consisting of linear or branched C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic heteroaryl-C.sub.1-C.sub.6-alkyl, (CH 2).sub.n+1OR.sub.4, (CH 2).sub.n+1SR.sub.4, (CH.sub.2).sub.n+1S(O)CH.sub.2R.sub.4, (CH.sub.2).sub.n+1S(O).sub.2CH.sub.2R.sub.4, (CH.sub.2).sub.n+1NR.sub.4R.sub.4, (CH.sub.2).sub.n+1NHC(O)R.sub.4, (CH.sub.2).sub.n+1NHS(O).sub.2CH.sub.2R.sub.4, (CH.sub.2).sub.n+1O(CH.sub.2).sub.mR.sub.5, (CH.sub.2).sub.n+1S(CH.sub.2).sub.mR.sub.5, (CH.sub.2).sub.n+1S(O)(CH.sub.2).sub.mR.sub.5, (CH.sub.2).sub.n+1S(O).sub.2(CH.sub.2).sub.mR.sub.5, (CH.sub.2).sub.n+1NH(CH.sub.2).sub.mR.sub.5, (CH.sub.2).sub.n+1N{(CH.sub.2).sub.mR.sub.5}.sub.2, (CH.sub.2).sub.n+1NHC(O)(CH.sub.2).sub.n+1R.sub.5, and (CH.sub.2).sub.n+1NHS(O).sub.2(CH.sub.2).sub.mR.sub.5; wherein R.sub.4 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl: mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S: mono- or bicyclic aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic heteroaryl-C.sub.1-C.sub.6-alkyl; and wherein R.sub.5 is selected from the group consisting of hydroxy, C.sub.1-C.sub.6-alkyloxy, aryloxy, heteroaryloxy, thio, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C.sub.1-C.sub.6-alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C.sub.1-C.sub.6-alkylamino, carboxylic acid, carboxamide, mono- or di-C.sub.1-C.sub.6-alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C.sub.1-C.sub.6-alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea: mono- di- or tri-substituted urea, wherein the subsitutent(s) is selected from the group consisting of C.sub.1-C.sub.6-alkyl, aryl, heteroaryl: O-alkylurethane, O-arylurethane, and O-heteroarylurethane; and m is an integer of from 2-6 and n is an integer of from 0-6; the substituents on heteroatoms of the ring being independently selected from the group consisting of S(O).sub.2CH.sub.2R.sub.4C(O)R.sub.4S(O).sub.2(CH.sub.2).sub.mR.sub.5, and C()(CH.sub.2).sub.n+1R.sub.5; wherein R.sub.4 and R.sub.5 are as defined hereinabove, and m is an integer of from 2-6 and n is an integer between 0 and 6; provided that when X and Y together with the carbons to which they are bonded define a five- or six-membered cycloalkyl or a five-membered heterocyclic ring having one nitrogen as the sole heteroatom, and the nitrogen is bonded to a carbon atom adjacent to the carboxy carbon of Formula I, the cycloalkyl or heterocyclic ring is substituted; R.sub.1 is selected from the group consisting hydrogen and an amino protecting group; R.sub.2 is selected from the group consisting of hydrogen and a carboxy protecting group: racemic mixtures thereof, isolated or enriched enantiomers thereof: isolated or enriched diastereomers thereof, and salts thereof.

[0250] A heterocyclic beta-amino acid is an amino acid of formula I, wherein X and Y combined, together with the carbon atoms to which they are bonded, define a substituted or unsubstituted C.sub.4-C.sub.8 cyclically or cycloalkenyl group having one or more nitrogen, oxygen or sulfur atoms as a heteroatom(s) within the cycloakyl or cycloalkenyl group: wherein substituents on carbon atoms of the cycloakyl or cycloalkenyl rings being independently selected from the group consisting of linear or branched C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl: mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic heteroaryl-C.sub.1-C.sub.6-alkyl, (CH 2).sub.n+1OR.sub.4, (CH2).sub.n+1SR.sub.4, (CH.sub.2).sub.n+1S(O)CH.sub.2R.sub.4, (CH.sub.2).sub.n+1S(O).sub.2CH.sub.2R.sub.4, (CH.sub.2).sub.n+1NR.sub.4R.sub.4, (CH.sub.2).sub.n+1NHC(O)R.sub.4, (CH.sub.2).sub.n+1NHS(O).sub.2CH.sub.2R.sub.4, (CH.sub.2).sub.n+1O(CH.sub.2).sub.mR.sub.5, (CH.sub.2).sub.n+1S(CH.sub.2).sub.mR.sub.5, (CH.sub.2).sub.n+1S(O)(CH.sub.2).sub.mR.sub.5, (CH.sub.2).sub.n+1S(O).sub.2(CH.sub.2).sub.mR.sub.5(CH.sub.2).sub.n+1NH(CH.sub.2).sub.mR.sub.5, (CH.sub.2).sub.n+1N{(CH.sub.2).sub.mR.sub.5}.sub.2, (CH.sub.2).sub.n+1NHC(O)(CH.sub.2).sub.n+1R.sub.5, and (CH.sub.2).sub.n+1NHS(O).sub.2(CH.sub.2).sub.mR.sub.5; wherein R.sub.4 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, alkenyl, or alkynyl: mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S: mono- or bicyclic aryl-C.sub.1-C.sub.6-alkyl, mono- or bicyclic heteroaryl-C.sub.1-C.sub.6-alkyl; and wherein R.sub.5 is selected from the group consisting of hydroxy, C.sub.1-C.sub.6-alkyloxy, aryloxy, heteroaryloxy, thio, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C.sub.1-C.sub.6-alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C.sub.1-C.sub.6-alkylamino, carboxylic acid, carboxamide, mono- or di-C.sub.1-C.sub.6-alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C.sub.1-C.sub.6-alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the subsitutent(s) is selected from the group consisting of C.sub.1-C.sub.6-alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane; and m is an integer of from 2-6 and n is an integer of from 0-6; the substituents on heteroatoms of the ring being independently selected from the group consisting of S(O).sub.2CH.sub.2R.sub.4C(O)R.sub.4S(O).sub.2(CH.sub.2).sub.mR.sub.5, and C(O)(CH.sub.2).sub.n+1R.sub.5; wherein R.sub.4 and R.sub.5 are as defined hereinabove, and m is an integer of from 2-6 and n is an integer between 0 and 6; provided that when X and Y together with the carbons to which they are bonded define a five- or six-membered cycloalkyl or a five-membered heterocyclic ring having one nitrogen as the sole heteroatom, and the nitrogen is bonded to a carbon atom adjacent to the carboxy carbon of Formula I, the cycloalkyl or heterocyclic ring is substituted: R.sub.1 is selected from the group consisting hydrogen and an amino protecting group; R.sub.2 is selected from the group consisting of hydrogen and a carboxy protecting group; racemic mixtures thereof, isolated or enriched enantiomers thereof; isolated or enriched diastereomers thereof; and salts thereof.

[0251] In some embodiments, at least one of the -amino acid residues in the analog is replaced with at least one -amino acid residue that is cyclically constrained via a ring encompassing its .sup.2 and .sup.3 carbon atoms. In another embodiment of the invention, most or all of the inserted -amino acid residues are cyclically constrained. In another version of the invention, at least one of the -amino acid residues is unsubstituted at its .sup.2 and .sup.3 carbon atoms. Alternatively, all of the -amino acid residues may be substituted at their .sup.2 and .sup.3 carbon atoms (with linear, branched or cyclic substituents). In some embodiments, the cyclic substituents of the claimed invention comprise side chains that are covalently bonded to the side chains of other contiguous amino acids. In some embodiments, the cyclic substituents of the claimed invention comprise side chains that are covalently bonded to the side chains of other non-contiguous amino acids. In some embodiments the cyclic substituents of the claimed invention do not include side chains that are covalently bonded to the side chains of other contiguous or non-contiguous amino acids. In some embodiments the terms beta-3 or beta-2 amino acid refers to -homo 2-homo amino acids.

[0252] A conservative amino acid substitution is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., K, R, H), acidic side chains (e.g., D. E), uncharged polar side chains (e.g., G, N, Q, S, T, Y, C, H), nonpolar side chains (e.g., G, A, V, L, I, P, F, M, W), beta-branched side chains (e.g., T, V, I) and aromatic side chains (e.g., Y, F, W, H). Thus, a predicted nonessential amino acid residue in a VIP analog, for example, replaced with another amino acid residue from the same side chain family. Other examples of acceptable substitutions are substitutions based on isosteric considerations (e.g. norleucine for methionine) or other properties (e.g. 2-thienylalanine for phenylalanine).

[0253] As used herein, the term derived from in the context of the relationship between a chemical structure or amino acid sequence and a related chemical structure or related amino acid sequence describes a chemical structure or amino acid sequence that may be homologous to or structurally similar to the related chemical structure or related amino acid sequence.

[0254] As used herein, the term inflammatory disease refers to any disease, condition, or ailment that results from an immune response or a pathogen infection, which in some instances may be characterized by one or more of pain, swelling, and redness of a tissue types. In some embodiments, inflammatory disease refers to rheumatoid arthritis, Crohn's disease, sepsis, ulcerative colitis, irritable bowel disease, chronic irritable bowel syndrome, and allergies such as allergic rhinitis.

[0255] A non-essential amino acid residue is a residue that can be altered from the wild-type sequence of a polypeptide (e.g., a short domain of VIP) without abolishing or substantially altering its essential biological or biochemical activity (e.g., receptor binding or activation). An essential amino acid residue is a residue that, when altered from the wild-type sequence of the polypeptide, results in abolishing or substantially abolishing the polypeptide's essential biological or biochemical activity.

[0256] A non-natural side chain is a modified or synthetic chain of atoms joined by covalent bond to the -carbon atom, -carbon atom, or -carbon atom which does not make up the backbone of the polypeptide chain of amino acids. The natural side chain, or R group, of alanine is a methyl group. In some embodiments, the non-natural side chain of the composition is a methyl group in which on e or more of the hydrogen atoms is replaced by a deuterium atom.

[0257] The term polypeptide encompasses two or more naturally or non-naturally-occurring amino acids joined by a covalent bond (e.g., an amide bond). Polypeptides as described herein include full-length proteins (e.g., fully processed pro-proteins or full-length synthetic polypeptides) as well as shorter amino acid sequences (e.g., fragments of naturally-occurring proteins or synthetic polypeptide fragments).

[0258] The term salt refers to acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. Examples of these acids and bases are well known to those of ordinary skill in the art. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.

[0259] In some embodiments, salts of the compositions comprising either a secretin or VIP analog may be formed by reacting the free base, or a salt, enantiomer or racemate thereof, with one or more equivalents of the appropriate acid. In some embodiments, pharmaceutical acceptable salts of the present invention refer to analogs having at least one basic group or at least one basic radical. In some embodiments, pharmaceutical acceptable salts of the present invention comprise a free amino group, a free guanidino group, a pyrazinyl radical, or a pyridyl radical that forms acid addition salts. In some embodiments, the pharmaceutical acceptable salts of the present invention refer to analogs that are acid addition salts of the subject compounds with (for example) inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane- or 2-hydroxyethane-sulfonic acid, or aromatic sulfonic acids, for example benzene-, p-toluene- or naphthalene-2-sulfonic acid. When several basic groups are present mono- or poly-acid addition salts may be formed. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, for example, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuo or by freeze drying. The reaction may also be a metathetical process or it may be carried out on an ion exchange resin. In some embodiments, the salts may be those that are physiologically tolerated by a patient. Salts according to the present invention may be found in their anhydrous form or as in hydrated crystalline form (i.e., complexed or crystallized with one or more molecules of water).

[0260] The term subject is used throughout the specification to describe an animal to whom treatment with the compositions according to the present invention is provided or administered. For treatment of those conditions which are specific for a specific subject, such as a human being, the term patient may be interchangeably used. In some instances in the description of the present invention, the term patient will refer to human patients. In some embodiments, the subject may be a mammal to whom the present invention is provided or administered. In some embodiments, the subject may be a non-human animal to whom the present invention is provided or administered.

[0261] The term soluble or water soluble refers to solubility that is higher than 1/100,000 (mg/ml). The solubility of a substance, or solute, is the maximum mass of that substance that can be dissolved completely in a specified mass of the solvent, such as water. Practically insoluble or insoluble, on the other hand, refers to an aqueous solubility that is 1/10,000 (mg/ml) or less. Water soluble or soluble substances include, for example, polyethylene glycol. In some embodiments, the polypeptide of the claimed invention may be bound by polyethylene glycol to better solubilize the composition comprising the peptide.

[0262] The terms treating and to treat, mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms. The term treatment includes alleviation, elimination of causation (temporary or permanent) of, or prevention of symptoms and disorders associated with any condition. The treatment may be a pre-treatment as well as a treatment at the onset of symptoms.

[0263] Effective amount refers to an amount of a compound, material, or composition, as described herein effective to achieve a particular biological result such as, but not limited to, biological results disclosed, described, or exemplified herein. Such results may include, but are not limited to, the effective reduction of symptoms associated with any of the disease states mentioned herein, as determined by any means suitable in the art. The effective amount of the composition may be dependent on any number of variables, including without limitation, the species, breed, size, height, weight, age, overall health of the subject, the type of formulation, the mode or manner or administration, the type and/or severity of the particular condition being treated, or the need to modulate the activity of the molecular pathway induced by association of the analog to its receptor. The appropriate effective amount can be routinely determined by those of skill in the art using routine optimization techniques and the skilled and informed judgment of the practitioner and other factors evident to those skilled in the art. A therapeutically effective dose of the analogs described herein may provide partial or complete biological activity as compared to the biological activity induced by the wild-type or naturally occurring polypeptides upon which the analogs are derived. A therapeutically effective dose of the analogs described herein may provide a sustained biochemical or biological affect and/or an increased resistance to degradation when placed in solution as compared with the normal affect observed when the naturally occurring and fully processed translated protein is administered to the same subject.

[0264] The term fragment refers to any analog of a naturally occurring polypeptide disclosed herein that comprises at least 4 amino acids identical to the naturally occurring polypeptide upon which the analog is based. The term functional fragment refers to any fragment of any analog of a naturally occurring polypeptide disclosed herein that comprises at least 4 amino acids identical to the naturally occurring polypeptide upon which the analog is based and shares the function of the naturally occurring polypeptide upon which the analog is based. In some embodiments, the compositions or pharmaceutical composition comprises an analog comprising at least one -amino acid, wherein the analog is a fragment of VIP, a secretin family member, an interleukin, or any of the polypeptides disclosed in the instant application. In some embodiments, the compositions or pharmaceutical composition comprises an analog comprising at least one -amino acid, wherein the analog is a fragment of VIP, a secretin family member, an interleukin, or any of the polypeptides disclosed in the instant application and wherein the fragment shares at least 4 contiguous amino acid residues with the naturally occurring polypeptide upon which the analog is based and wherein the fragment retains the biological activity of the naturally occurring polypeptide upon which the analog is based. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 27 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 26 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 25 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 24 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 23 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 22 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 21 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 20 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 19 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 18 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 19 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 17 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 16 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 15 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 14 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 13 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 12 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 11 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 10 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 9 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment of VIP that comprises between about 1 to about 8 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 7 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 6 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 5 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 4 amino acids of the naturally occurring VIP sequence. In some embodiments, the analog is modified with at least one PEG molecule on at least one of the non-natural amino acids.

[0265] The term halo or halogen refers to fluorine, chlorine, bromine or iodine or a radical thereof.

[0266] The term alkyl refers to a hydrocarbon chain that is a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C.sub.1-C.sub.10 indicates that the group has from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, alkyl is a chain (straight or branched) having 1 to 20 (inclusive) carbon atoms in it. In some embodiments the alkyl group is chosen from: C.sub.1-C.sub.10, C.sub.2-C.sub.10, C.sub.3-C.sub.10, C.sub.4-C.sub.10. C.sub.5-C.sub.10, C.sub.6-C.sub.10, C.sub.7-C.sub.10, C.sub.5-C.sub.10, C.sub.9-C.sub.10, C.sub.1-C.sub.10, C.sub.1-C.sub.2, C.sub.1-C.sub.3, C.sub.1-C.sub.4, C.sub.1-C.sub.5, C.sub.1- C.sub.6, C.sub.1-C.sub.7, C.sub.1-C.sub.8, or C.sub.1-C.sub.9,

[0267] The term alkylene refers to a divalent alkyl (i.e., R).

[0268] The term alkenyl refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C.sub.2-C.sub.10 indicates that the group has from 2 to 10 (inclusive) carbon atoms in it. The term lower alkenyl refers to a C.sub.2-C.sub.6 alkenyl chain. In the absence of any numerical designation, alkenyl is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it.

[0269] The term alkynyl refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C.sub.2-C.sub.10 indicates that the group has from 2 to 10 (inclusive) carbon atoms in it. The term lower alkynyl refers to a C.sub.2-C.sub.6 alkynyl chain. In the absence of any numerical designation. alkynyl is a chain (straight or branched) having about 2 to about 20 (inclusive) carbon atoms in it.

[0270] The term aryl refers to an aromatic ring system. In some embodiments, the aryl group of the analog include substituents, wherein 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 atoms of each ring are substituted by a substituent. In some embodiments, the aryl group refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like. The term arylalkyl or the term aralkyl refers to alkyl substituted with an aryl. The term arylalkoxy refers to an alkoxy substituted with aryl. Arylalkyl refers to an aryl group, as defined above, wherein one of the aryl group's hydrogen atoms has been replaced with an alkyl group, as defined above. Representative examples of an arylalkyl group include, but are not limited to, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl, 3-propylphenyl, 4-propylphenyl, 2-butylphenyl, 3-butylphenyl, 4-butylphenyl, 2-pentylphenyl, 3-pentylphenyl, 4-pentylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2-sec-butylphenyl, 3-sec-butylphenyl, 4-sec-butylphenyl, 2-t-butylphenyl, 3-t-butylphenyl and 4-t-butylphenyl.

[0271] Arylamido refers to an aryl group, as defined above, wherein one of the aryl group's hydrogen atoms has been replaced with one or more C(O)NH.sub.2 groups. Representative examples of an arylamido group include 2-C(O)NH.sub.2-phenyl, 3-C(O)NH.sub.2-phenyl, 4-C(O)NH.sub.2-phenyl, 2-C(O)NH.sub.2-pyridyl, 3-C(O)NH.sub.2-pyridyl, and 4-C(O)NH.sub.2-pyridyl.

[0272] Alkylheterocycle refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a heterocycle. Representative examples of an alkylheterocyclo group include, but are not limited to, CH.sub.2CH.sub.2-morpholine, CH.sub.2CH.sub.2piperidine, CH.sub.2CH.sub.2CH.sub.2-morpholine, and CH.sub.2CH.sub.2CH.sub.2-imidazole.

[0273] Alkylamido refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a C(O)NH.sub.2 group. Representative examples of an alkylamido group include, but are not limited to, CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2C(O)NH.sub.2, CH.sub.2CH(C(O)NH.sub.2)CH.sub.3, CH.sub.2CH(C(O)NH.sub.2)CH.sub.2CH.sub.3, CH(C(O)NH.sub.2)CH.sub.2CH.sub.3, C(CH.sub.3).sub.2CH.sub.2C(O)NH.sub.2, CH.sub.2CH.sub.2NHC(O)CH.sub.3, CH.sub.2CH.sub.2NHC(O)CH.sub.2CH.sub.3, and CH.sub.2CH.sub.2NHC(O)CHCH.sub.2.

[0274] Alkylamino refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a NH.sub.2 group. Representative examples of an alkylamido group include, but are not limited to CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2.

[0275] Alkylguanidino refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a NH.sub.2(CNH)NH.sub.2 group. Representative examples of an alkylamido group include, but are not limited to CH.sub.2 NH.sub.2(CNH)NH.sub.2, CH.sub.2CH.sub.2 NH.sub.2(CNH)NH.sub.2, CH.sub.2CH.sub.2CH.sub.2 NH.sub.2(CNH)NH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2 NH.sub.2(CNH)NH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2 NH.sub.2(CNH)NH.sub.2. In some embodiments alkyl units can be found on the N atom(s) of the alkylamino or alkylguanidino groups (for example, CH.sub.2NH(CH.sub.3), CH.sub.2N(CH.sub.3).sub.2).

[0276] Alkanol refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a hydroxyl group. Representative examples of an alkanol group include, but are not limited to, CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, CH.sub.2CH(OH)CH.sub.3, CH.sub.2CH(OH)CH.sub.2CH.sub.3, CH(OH)CH.sub.3 and C(CH.sub.3).sub.2CH.sub.2OH.

[0277] Alkylcarboxy refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a COOH group. Representative examples of an alkylcarboxy group include, but are not limited to, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH.sub.2CH.sub.2CH.sub.2COOH, CH.sub.2CH.sub.2CH.sub.2CH.sub.2COOH, CH.sub.2CH(COOH)CH.sub.3, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2COOH, CH.sub.2CH(COOH)CH.sub.2CH.sub.3, CH(COOH)CH.sub.2CH.sub.3 and C(CH.sub.3).sub.2CH.sub.2COOH.

[0278] The term cycloalkyl as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, 3 to 8 carbons, or 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Some cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0279] The term heteroaryl refers to an aromatic 5-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. Examples of heteroaryl groups include, but are not limited to, pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.

[0280] The term heteroarylalkyl or the term heteroaralkyl refers to an alkyl substituted with a heteroaryl. The term heteroarylalkoxy refers to an alkoxy substituted with heteroaryl.

[0281] The term heterocyclyl refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring are substituted by a substituent. Examples of heterocyclyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

[0282] The term substituent refers to a group replacing a second atom or group such as a hydrogen atom on any molecule, compound or moiety. Suitable substituents include, without limitation, halo, hydroxy, mercapto, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, amino, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, and cyano groups.

[0283] In some embodiments, the composition comprises an analog comprises one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. Preparation of pure enantiomers or mixtures of desired enantiomeric excess (ee) or enantiomeric purity are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof. These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T. E. Beesley and R P. W. Scott, Chiral Chromatography. John Wiley & Sons, 1999; and Satinder Ahuja. Chiral Separations by Chromatography, Am. Chem. Soc., 2000. Furthermore, there are equally well-known methods for the quantitation of enantiomeric excess or purity, for example, GC, HPLC, CE, or NMR, and assignment of absolute configuration and conformation, for example, CD ORD, X-ray crystallography, or NMR.

[0284] All tautomeric forms and isomeric forms and mixtures, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, of a chemical structure or entire analog is intended, unless the specific stereochemistry or isomeric form is specifically indicated in the analog name, chemical name or structure. All such isomeric forms of these compositions are included in the present invention unless expressly provided otherwise. In some embodiments, the analogs of this invention are also represented in multiple tautomeric forms, in such instances, the invention includes all tautomeric forms of the analogs described herein (e.g., if alkylation of a ring system results in alkylation at multiple sites, the invention includes all such reaction products). All such isomeric forms of such analogs are included in the present invention unless expressly provided otherwise. All crystal forms of the analogs described herein are included in the present invention unless expressly provided otherwise. All deuterated form of the analogs described herein are included in the present invention. In some embodiments as least one hydrogen atom of the analog is replace with a deuterium atom. In some embodiments at least one hydrogen atom that is involved with a hydrogen-bond is replaced with a deuterium atom. In some embodiments at least one solvent exchangeable hydrogen atom is replaced with a deuterium atom. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 1% to about 100% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 90% to about 100% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 80% to about 90% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 70% to about 80% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 60% to about 70% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 50% to about 60% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 40% to about 50% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 30% to about 40% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 20% to about 30% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 10% to about 20% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 5% to about 10% of their hydrogen replaced with deuterium atoms. If the analog of the claimed invention includes a methyl group, a deutrated analog may have one, two, or three of the hydrogens replaced by deuterium atoms. In some embodiments, the analog may contain one or more radioisotopes. In some embodiments, as least one hydrogen atom of the analog is replace with a tritium atom. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 1% to about 5% of their hydrogens are replaced with tritium atoms.

[0285] As used herein, the terms increase and decrease mean, respectively, to cause a statistically significantly (i.e., p<0.15) increase or decrease of at least 1%. 2%, or 5%.

[0286] As used herein, the recitation of a numerical range for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable is equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable is equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 takes the values 0, 1 or 2 if the variable is inherently discrete, and takes the values 0.0, 0.1, 0.01, 0.001, 10.sup.12, 10.sup.11, 10.sup.10, 10.sup.9, 10.sup.8, 10.sup.7, 10.sup.6, 10.sup.5, 10.sup.4 or any other real values 0 and 2 if the variable is inherently continuous.

[0287] As used herein, unless specifically indicated otherwise, the word or is used in the inclusive sense of and/or and not the exclusive sense of either/or.

[0288] The term biological activity encompasses structural and functional properties of a macrocycle of the invention. Biological activity is, for example, structural stability, alpha-helicity, affinity for a target, resistance to proteolytic degradation, cell penetrability, intracellular stability, in vivo stability, or any combination thereof.

[0289] The terms prodrug or prodrug derivative mean a covalently-bonded derivative or carrier of the analog of the claimed invention or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). In general, such prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the analog of the claimed invention, for example, by hydrolysis in blood, and generally include esters and amide analogs of the analogs. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the analogs using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: Design and Applications of Prodrugs, Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985: Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998: Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982: Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; and Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in their entireties. In some embodiments, the analog may be a prodrug that, w % ben administered to the subject becomes biologically active.

[0290] In some embodiments, the invention relates to a composition or pharmaceutical composition comprising a pharmaceutically acceptable prodrug that, when administered to the subject becomes biologically active. The term pharmaceutically acceptable prodrug as used herein means a prodrug of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.

[0291] In some embodiments, the analog of the claimed invention is a pharmaceutically-acceptable acid addition salt. The term pharmaceutically-acceptable acid addition salt means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, heptanoic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, and the like.

[0292] In some embodiments, the analog of the claimed invention is a pharmaceutically-acceptable base addition salt. The term pharmaceutically-acceptable base addition salt means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically-acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N-dibenzylethylenediamine, polyamine resins, and the like. In some embodiments, the composition of the claimed invention comprises at least one organic nontoxic bases chosen from isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0293] The term solvate means a physical association of a compound with one or more solvent molecules or a complex of variable stoichiometry formed by a solute (the analog of the claimed invention) and a solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. In general, the solvents selected do not interfere with the biological activity of the solute. Solvates encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0294] The invention relates to compositions comprising an analog of a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is from about 80% to 99% homologous to a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is from about 80% to 85% homologous to a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is from about 85% to 90% homologous to a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is from about 90% to 95% homologous to a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is from about 95% to 99% homologous to a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is about 95%, 96%, 97%, 98%, or 99% homologous to a naturally occurring polypeptide sequence. In some embodiments the analog is derived from the naturally occurring polypeptide of the secretin family. In some embodiments, the analog is derived from the naturally occurring polypeptide of the secretin family and has at least one -amino acid residue and/or at least one modified amino acid residue comprising APC or ACPC. Table I below illustrates the known wild-type sequences of each naturally occurring human secretin family members:

TABLE-US-00003 TABLE1 AminoAcidSequencesforPeptidesoftheSecretinFamily GHRF YADAIFTNSYRKVLGOLSARKLLQDIMSRQQGESNQERGARARL(SEQID NO:1) GIP YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ(SEQID NO:2) GLP-1HDEFERHAEGTFTSDVSSYLEGQAAQGFIAWLVKGRG (SEQIDNO:3) GlucagonHSQGTFTSDYSKYLDSRRAQDFVQWLMNT(SEQIDNO:4) PACAP-27HSDGIFTDSYSRYRKQMAVKKYLAAVL(SEQIDNO:5) PACAP-38HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK(SEQID NO:6) PHMHADGVFTSDFSKLLGQLSAKKYLESLM(SEQIDNO:7) PrPDVAHGILNEAYRKVLGQLSAGKHLQSLVA(SEQIDNO:8) SecretinHSDGTFTSELSRLREGARLQRLLQGLV(SEQIDNO:9) VIPHSDAVFTDNYTRLRKQMAVKKYLNSILN(SEQIDNO:10)

TABLE-US-00004 TABLE2 AminoAcidSequencesforInterleukins IL-10 >gi|10835141|ref|NP_000563.1|interleukin-10precursor{Homosapiens} MHSSALLCCLVLLTGVRASPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQ MKDQLDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSL GENLKTLRLRLRRCHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEA YMTMKIRN(SEQIDNO:11) IL-4 >gi|4504669|ref]NP_000580.1|interleukin-4isoform1precursor{Homosapiens} MGLTSQLLPPLFFLLACAGNFVHGHKCDITLQEIIKTLNSLTEQKTLCTELTVTDIFAASKNTT EKETFCRAATVLRQFYSHHEKDTRCLGATAQQFHRHKQLIRFLKRLDRNLWGLAGLNSCPV KEANQSTLENFLERLKTIMREKYSKCSS(SEQIDNO:12) >gi|27477092|ref|NP_758858.1|interleukin-4isoform2precursor{Homosapiens} MGLTSQLLPPLFFLLACAGNFVHGHKCDITLQEIIKTLNSLTEQKNTTEKETFCRAATVLRQF YSHHEKDTRCLGATAQQFHRHKQLIRFLKRLDRNLWGLAGLNSCPVKEANQSTLENFLERL KMREKYSKCSS(SEQIDNO:13) IL-5 >gi|4504671|ref]NP_000870.1|interleukin5precursor{Homosapiens} MRMLLHLSLLALGAAYVYAIPTEIPTSALVKETLALLSTHRTLLIANETLRIPVPVHKNHQLCT EEIFQGIGTLESQTVQGGTVERLFKNLSLIKKYIDGQKKKCGEERRRVNQFLDYLQEFLGVMN TEWIIES(SEQIDNO:14) IL-8 >gi|10834978|ref|NP_000575.1|interleukin-8precursor{Homosapiens} MTSKLAVALLAAFLISAALCEGAVLPRSAKELRCQCIKTYSKPFHPKFIKELRVIESGPHCANT EIIVKLSDGRELCLDPKENWVQRVVEKFLKRAENS(SEQIDNO:15) IL-12A >gi|24430219|ref|NP_000873.2|interleukin-12subunitalphaprecursor{Homosapiens} MWPPGSASQPPPSPAAATGLHPAARPVSLQCRLSMCPARSLLLVATLVLLDHLSLARNLPVA TPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELT KNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQI FLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYL NAS(SEQIDNO:16) IL-12B >gi|24497438|ref|NP_002178.2|interleukin-12subunitbetaprecursor{Homosapiens} MCHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWT LDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEP KNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNK EYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNS RQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQ DRYYSSSWSEWASVPCS(SEQIDNO:17) IL-2 >gi|28178861|ref|NP_000577.2|interleukin2precursor{Homosapiens} MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMC EYADETATIVEFLNRWITFCQSIISTLT(SEQIDNO:18) IL-15 gi|26787984|ref|NP_751914.1|interleukin15preproprotein{Homosapiens} MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANWVNVISDLKKIEDLIQ SMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVT ESGCKECEELEEKNIKEFLQSFVHIVQMFINTS(SEQIDNO:19) gi|10835153|ref|NP_000576.1|interleukin15preproprotein{Homosapiens} MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANWVNVISDLKKIEDLIQ SMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVT ESGCKECEELEEKNIKEFLQSFVHIVQMFINTS(SEQIDNO:20) IL-17 >gi|4504651|ref]NP_002181.1|interleukin17Aprecursor{Homosapiens} MTPGKTSLVSLLLLLSLEAIVKAGITIPRNPGCPNSEDKNFPRTVMVNLNIHNRNTNTNPKRSS DYYNRSTSPWNLHRNEDPERYPSVIWEAKCRHLGCINADGNVDYHMNSVPIQQEILVLRREP PHCPNSFRLEKILVSVGCTCVTPIVHHVA(SEQIDNO:21) IL-18 >gi|4504653|ref]NP_001553.1|interleukin-18proprotein{Homosapiens} MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLESDYFGKLESKLSVIRNLNDQVLFIDQGNR PLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNI KDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQN ED(SEQIDNO:22) Interleukin-18-bindingproteinisoformaprecursor(Homosapiens} >gi|89111125|ref|NP_001034748.1|interleukin-18-bindingproteinisoformaprecursor {Homosapiens} MTMRHNWTPDLSPLWVLLLCAHVVTLLVRATPVSQTTTAATASVRSTKDPCPSQPPVFPAA KQCPALEVTWPEVEVPLNGTLSLSCVACSRFPNFSILYWLGNGSFIEHLPGRLWEGSTSRERG STGTQLCKALVLEQLTPALHSTNFSCVLVDPEQVVQRHVVLAQLWAGLRATLPPTQEALPSS HSSPQQQ(SEQIDNO:23) IL-21 >gi|11141875|ref|NP_068575.1|interleukin-21{Homosapiens} MRSSPGNMERIVICLMVIFLGTLVHKSSSQGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPA PEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCD SYEKKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS(SEQIDNO:24) IL-22 >gi|10092625|ref|NP_065386.1|interleukin-22precursor{Homosapiens} MAALQKSVSSFLMGTLATSCLLLLALLVQGGAAAPISSHCRLDKSNFQQPYITNRTFMLAKE ASLADNNTDVRLIGEKLFHGVSMSERCYLMKQVLNFTLEEVLFPQSDRFQPYMQEVVPFLAR LSNRLSTCHIEGDDLHIQRNVQKLKDTVKKLGESGEIKAIGELDLLFMSLRNACI(SEQID NO:25) IL-24 >gi|5803086|ref]NP_006841.1|interleukin24isoform1precursor{Homosapiens} MNFQQRLQSLWTLARPFCPPLLATASQMQMVVLPCLGFTLLLWSQVSGAQGQEFHFGPCQV KGVVPQKLWEAFWAVKDTMQAQDNITSARLLQQEVLQNVSDAESCYLVHTLLEFYLKTVF KNYHNRTVEVRTLKSFSTLANNFVLIVSQLQPSQENEMFSIRDSAHRRFLLFRRAFKOLDVEA ALTKALGEVDILLTWMQKFYKL(SEQIDNO:26) >gi|31317246|ref]NP_851936.1|interleukin-24isoform2{Homosapiens} MFSIRDSAHRRFLLFRRAFKQLDVEAALTKALGEVDILLTWMQKFYKL(SEQIDNO:27) IL-26 >gi|8923756|ref]NP_060872.1|interleukin-26precursor{Homosapiens} MLVNFILRCGLLLVTLSLAIAKHKQSSFTKSCYPRGTLSQAVDALYIKAAWLKATIPEDRIKNI RLLKKKTKKQFMKNCQFQEQLLSFFMEDVFGQLQLQGCKKIRFVEDFHSLRQKLSHCISCAS SAREMKSITRMKRIFYRIGNKGIYKAISELDILLSWIKKLLESSQ(SEQIDNO:28)

TABLE-US-00005 TABLE3 AminoAcidSequencesforAnti-inflammatoryNeuropeptides pro-opiomelanocortinpreproprotein{Homosapiens) >gi|4505949|refNP_000930.1|pro-opiomelanocortinpreproprotein{Homosapiens} MPRSCCSRSGALLLALLLQASMEVRGWCLESSQCQDLTTESNLLECIRACKPDLSAE TPMFPGNGDEQPLTENPRKYVMGHFRWDRFGRRNSSSSGSSGAGQKREDVSAGEDC GPLPEGGPEPRSDGAKPGPREGKRSYSMEHFRWGKPVGKKRRPVKVYPNGAEDESA EAFPLEFKRELTGQRLREGDGPDGPADDGAGAQADLEHSLLVAAEKKDEGPYRMEH FRWGSPPKDKRYGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE(SEQIDNO:29) Activeform: -MSHSYSMEHFRWGKPV-NH2(SEQIDNO:581) >gi|490074|emb|CAA00890.1|ACTH{Homosapiens} GPSYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF urocortinpreproprotein{Homosapiens} >gi|4507803|ref]NP_003344.1|urocortinpreproprotein{Homosapiens} MRQAGRAALLAALLLLVQLCPGSSQRSPEAAGVQDPSLRWSPGARNQGGGARALL LLLAERFPRRAGPGRLGLGTAGERPRRDNPSLSIDLTFHLLRTLLELARTQSQRERA (SEQIDNO:30)EQNRIIFDSVGK Activeform: UrocortinDNPSLSIDLTFHLLRTLLELADTQSQRERAQNRIIFDSV- NH2(SEQIDNO:1336) urocortin-2preproprotein{Homosapiens} >gi|15082240|refNP_149976.1|urocortin-2preproprotein{Homosapiens} MTRCALLLLMVLMLGRVLVVPVTPIPTFQLRPQNSPQTTPRPAASESPSAAPTWPWA AQSHCSPTRHPGSRIVLSLDVPIGLLQILLEQARARAAREQATTNARILARVGHC (SEQIDNO:31) urocortin-3preproprotein{Homosapiens} >gi|45238845|ref|NP_444277.2|urocortin-3preproprotein{Homosapiens} MLMPVHFLLLLLLLLGGPRTGLPHKFYKAKPIFSCLNTALSEAEKGQWEDASLLSKR SFHYLRSRDASSGEEEEGKEKKTFPISGARGGARGTRYRYVSQAQPRGKPRQDTAKS PHRTKFTLSLDVPTNIMNLLENIAKAKNLRAQAAANAHLMAQIGRKK(SEQID NO:32) adrenomedullinprecursor{Homosapiens} >gi|4501945|refNP_001115.1|adrenomedulinprecursor{Homosapiens} MKLVSVALMYLGSLAFLGADTARLDVASEFRKKWNKWALSRGKRELRMSSSYPTG LADVKAGPAQTLIRPQDMKGASRSPEDSSPDAARIRVKRYRQSMNNFQGLRSFGCRF GTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGYGRRRRRSLPEAGPGRTLVSSKPQ AHGAPAPPSGSAPHFL(SEQIDNO:33) gi|41152110|ref|NP_079142.2|adrenomedullin2precursor{Homosapiens} MARIPTAALGCISLLCLQLPGSLSRSLGGDPRPVKPREPPARSPSSSLQPRHPAPRPVV WKLHRALQAQRGAGLAPVMGQPLRDGGRQHSGPRRHSGPRRTQAQLLRVGCVLGT CQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSYG(SEQIDNO:1337) Activeportion: Adrenomedullin YRQSMNNFQGLRFG{CRFGTC}TVQKLAHQIYQFTDKDKDNVAPRNKISPQ GY-NH2(SEQIDNO:1338) cortistatinpreproprotein{Homosapiens} >gi|41327683|ref|NP_001293.2|cortistatinpreproprotein{Homosapiens} MYRHKNSWRLGLKYPPSSKEETQVPKTLISGLPGRKSSSRVGEKLQSAHKMPLSPGL LLLLLSGATATAALPLEGGPTGRDSEHMQEAAGIRKSSLLTFLAWWFEWTSQASAGP LIGEEAREVARRQEGAPPQQSARRDRMPCRNFFWKTFSSCK(SEQIDNO:34) Activeform: CortistatinDRMP{CKNFFWKTFSSC}K-NH2(SEQIDNO:1339) somatostatinpreproprotein{Homosapiens} >gi|4507243|ref|NP_001039.1|somatostatinpreproprotein{Homosapiens} MLSCRLQCALAALSIVLALGCVTGAPSDPRLRQFLQKSLAAAAGKQELAKYFLAELL SEPNQTENDALEPEDLSQAAEQDEMRLELQRSANSNPAMAPRERKAGCKNFFWKTF TSC(SEQIDNO:35) appetite-regulatinghormoneisoform1preproprotein{Homosapiens} >gi|7706519|ref|NP_057446.1|appetite-regulatinghormoneisoform1preproprotein {Homosapiens} MPSPGTVCSLLLLGMLWLDLAMAGSSFLSPEHQRVQQRKESKKPPAKLQPRALAGW LRPEDGGQAEGAEDELEVRFNAPFDVGIKLSGVQYQQHSQALGKFLQDILWEEAKE APADK(SEQIDNO:36) appetite-regulatinghormoneisoform2preproprotein{Homosapiens} >gi|201860279|ref|NP_001128413.1|appetite-regulatinghormoneisoform2preproprotein {Homosapiens} MPSPGTVCSLLLLGMLWLDLAMAGSSFLSPEHQRVQRKESKKPPAKLQPRALAGWL RPEDGGQAEGAEDELEVRFNAPFDVGIKLSGVQYQQHSQALGKFLQDILWEEAKEA PADK(SEQIDNO:37) appetite-regulatinghormoneisoform3preproprotein{Homosapiens} >gi|201860281|ref|NP_001128416.1|appetite-regulatinghormoneisoform3preproprotein {Homosapiens} MFTCWWSYLRSTLAAVPGEASRVQQRKESKKPPAKLQPRALAGWLRPEDGGQAEG AEDELEVRFNAPFDVGIKLSGVQYQQHSQALGKFLQDILWEEAKEAPADK{SEQID NO:38) appetite-regulatinghormoneisoform4preproprotein{Homosapiens} >gi|201860283|ref|NP_001128417.1|appetite-regulatinghormoneisoform4preproprotein {Homosapiens} MFTCWWSYLRSTLAAVPGEASRVQRKESKKPPAKLQPRALAGWLRPEDGGQAEGA EDELEVRFNAPFDVGIKLSGVQYQQHSQALGKFLQDILWEEAKEAPADK{SEQID NO:39) appetite-regulatinghormoneisoform5preproprotein{Homosapiens} >gi|201860285|ref|NP_001128418.1|appetite-regulatinghormoneisoform5preproprotein {Homosapiens} MFTCWWSYLRSTLAAVPGEASRVQFNAPFDVGIKLSGVQYQQHSQALGKFLQDILW EEAKEAPADK(SEQIDNO:40) ghrelin{Homosapiens) >gi|53794041|gb|AAU93610.1|ghrelin{Homosapiens} MPSPGTVCSLLLLGMLWLDLAMAGSSFLSPEHQRVQ(SEQIDNO:41) Activeform:GhrelinGSSFLSPEHQRVQQRKESKKPPAKLPQR-NH2(SEQIDNO:567) (ExpertOpin.Biol.Ther.(2007)7(4):461-478)

[0295] In some embodiments, the composition comprises a VIP analog. In some embodiments, the composition comprises a Secretin analog. In some embodiments, the composition comprises a PrP analog. In some embodiments, the composition comprises a PrP analog. In some embodiments, the composition comprises a PHM analog. In some embodiments, the composition comprises a PACAP-27 analog. In some embodiments, the composition comprises a PACAP-38 analog. In some embodiments, the composition comprises a Glucagon analog. In some embodiments, the composition comprises a GLP-1 analog. In some embodiments, the composition comprises a GIP analog. In some embodiments, the composition comprises a GHRF analog. In some embodiments, the composition comprises a secretin family analog that is derived from mammalian amino acid sequences of secretin family polypeptides other than humans. In some embodiments, the secretin family analog may be selective for one particular receptor versus another. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds to, VPAC1, VPAC2, PAC1, VIPR1, or VIPR2. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds, VPAC1. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds, VPAC2. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds, PAC1. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds, VIPR1. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds, VIPR2. In some embodiments, the secretin analog is an agonist of at least one of the following: VPAC1, VPAC2, PAC1, VIPR1, or VIPR2. In some embodiments, the secretin analog is an antagonist of at least one of the following: VPAC1, VPAC2, PAC1, VIPR1, or VIPR2.

[0296] In some embodiments, the composition comprises a apolipoprotein A-1 analog. In some embodiments the apoA-1 analog is from about 80% to about 99% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is from about 80% to about 85% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is from about 85% to about 90% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is from about 90% to about 95% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is from about 95% to about 99% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is about 95%, 96%, 97%, 98%, or 99% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is from about 80% to about 85% homologous to the following of apolipoprotein A-1 analog: DWFKAFYDKVAEKFKEAF (SEQ ID NO:533).

[0297] In some embodiments, the composition comprises a cytokine or interleukin analog. In some embodiments the cytokine or interleukin analog is from about 80% to about 99% homologous to the human sequence of cytokine or interleukin. In some embodiments the cytokine or interleukin analog is from about 80% to about 85% homologous to the human sequence of a cytokine or interleukin. In some embodiments the cytokine or interleukin analog is from about 85% to about 90% homologous to the human sequence of a cytokine or interleukin. In some embodiments the cytokine or interleukin analog is from about 90% to about 95% homologous to the human sequence of a cytokine or interleukin. In some embodiments the cytokine or interleukin analog is from about 95% to about 99% homologous to the human sequence of a cytokine or interleukin. In some embodiments the cytokine or interleukin analog is about 95%, 96%, 97%, 98%, or 99% homologous to the human sequence of a cytokine or interleukin. In some embodiments the cytokine or interleukin analog is from about 80% to about 99% homologous to a cytokine or interleukin chosen from IL-2, IL-4, IL-5, IL-6. IL-7, IL-10, IL-12, IL-15, IL-17, IL-18, IL-21, IL-22, IL-23, IL-24, IL-26, IFN-, TNF-, and TNF-. In some embodiments, the cytokine or interleukin analog comprises at least one non-natural amino acid within the structure that corresponds to helix F in the naturally occurring polypeptide sequence upon which the analog is based or derived. In some embodiments, the cytokine or interleukin analog comprises at least one non-natural amino acid within the structure that corresponds to AB loop in the naturally occurring polypeptide sequence upon which the analog is based or derived.

[0298] The invention relates to the manufacturing of a synthetic polypeptide which is an amino acid sequence that corresponds to the sequence of a biologically active polypeptide or fragment thereof. In the synthetic polypeptide, from about 14% to about 50% of the -amino acid residues found in the biologically active polypeptide or fragment are replaced with -amino acid residues. In another embodiment of the invention, the -amino acid residues and the -amino acid residues are distributed in a repeating pattern. Human cells are then contacted with the synthetic polypeptide to induce the biochemical pathway or biological activity ordinarily induced by the naturally occurring polypeptide upon which the analog is based.

[0299] The compositions of the invention may be prepared by the synthetic chemical procedures described herein, as well as other procedures similar to those which may be used for making -amino acid peptides. Such procedures include both solution and solid phase procedures, e.g., using either Boc and Fmoc methodologies. The compounds of the invention may be synthesized using solid phase synthesis techniques. Fmoc-N-Protected -amino acids can be used to synthesize poly-/-peptides by conventional manual solid-phase synthesis procedures under standard conditions on any number of solid supports, including ortho-chloro-trityl chloride resin. Esterification of Fmoc--amino acids with the ortho-chloro-trityl resin can be performed according to the method of Barlos et. al., Tetrahedron Lett., 1989, 30, 3943. The resin (150 mg, 1.05 mmol Cl) is swelled in 2 ml CH.sub.2Cl.sub.2 for 10 min. A solution of the Fmoc-protected -amino acid in CH.sub.2Cl.sub.2 and iPr.sub.2EtN are then added successively and the suspension is mixed under argon for 4 h. Subsequently, the resin is filtered and washed with CH.sub.2Cl.sub.2/MeOH/iPr.sub.2EtN (17:2:1, 33 min), CH.sub.2Cl.sub.2 (33 min), DMF (23 min), CH.sub.2Cl.sub.2 (33 min), and MeOH (23 min). The substitution of the resin is determined on a 3 mg sample by measuring the absorbance of the dibenzofulvene adduct at 300 nm. The Fmoc group is removed using 20% piperidine in DMF (4 ml, 220 min) under Ar bubbling. The resin is then filtered and washed with DMF (63 min). For each coupling step, a solution of the -amino acid (3 equiv.), BOP (3 equiv.) and HOBT (3 equiv.) in DMF (2 ml) and iPr.sub.2EtN (9 eq) are added successively to the resin and the suspension is mixed for 1 h under Ar. Monitoring of the coupling reaction is performed with 2,4,6-trinitrobenzene-sulfonic acid (TNBS) (W. S. Hancock and J. E. Battersby, Anal. Biochem. (1976), 71, 260). In the case of a positive TNBS test (indicating incomplete coupling), the suspension is allowed to react for a further I h. The resin is then filtered and washed with DMF (33 min) prior to the following Fmoc deprotection step. After the removal of the last Fmoc protecting group, the resin is washed with DMF (63 min), CH.sub.2Cl.sub.2 (33 min), Et.sub.2O (33 min) and dried under vacuum for 3 h. Finally the peptides are cleaved from the resin using 2% TFA in CH.sub.2Cl.sub.2 (2 ml, 515 min) under Ar. The solvent is removed and the oily residues are triturated in ether to give the crude -/-polypeptides. The compounds are further purified by HPLC.

[0300] The compositions of the invention may be prepared by the synthetic chemical procedures described herein, as well as other procedures similar to those which may be used for making -amino acid peptides. Such procedures include both solution and solid phase procedures, e.g., using either Boc or Fmoc methodologies. The compounds of the invention may be synthesized using solid phase synthesis techniques. Fmoc-N-Protected -amino acids can be used to synthesize poly-/-peptides by conventional manual solid-phase synthesis procedures under standard conditions on any number of solid supports, including ortho-chloro-trityl chloride resin, Wang resin (NovaBiochem 0.75 mmol substitution) and Rink amid resin (NovaBiochem 0.55 mmol substitution). Resin is typically swelled in 100% DMF for 30 minutes then deprotected using 20% piperidine in DMF for 2 minutes at 80 (3). Fmoc protected amino acids (natural or non-natural) can then be coupled to the resin using a cocktail of AA:HATU:DIEA:Resin (3:2.5:4:1, LiCL 0.8M final concentration) in DMF for 2 minutes at 70 (3). The resin is then washed (3) with DMF, DCM (dichloromethane) (3) and again with DMF (3) between deprotection and coupling steps. Monitoring of the coupling reaction is performed with 2,4,6-trinitrobenzene-sulfonic acid (TNBS) (W. S. Hancock and J. E. Battersby, Anal. Biochem. (1976), 71, 260). In the case of a positive TNBS test (indicating incomplete coupling), the suspension is allowed to react for another three times. This process is repeated until the desired product has been achieved. After the removal of the last Fmoc protecting group, the resin is washed with DMF (3), CH.sub.2Cl.sub.2 (3) and DMF again (3). The remaining free-amine group is then acetylated using a cocktail of DIEA:Ac.sub.2O (1:1) for 5 minutes at room temperature. Full-length peptides were then cleaved from solid support using TFA:TIS:H.sub.2O (95:2.5:2.5) for 150 minutes, precipitated in cold ethyl ether and lyophilized. The polymer was reconstituted in a 1:1 solution of A:B (A: H.sub.2O, 0.1% TFA) (B: 90:10:0.1 acetonitrile/H.sub.2O/TFA).

[0301] The compositions described herein may be prepared by successive amide bond-forming procedures in which amide bonds are formed between the -amino group of a first -amino acid residue or a precursor thereof and the -carboxyl group of a second -amino acid residue or -amino acid residue or a precursor thereof. The amide bond-forming step may be repeated as many times, and with specific -amino acid residues and/or -amino acid residues and/or precursors thereof, as required to give the desired /-polypeptide. Also analogs comprising two, three, or more amino acid residues (- or -) may be joined together to yield larger analogs comprising any combination of -, or -amino acids. Cyclic compounds may be prepared by forming peptide bonds between the N-terminal and C-terminal ends of a previously synthesized linear polypeptide or through the disulfide crosslinking of sidechains of non-adjacent residues. .sup.3-amino acids may be produced enantioselectively from corresponding -amino acids. For instance, by Arndt-Eisert homologation of N-protected -amino acids. Homologation may be followed by coupling of the reactive diazoketone intermediate of the Wolff rearrangement with a -amino acid residue.

[0302] In some embodiments, the analog of the invention comprises a repeating pattern of the -amino acid residues in alignment on a longitudinal axis of the analog in order to constrain the conformation of the analog in an active state or to avoid disruption of the active site. That is, in the folded structure adopted by the analogs of the present invention, the repeating pattern of - or -amino acids residues disposes the synthetic non-natural amino acid residues in alignment along one longitudinal axis of the folded molecular structure from N-terminus to C-terminus when the unnatural polypeptides adopt a helical conformation. In some embodiments, the analog of the invention comprises the alignment of -amino acids or ACPC or APC along a longitudinal axis of the folded molecular structure from N-terminus to C-terminus when the polypeptide adopts a helical conformation chosen from any of the conformations shown in FIG. 5, wherein the residue positions in a solid dot represent non-natural amino acid residues.

[0303] In some embodiments, the analog of the invention comprises the alignment along a longitudinal axis of the folded molecular structure from N-terminus to C-terminus when the polypeptide adopts a helical conformation chosen from any of the conformations shown in FIG. 5, wherein the positions with solid dots represent .sup.3-amino acid residues.

[0304] In some embodiments, the analog of the invention comprises the alignment along a longitudinal axis of the folded molecular structure from N-terminus to C-terminus when the polypeptide adopts a helical conformation chosen from any of the conformations shown in FIG. 5, wherein the positions with solid dots represent -amino acid residues.

[0305] The repeating pattern of -amino acid residues and -amino acid residues may be a pattern of from about two to about seven residues in length, such as (), (), (), (), (), (), (), (), and (). All unique patterns of - or -amino acids residues from about two to about fourteen residues in length are explicitly within the scope of the invention. All unique patterns of - or -amino acids residues from about two to about seven residues in length are explicitly within the scope of the invention. In some embodiments, the composition comprises an analog, wherein the analog wherein the analog comprises a repetitive pattern of sequential -amino acids from the amino-terminus to the carboxy-terminus, and wherein the analog is an agonist or antagonist of the receptor to which it selectively binds or associates. For instance, in some embodiments, the analog is a VIP analog or a functional fragment thereof that selectivity binds to VPAC1, VPAC2, or PAC1 and wherein the VIP analog of functional fragment thereof is an agonist or antagonist of at least one receptor chosen from: VPAC1, VPAC2, and PAC1. In some embodiments, the methods of treatment or prevention include administration of VIP analogs, wherein the VIP analog is an agonist or antagonist of at least one receptor chosen from: VPAC1, VPAC2, and PAC1. In some embodiments, the composition comprises an analog, wherein the analog wherein the analog comprises a repetitive pattern of sequential -amino acids from the amino-terminus to the carboxy-terminus chosen from the following: , , , , , , , , , , , , , , , , , , , , , , , , , , , and . In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential -amino acids from the amino-terminus to the carboxy-terminus chosen from the following: , , , and . In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential -amino acids from the amino-terminus to the carboxy-terminus chosen from the following: ; ; ; ; ; ; ; ; ; ; ; and .

[0306] In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential -amino acids from the amino-terminus to the carboxy-terminus chosen from the following: ; ; ; ; ; ; ; ; ; ; ; and .

[0307] In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential -amino acids from the amino-terminus to the carboxy-terminus chosen from the following: , , , and , wherein any -amino acid residue may be a non-natural amino acid. In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential -amino acids from the amino-terminus to the carboxy-terminus chosen from the following: , , , and , wherein at least one -amino acid residue may be a non-natural amino acid. In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential -amino acids from the amino-terminus to the carboxy-terminus chosen from the following: , , , and , wherein from about 1 to about 10 -amino acid residues may be a non-natural amino acid. In any of the above-mentioned patterns one or more of the -amino acid residues may be replaced or modified with cyclic -amino acid (cyclically-constrained beta amino acid), such as APC or ACPC.

[0308] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus to the carboxy-terminus: . In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid: .sub.7=any alpha amino acid; .sub.4=any beta amino acid; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid.

[0309] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid, .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid.

[0310] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta-3 amino acid; .sub.1=any alpha amino acid, .sub.2=any alpha amino acid, .sub.2=any beta-3 amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta-3 amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid, .sub.4=any beta-3 amino acid; .sub.5=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta-3 amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta-3 amino acid.

[0311] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta-2 amino acid; .sub.1=any alpha amino acid, .sub.2=any alpha amino acid, .sub.2=any beta-2 amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta-2 amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid, .sub.4=any beta-2 amino acid; .sub.5=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta-2 amino acid; .sub.11=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any beta-2 amino acid.

[0312] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any cyclic or heterocyclic beta-amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any cyclic or heterocyclic beta-amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=cyclic or heterocyclic beta-amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=cyclic or heterocyclic beta-amino acid; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=cyclic or heterocyclic beta-amino acid, .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=cyclic or heterocyclic beta-amino acid.

[0313] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta-3 amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta-3 amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta-3 amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta-3 amino acid; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 alanine, .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta-3 amino acid.

[0314] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta-3 amino acid. .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta-3 amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine; .sub.3=any beta-3 amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta-3 amino acid, .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 alanine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta-3 amino acid.

[0315] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta-3 amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta-3 amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine. .sub.3=any beta-3 amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta-3 amino acid; .sub.5=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 amino acid; .sub.11=any alpha amino acid; .sub.1=any alpha amino acid; .sub.6=any beta-3 amino acid.

[0316] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=a beta 3-threonine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=a beta-3 arginine; .sub.3=any alpha amino acid, .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=a beta-3 alanine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=a beta-3 lysine; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 alanine: .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=a beta-3 asparagine.

[0317] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=a beta 3-threonine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=a beta-3 arginine. .sub.3=any alpha amino acid, .sub.4=any alpha amino acid. .sub.5=an alpha leucine; .sub.1=a beta-3 alanine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=a beta-3 lysine: .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 alanine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=a beta-3 asparagine.

[0318] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta amino acid; .sub.1=an alpha arginine: .sub.2=an alpha leucine: .sub.2=any beta amino acid; .sub.3=an alpha lysine; .sub.4=an alpha glutamine: .sub.5=an alpha-leucine: .sub.3=any beta amino acid; .sub.6=an alpha valine; .sub.7=an alpha lysine: .sub.4=any beta amino acid; .sub.8=an alpha tyrosine; .sub.9=an alpha leucine; .sub.10=an alpha asparagine: .sub.5=a beta-3 alanine, .sub.11=an alpha isoleucine; .sub.12=an alpha leucine; .sub.6=any beta amino acid.

[0319] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta-3 amino acid; .sub.1=an alpha arginine; .sub.2=an alpha leucine; .sub.2=any beta-3 amino acid; .sub.3=an alpha lysine, .sub.4=an alpha glutamine: .sub.5=an alpha leucine; .sub.3=any beta-3 amino acid; .sub.6=an alpha valine; .sub.7=an alpha lysine: .sub.4=any beta-3 amino acid; .sub.5=an alpha tyrosine; .sub.9=an alpha leucine; .sub.10=an alpha asparagine: .sub.5=any beta-3 amino acid; .sub.11=an alpha isoleucine; .sub.12=an alpha leucine; .sub.6=any beta amino acid.

[0320] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=a beta-2 threonine; .sub.1=an alpha arginine; .sub.2=an alpha leucine; .sub.2=a beta-2 arginine: .sub.3=an alpha lysine; .sub.4=an alpha glutamine: .sub.5=an alpha leucine; .sub.3=a beta-2 alanine. .sub.6=an alpha valine; .sub.7=an alpha lysine; .sub.4=a beta-2 lysine; .sub.8=an alpha tyrosine; .sub.9=an alpha leucine: .sub.10=an alpha asparagine; .sub.5=a beta-2 alanine; a.sub.11=an alpha isoleucine, .sub.12=an alpha leucine, .sub.6=a beta-2 asparagine.

[0321] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=a beta-3 threonine or ACPC; .sub.1=an alpha arginine; .sub.2=an alpha leucine; .sub.2=a beta-3 arginine or APC: .sub.3=an alpha lysine; .sub.4=an alpha glutamine; .sub.5=an alpha-leucine; .sub.3=a beta-3 alanine or ACPC; .sub.6=an alpha valine: .sub.7=an alpha lysine; .sub.4=a beta-3 lysine or APC, .sub.8=an alpha tyrosine: .sub.9=an alpha leucine; .sub.10=an alpha asparagine; .sub.5=a beta-3 alanine or ACPC: .sub.11=an alpha isoleucine; .sub.12=an alpha leucine; .sub.6=a beta-3 asparagine.

[0322] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid.

[0323] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid.

[0324] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=any beta-3 amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta-3 amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta-3 amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta-3 amino acid; .sub.9=any alpha amino acid. .sub.10=any alpha amino acid; .sub.3=any beta-3 amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid.

[0325] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=any beta-2 amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta-2 amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta-2 amino acid; .sub.6=any alpha amino acid, .sub.7=any alpha amino acid, .sub.8=any alpha amino acid, .sub.4=any beta-2 amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta-2 amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid.

[0326] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=any cyclic or heterocyclic beta-amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any cyclic or heterocyclic beta-amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any cyclic or heterocyclic beta-amino acid; .sub.6=any alpha amino acid: .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any cyclic or heterocyclic beta-amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any cyclic or heterocyclic beta-amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid.

[0327] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=a beta-3 threonine: .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=a beta-3 lysine; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=a beta-3 alanine: .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=a beta-3 tyrosine; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 alanine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid.

[0328] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any beta amino acid: .sub.1=an alpha arginine, .sub.2=an alpha leucine; .sub.3=an alpha arginine. .sub.2=any beta amino acid; .sub.4=an alpha glutamine; .sub.5=an alpha leucine; .sub.3=any beta amino acid; .sub.6=an alpha valine acid; .sub.7=an alpha lysine; .sub.8=an alpha lysine, .sub.4=any beta amino acid; .sub.9=an alpha leucine; .sub.10=an alpha asparagine; .sub.5=any beta amino acid; .sub.11=an alpha isoleucine: .sub.12=an alpha leucine; .sub.13=an alpha asparagine.

[0329] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any beta-3 amino acid; .sub.1=an alpha arginine; .sub.2=an alpha leucine: .sub.3=an alpha arginine; .sub.2=any beta-3 amino acid; .sub.4=an alpha glutamine; .sub.5=an alpha leucine; .sub.3=any beta-3 amino acid; .sub.6=an alpha valine acid; .sub.7=an alpha lysine; .sub.8=an alpha lysine; .sub.4=any beta-3 amino acid; .sub.9=an alpha leucine: .sub.10=an alpha asparagine; .sub.5=any beta-3 amino acid; .sub.11=an alpha isoleucine; .sub.12=an alpha leucine, .sub.13=an alpha asparagine.

[0330] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any beta-2 amino acid; .sub.1=an alpha arginine; .sub.2=an alpha leucine; .sub.3=an alpha arginine; .sub.2=any beta-2 amino acid; .sub.4=an alpha glutamine; .sub.5=an alpha leucine; .sub.3=any beta-2 amino acid; .sub.6=an alpha valine acid; .sub.7=an alpha lysine; .sub.8=an alpha lysine; .sub.4=any beta-2 amino acid; .sub.9=an alpha leucine; .sub.10=an alpha asparagine; .sub.5=any beta-2 amino acid; .sub.11=an alpha isoleucine. .sub.12=an alpha leucine; .sub.13=an alpha asparagine.

[0331] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any cyclic and heterocyclic beta amino acid; .sub.1=an alpha arginine; .sub.2=an alpha leucine; .sub.3=an alpha arginine; .sub.2=any cyclic and heterocyclic beta amino acid; .sub.4=an alpha glutamine; .sub.5=an alpha leucine; .sub.3=any cyclic and heterocyclic beta amino acid; .sub.6=an alpha valine acid; .sub.7=an alpha lysine; .sub.8=an alpha lysine: .sub.4=any cyclic and heterocyclic beta amino acid; .sub.9=an alpha leucine; .sub.10=an alpha asparagine; .sub.5=any cyclic and heterocyclic beta amino acid; .sub.11=an alpha isoleucine: .sub.12=an alpha leucine; .sub.13=an alpha asparagine.

[0332] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=a beta-3 threonine or an ACPC; .sub.1=an alpha arginine; .sub.2=an alpha leucine; .sub.3=an alpha arginine; .sub.2=a beta-3 lysine or APC: .sub.4=an alpha glutamine; .sub.5=an alpha leucine: .sub.3=a beta-3 alanine or ACPC; .sub.6=an alpha valine acid; .sub.7=an alpha lysine; .sub.8=an alpha lysine; .sub.4=a beta-3 tyrosine or; .sub.9=an alpha leucine; .sub.10=an alpha asparagine; .sub.5=a beta-3 alanine or ACPC; .sub.11=an alpha isoleucine: .sub.12=an alpha leucine; .sub.13=an alpha asparagine.

[0333] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid, .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid.

[0334] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid.

[0335] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta-3 amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid, .sub.2=any beta-3 amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta-3 amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta-3 amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid, .sub.5=any beta-3 amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta-3 amino acid.

[0336] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta-2 amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta-2 amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; 3=any beta-2 amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.5=any alpha amino acid; .sub.4=any beta-2 amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta-2 amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta-2 amino acid.

[0337] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any cyclic or heterocyclic beta-amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any cyclic or heterocyclic beta-amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any cyclic or heterocyclic beta-amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any cyclic or heterocyclic beta-amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any cyclic or heterocyclic beta-amino acid; .sub.11=any alpha amino acid. .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any cyclic or heterocyclic beta-amino acid.

[0338] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=a beta-2 tyrosine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=a beta-2 arginine; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid, .sub.3=a beta-2 leucine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=a beta-2 lysine; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-2 asparagine; .sub.11=any alpha amino acid .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.13=a beta-2 asparagine.

[0339] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=a beta-3 tyrosine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=a beta-3 arginine; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid, .sub.3=a beta-3 leucine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=a beta-3 lysine; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 asparagine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=a beta-3 asparagine.

[0340] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=an alpha threonine: .sub.2=an alpha arginine: .sub.3=an alpha leucine; .sub.2=any beta amino acid; .sub.4=an alpha lysine; .sub.5=an alpha glutamine; .sub.3=any beta amino acid; .sub.6=an alpha alanine; .sub.7=an alpha valine; .sub.8=an alpha lysine; .sub.4=any beta amino acid; .sub.9=an alpha tyrosine: .sub.10=an alpha leucine; .sub.5=any beta amino acid; .sub.11=an alpha alanine; .sub.12=an alpha isoleucine; .sub.13=an alpha leucine; and .sub.6=any beta amino acid.

[0341] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta-3 amino acid; .sub.1=an alpha threonine; .sub.2=an alpha arginine; .sub.3=an alpha leucine; .sub.2=any beta-3 amino acid; .sub.4=an alpha lysine: .sub.5=an alpha glutamine; .sub.3=any beta-3 amino acid; .sub.6=an alpha alanine; .sub.7=an alpha valine; .sub.8=an alpha lysine; .sub.4=any beta-3 amino acid; .sub.9=an alpha tyrosine; .sub.10=an alpha leucine: .sub.5=any beta-3 amino acid; .sub.11=an alpha alanine; .sub.12=an alpha isoleucine; .sub.13=an alpha leucine; and .sub.6=any beta-3 amino acid.

[0342] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta-2 amino acid; .sub.1=an alpha threonine; .sub.2=an alpha arginine; .sub.3=an alpha leucine; .sub.2=any beta-2 amino acid; .sub.4=an alpha lysine; .sub.5=an alpha glutamine; .sub.3=any beta-2 amino acid; .sub.6=an alpha alanine; .sub.7=an alpha valine, .sub.8=an alpha lysine; .sub.4=any beta-2 amino acid; .sub.9=an alpha tyrosine: .sub.10=an alpha leucine; .sub.5=any beta-2 amino acid; .sub.11=an alpha alanine; .sub.12=an alpha isoleucine, .sub.13=an alpha leucine; and .sub.6=any beta-2 amino acid.

[0343] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any cyclic or heterocyclic beta amino acid; .sub.1=an alpha threonine; .sub.2=an alpha arginine; .sub.3=an alpha leucine; .sub.2=any cyclic or heterocyclic beta amino acid; .sub.4=an alpha lysine; .sub.5=an alpha glutamine; .sub.3=any cyclic or heterocyclic beta amino acid; .sub.6=an alpha alanine; .sub.7=an alpha valine; .sub.8=an alpha lysine; .sub.4=any cyclic or heterocyclic beta amino acid; .sub.9=an alpha tyrosine; .sub.10=an alpha leucine; .sub.5=any cyclic or heterocyclic beta amino acid; .sub.11=an alpha alanine; .sub.12=an alpha isoleucine; .sub.13=an alpha leucine; and .sub.6=any cyclic or heterocyclic beta amino acid.

[0344] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=an alpha threonine, .sub.2=an alpha arginine. .sub.3=an alpha leucine; .sub.2=a beta-2 arginine or APC, .sub.4=an alpha lysine; .sub.5=an alpha glutamine; .sub.3=any beta-2 amino acid; .sub.6=an alpha alanine; .sub.7=an alpha valine; .sub.8=an alpha lysine; .sub.4=any beta-2 amino acid; .sub.9=an alpha tyrosine; .sub.10=an alpha leucine; .sub.5=any beta-2 amino acid; .sub.11=an alpha alanine; .sub.12=an alpha isoleucine; .sub.13=an alpha leucine; and .sub.3=any beta-2 amino acid.

[0345] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=a beta-3 tyrosine; .sub.1=an alpha threonine; .sub.2=an alpha arginine; .sub.3=an alpha leucine; .sub.2=a beta-3 arginine or APC; .sub.4=an alpha lysine. .sub.5=an alpha glutamine; .sub.3=a beta-3 leucine or ACPC; .sub.6=an alpha alanine; .sub.7=an alpha valine; .sub.8=an alpha lysine; .sub.4=a beta-3 lysine or APC; .sub.9=an alpha tyrosine; .sub.10=an alpha leucine, .sub.5=a beta-3 asparagine or ACPC; .sub.11=an alpha alanine; .sub.12=an alpha isoleucine; .sub.13=an alpha leucine; and .sub.6=a beta-3 asparagine.

[0346] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: [0347] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid, .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; and [0348] wherein the repetitive pattern is, optionally, preceded by: [0349] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; or [0350] HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; and [0351] wherein the C-terminus is optionally amidated; and [0352] wherein the N-terminus is optionally acylated; [0353] or functional fragments thereof.

[0354] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: [0355] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid, .sub.13=any alpha amino acid; [0356] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid, .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and [0357] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; and [0358] wherein the repetitive pattern is, optionally, preceded by: [0359] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; or .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; or [0360] HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; and [0361] wherein the C-terminus is optionally amidated; and [0362] wherein the N-terminus is optionally acylated; [0363] or functional fragments thereof.

[0364] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: [0365] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.2=any alpha amino acid, .sub.13=any alpha amino acid; [0366] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid, .sub.2=any beta amino acid, .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid, .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 alanine or an ACPC; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and [0367] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; and [0368] wherein the repetitive pattern is, optionally, preceded by: [0369] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13 or .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; or [0370] HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; and [0371] wherein the C-terminus is optionally amidated; and [0372] wherein the N-terminus is optionally acylated; [0373] or functional fragments thereof.

[0374] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid, .sub.13=any alpha amino acid; [0375] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid, .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and [0376] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid, .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid: .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; [0377] wherein the repetitive pattern is, optionally, preceded by: [0378] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; or .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; or a fragment thereof; and wherein at least one or more of the amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a non-natural amino acid.

[0379] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: [0380] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid: .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; [0381] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine; .sub.3=any beta amino acid, .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid, .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 alanine or an ACPC; .sub.11=any alpha amino acid, .sub.12=any alpha amino acid, .sub.6=any beta amino acid; and [0382] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid: .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid, .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.5=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid, .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; [0383] wherein the repetitive pattern is, optionally, preceded by: [0384] HSDAVFTDNY (SEQ ID NO; 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13 or .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; or a fragment thereof; and wherein at least one or more of the amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a non-natural amino acid.

[0385] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: [0386] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.3=any alpha amino acid; [0387] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid, .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid, .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.3=any beta amino acid; and [0388] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid, .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid: .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; [0389] wherein the repetitive pattern is, optionally, preceded by: [0390] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13 or .sub.1.sub.1.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; and wherein at least one or more of the amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence.

[0391] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: [0392] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.5=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.3=any alpha amino acid; [0393] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid, .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid, .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and [0394] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid, .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.12=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; [0395] wherein the repetitive pattern is, optionally, preceded by: [0396] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13 or .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; and wherein at least one or more of the amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a beta amino acid selected from the group chosen from: APC, ACPC, a beta-2 homolog of a wild-type amino acid, or a beta-3 homolog of a wild-type amino acid.

[0397] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: [0398] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.5=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.3=any alpha amino acid; [0399] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid, .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid, .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and [0400] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid, .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.12=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; [0401] wherein the repetitive pattern is, optionally, preceded by: [0402] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13 or .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; and wherein at least one or more of the amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence, a beta-2 homolog of the wild-type amino acid sequence, ACPC, or APC.

[0403] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: [0404] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.5=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.3=any alpha amino acid; [0405] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid, .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid, .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and [0406] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid, .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.12=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; [0407] wherein the repetitive pattern is, optionally, preceded by: [0408] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13 or .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; and wherein the D at position 8 of HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence, a beta-2 homolog of the wild-type amino acid sequence, ACPC, or APC.

[0409] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: [0410] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.5=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.3=any alpha amino acid; [0411] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid, .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid, .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and [0412] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid, .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.12=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; [0413] wherein the repetitive pattern is, optionally, preceded by: [0414] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13 or .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; and wherein the T at position 7 of HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence, a beta-2 homolog of the wild-type amino acid sequence, ACPC, or APC.

[0415] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: [0416] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.5=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.3=any alpha amino acid; [0417] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid, .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid, .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and [0418] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid, .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.12=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; [0419] wherein the repetitive pattern is, optionally, preceded by: [0420] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13 or .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; and wherein the D at position 8 of HSDAVFTDNY (SEQ ID NO: 1340) and, optionally, the T at position 7 of HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence, a beta-2 homolog of the wild-type amino acid sequence, ACPC, or APC.

[0421] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus selected from the following: [0422] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.5=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.3=any alpha amino acid; [0423] .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid, .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid, .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and [0424] .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid, .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.12=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; [0425] wherein the repetitive pattern is, optionally, preceded by: [0426] HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13 or .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; and wherein the T at position 7 of HSDAVFTDNY (SEQ ID NO: 1340) and, optionally, the D at position 8 of HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence, a beta-2 homolog of the wild-type amino acid sequence ACPC, or APC.

[0427] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus to the carboxy-terminus: . In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta amino acid, .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises, and [0428] wherein the C-terminus is, optionally, amidated; and [0429] wherein the N-terminus is, optionally, acylated; [0430] or functional fragments thereof.

[0431] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=a beta 3-threonine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=a beta-3 arginine: .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid, .sub.3=a beta-3 alanine; .sub.6=any alpha amino acid: .sub.7=any alpha amino acid; .sub.4=a beta-3 lysine; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 asparagine; .sub.12=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid: wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and [0432] wherein the C-terminus is, optionally, amidated; and [0433] wherein the N-terminus is, optionally, acylated; [0434] or functional fragments thereof.

[0435] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=a beta 3-threonine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=a beta-3 arginine; .sub.3=any alpha amino acid, .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=a beta-3 alanine, .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=a beta-3 lysine; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 alanine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises, and [0436] wherein the C-terminus is, optionally, amidated; and [0437] wherein the N-terminus is, optionally, acylated; [0438] or functional fragments thereof.

[0439] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=a beta 3-threonine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=a beta-3 arginine: .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine, .sub.3=a beta-3 alanine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=a beta-3 lysine; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 alanine; .sub.11=any alpha amino acid, .sub.12=any alpha amino acid, .sub.6=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises, and [0440] wherein the C-terminus is, optionally, amidated; and [0441] wherein the N-terminus is, optionally, acylated; [0442] or functional fragments thereof.

[0443] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta amino acid, .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid, .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 alanine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and [0444] wherein the C-terminus is, optionally, amidated; and [0445] wherein the N-terminus is, optionally, acylated; [0446] or functional fragments thereof.

[0447] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta amino acid; .sub.1=an alpha arginine; .sub.2=an alpha leucine; .sub.2=any beta amino acid; .sub.3=an alpha lysine; .sub.4=an alpha glutamine; .sub.5=an alpha leucine, .sub.3=any beta amino acid; .sub.6=an alpha valine; .sub.7=an alpha lysine: .sub.4=any beta amino acid; .sub.8=an alpha tyrosine: .sub.9=an alpha leucine; .sub.10=an alpha asparagine. .sub.5=any beta amino acid; .sub.11=an alpha isoleucine; .sub.12=an alpha leucine; .sub.6=any beta amino acid, wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and [0448] wherein the C-terminus is, optionally, amidated; and [0449] wherein the N-terminus is, optionally, acylated; [0450] or functional fragments thereof.

[0451] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=a beta-3 threonine or ACPC; .sub.1=an alpha arginine; .sub.2=an alpha leucine; .sub.2=a beta-3 arginine or APC; .sub.3=an alpha lysine; .sub.4=an alpha glutamine; .sub.5=an alpha leucine; .sub.3=a beta-3 alanine or ACPC; .sub.6=an alpha valine; .sub.7=an alpha lysine; .sub.4=a beta-3 lysine or APC; .sub.8=an alpha tyrosine; .sub.9=an alpha leucine; .sub.10=an alpha asparagine; .sub.5=a beta-3 alanine or ACPC; .sub.11=an alpha isoleucine, .sub.12=an alpha leucine, .sub.6=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and [0452] wherein the C-terminus is, optionally, amidated; and [0453] wherein the N-terminus is, optionally, acylated; [0454] or functional fragments thereof.

[0455] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid: .sub.3=any alpha amino acid; .sub.2=any beta amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid, .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; ; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and [0456] wherein the C-terminus is, optionally, amidated; and [0457] wherein the N-terminus is, optionally, acylated; [0458] or functional fragments thereof.

[0459] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=a beta-3 threonine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=any alpha amino acid; .sub.2=a beta-3 lysine; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=a beta-3 alanine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=a beta-3 tyrosine; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 alanine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and [0460] wherein the C-terminus is, optionally, amidated; and [0461] wherein the N-terminus is, optionally, acylated; [0462] or functional fragments thereof.

[0463] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=any beta amino acid; .sub.1=an alpha arginine, .sub.2=an alpha leucine; .sub.3=an alpha arginine; .sub.2=any beta amino acid; .sub.4=an alpha glutamine; .sub.5=an alpha leucine; .sub.3=any beta amino acid; .sub.6=an alpha valine acid; .sub.7=an alpha lysine; .sub.8=an alpha lysine; .sub.4=any beta amino acid; .sub.9=an alpha leucine; .sub.10=an alpha asparagine; .sub.5=any beta amino acid; .sub.11=an alpha isoleucine; .sub.12=an alpha leucine; .sub.13=an alpha asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and [0464] wherein the C-terminus is, optionally, amidated; and [0465] wherein the N-terminus is, optionally, acylated; [0466] or functional fragments thereof.

[0467] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13, wherein .sub.1=a beta-3 threonine or an ACPC; .sub.1=an alpha arginine; .sub.2=an alpha leucine: .sub.3=an alpha arginine; .sub.2=a beta-3 lysine or APC: .sub.4=an alpha glutamine; .sub.5=an alpha leucine; .sub.3=a beta-3 alanine or ACPC; .sub.6=an alpha valine acid; .sub.7=an alpha lysine; .sub.8=an alpha lysine; .sub.4=a beta-3 tyrosine or; .sub.9=an alpha leucine; .sub.10=an alpha asparagine; .sub.5=a beta-3 alanine or ACPC; .sub.11=an alpha isoleucine: .sub.12=an alpha leucine; .sub.13=an alpha asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises, and [0468] wherein the C-terminus is, optionally, amidated; and [0469] wherein the N-terminus is, optionally, acylated; [0470] or functional fragments thereof.

[0471] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid, .sub.8=any alpha amino acid; .sub.4=any beta amino acid: .sub.9=any alpha amino acid, .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=any beta amino acid: wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDN (SEQ ID NO: 1341); and [0472] wherein the C-terminus is, optionally, amidated, and [0473] wherein the N-terminus is, optionally, acylated; [0474] or functional fragments thereof.

[0475] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6, wherein .sub.1=a beta-3 tyrosine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=a beta-3 arginine; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid, .sub.3=a beta-3 leucine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid: .sub.4=a beta-3 lysine; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 asparagine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDN (SEQ ID NO: 1341); and [0476] wherein the C-terminus is, optionally, amidated; and [0477] wherein the N-terminus is, optionally, acylated; [0478] or functional fragments thereof.

[0479] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6, wherein .sub.1=a beta-3 tyrosine; .sub.1=an alpha threonine; .sub.2=an alpha arginine; .sub.3=an alpha leucine: .sub.2=a beta-3 arginine or APC; .sub.4=an alpha lysine; .sub.5=an alpha glutamine; .sub.3=a beta-3 leucine or ACPC; .sub.6=an alpha alanine: .sub.7=an alpha valine; .sub.8=an alpha lysine; .sub.4=a beta-3 lysine or APC; .sub.9=an alpha tyrosine; .sub.10=an alpha leucine, .sub.5=a beta-3 asparagine or ACPC: .sub.11=an alpha alanine; .sub.12=an alpha isoleucine: .sub.13=an alpha leucine; and .sub.6=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDN (SEQ ID NO: 1341); and [0480] wherein the C-terminus is, optionally, amidated; and [0481] wherein the N-terminus is, optionally, acylated; [0482] or functional fragments thereof.

[0483] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6, wherein .sub.1=a beta-3 tyrosine; .sub.1=an alpha threonine, .sub.2=an alpha arginine, .sub.3=an alpha leucine; .sub.2=a beta-3 arginine or APC; .sub.4=an alpha lysine; .sub.5=an alpha glutamine; .sub.3=a beta-3 leucine or ACPC; .sub.6=an alpha alanine; .sub.7=an alpha valine; .sub.8=an alpha lysine; .sub.4=a beta-3 lysine or APC: .sub.9=an alpha tyrosine: .sub.10=an alpha leucine; .sub.5=a beta-3 asparagine or ACPC; .sub.11=an alpha alanine; .sub.12=an alpha isoleucine; .sub.13=an alpha leucine; and .sub.6=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDN (SEQ ID NO: 1341); and [0484] wherein the C-terminus is, optionally, amidated; and [0485] wherein the N-terminus is, optionally, acylated; [0486] or functional fragments thereof.

[0487] In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein at least one of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are non-natural or beta amino acids. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein at least one of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) is a beta-3, beta-2, cyclic, or heterocyclic beta amino acids. In some embodiments, the C-terminus is not amidated. In some embodiments, the N-terminus is not acylated. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein the amino acids from HSDAVFTDN or HSDAVFTDNY (SEQ ID NO: 1340) are alpha amino acids. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are not alpha amino acids. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are beta-3 amino acids. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino acids from HSDAVFTDN or HSDAVFTDNY (SEQ ID NO: 1340) are beta-2 amino acids. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are ACPC or APC. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are cyclic. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are heterocyclic.

[0488] Selective or Selectivity means that the analog of the present invention has a binding preference for one protein as compared to another protein. In some embodiments, the binding preference may be measured as an affinity for a protein in terms of half maximal inhibitory concentration (IC50). In some embodiments, the binding preference may be measured as an affinity for a protein in terms of half maximal effective concentration (EC50). For example, an analog selective to VPAC2 receptor with a selectivity to VPAC2 means that the analog may bind to VPAC1 receptor but has a higher binding affinity for a domain of the VPAC2 receptor if the analog is exposed to both VPAC1 and VPAC2 at similar or equivalent concentrations. As used herein, an analog that selectively binds to VPAC2 refers to an analog with increased selectivity for the VPAC2 receptor compared to other known receptors or proteins to which the peptide may bind. In some embodiments, the analog selective for VPAC2 may be an agonist of the VPAC2 receptor peptide. In some embodiments, the analog selective for VPAC2 may be an antagonist of VPAC2 receptor. In some embodiments, an analog selective to VPAC2 receptor means that the analog may bind to VPAC1 receptor but has a higher binding affinity for a domain of the VPAC2 receptor if the analog is exposed to PAC1, VPAC1 receptor and VPAC2 receptors at similar or equivalent concentrations. In some embodiments, an analog selective to VPAC1 receptor means that the analog may bind to a domain of VPAC2 or PAC1 receptor but has a higher binding affinity for a domain of the VPAC1 receptor if the analog is exposed to PAC1, VPAC1 receptor and VPAC2 receptors at similar or equivalent concentrations. As used herein, an analog that selectively binds to VPAC1 refers to an analog with increased selectivity for the VPAC1 receptor compared to other known receptors or proteins to which the peptide may bind. In some embodiments, the analog selective for VPAC1 may be an agonist of the VPAC1 receptor peptide. In some embodiments, the analog selective for VPAC1 may be an antagonist of VPAC1 receptor. In some embodiments, an analog selective to VPAC1 receptor means that the analog may bind to VPAC2 receptor but has a higher binding affinity for a domain of the VPAC1 receptor if the analog is exposed to both VPAC1 receptor and VPAC2 receptor at similar or equivalent concentrations. As used herein, an analog that selectively binds to PAC1 refers to an analog with increased selectivity for the PAC1 receptor as compared to other known receptors or proteins to which the peptide may bind. In some embodiments, the analog selective for PAC1 may be an agonist of the PAC1 receptor peptide. In some embodiments, the analog selective for PAC1 may be an antagonist of PAC1 receptor. In some embodiments, an analog selective to PAC1 receptor means that the analog may bind to VPAC2 or VPAC1 receptors but has a higher binding affinity for a domain of the PAC1 receptor if the analog is exposed to PAC1, VPAC1 receptor and VPAC2 receptors at similar or equivalent concentrations. The degree of selectivity may be determined by a ratio of VPAC2 receptor binding affinity to VPAC1 receptor binding affinity or by a ratio of VPAC2 receptor binding affinity to PAC1 receptor binding affinity. Binding affinity is determined as described below in Example 1.

[0489] In any of the embodiments described below wherein the polypeptide comprises a residue designated f, the residue designated f is D-Phe or L-Phe or S. In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 99% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL; where residue designated f (position 2) is D-Phe, and wherein the analog interferes with the VPAC1 receptor signaling pathway. In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 99% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe, and wherein the analog is an antagonist of the VPAC1 receptor. In some embodiments, the composition comprises a VIP analog is from about 80% to about 99% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments the VIP analog is from about 80% to about 85% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments the VIP analog is from about 85% to about 90% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments the VIP analog is from about 90% to about 95% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments the VIP analog is from about 95% to about 99% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments the VIP analog is about 95%, 96%, 97%, 98%, or 99% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments, the composition or pharmaceutical compositions comprise a VIP analog, wherein the analog is either: (a) an antagonist of VPAC1 receptor; or (b) interferes with VPAC1 receptor signaling pathway and comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid; .sub.8=any alpha amino acid: .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY; and [0490] wherein residue designated f (position 2) is D-Phe [0491] wherein the C-terminus is, optionally, amidated; and [0492] wherein the N-terminus is, optionally, acylated; [0493] or functional fragments thereof.

[0494] In some embodiments, the composition or pharmaceutical compositions comprise a VIP analog, wherein the analog is either: (a) an antagonist of VPAC1 receptor; or (b) interferes with VPAC1 receptor signaling pathway and comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5, wherein .sub.1=any beta 3 amino acid; .sub.1=any alpha amino acid, .sub.2=any alpha amino acid, .sub.2=any beta 3 amino acid, .sub.3=any alpha amino acid, .sub.4=any alpha amino acid, .sub.5=any alpha amino acid; .sub.3=any beta 3 amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta 3 amino acid: .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta 3 amino acid; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY; and [0495] wherein residue designated f (position 2) is D-Phe [0496] wherein the C-terminus is, optionally, amidated; and [0497] wherein the N-terminus is, optionally, acylated; [0498] or functional fragments thereof.

[0499] In some embodiments, the composition or pharmaceutical compositions comprise a VIP analog, wherein the analog is either: (a) an antagonist of VPAC1 receptor: or (b) interferes with VPAC1 receptor signaling pathway and comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5, wherein .sub.1=a beta-3 arginine, .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=a beta-3 leucine; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=a beta-3 serine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=a beta-3 lysine; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 aspartic acid; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY; and [0500] wherein residue designated f (position 2) is D-Phe [0501] wherein the C-terminus is, optionally, amidated; and [0502] wherein the N-terminus is, optionally, acylated; [0503] or functional fragments thereof.

[0504] In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein at least one of the amino acids from HfDAVFTDN or HfDAVFTDNY are non-natural or beta amino acids, wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein at least one of the amino acids from HfDAVFTDN or HfDAVFTDNY is a beta-3, beta-2, cyclic, or heterocyclic beta amino acids, and wherein residue designated f (position 2) is D-Phe. In some embodiments, the C-terminus is not amidated. In some embodiments, the N-terminus is not acylated. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein the amino acids from HfDAVFTDN or HfDAVFTDNY are alpha amino acids, and wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein the amino acids from HfDAVFTDN or HfDAVFTDNY are not alpha amino acids, and wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the amino acids from HfDAVFTDN or HfDAVFTDNY are beta-3 amino acids, and wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the amino acids from HfDAVFTDN or HfDAVFTDNY are beta-2 amino acids, and wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the amino acids from HfDAVFTDN or HfDAVFTDNY are ACPC or APC and wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the amino acids from HfDAVFTDN or HfDAVFTDNY are cyclic, wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the amino acids from HfDAVFTDN or HfDAVFTDNY are heterocyclic, and wherein residue designated f (position 2) is D-Phe.

[0505] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid, .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY or HfDAV FTNS; and [0506] wherein the C-terminus is, optionally, amidated; and [0507] wherein the N-terminus is, optionally, acylated; [0508] or functional fragments thereof; and wherein residue designated f (position 2) is D-Phe.

[0509] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5; wherein .sub.1=a beta-3 arginine or beta-3 tyrosine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=a beta-3 lysine or beta-3 leucine: .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=a beta-3 serine or a beta-3 leucine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=a beta-3 leucine or beta-3 lysine; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 aspartic acid or beta-3 glutamine; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY or HfDAV FTNS, and [0510] wherein the C-terminus is, optionally, amidated; and [0511] wherein the N-terminus is, optionally, acylated; [0512] or functional fragments thereof, and wherein residue designated f (position 2) is D-Phe.

[0513] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5; wherein .sub.1=a beta-3 arginine, beta-3 tyrosine, or APC; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=ACPC or APC; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=ACPC or a beta-3 leucine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=a beta-3 leucine, beta-3 lysine, or APC; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 aspartic acid or ACPC; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY or HfDAV FTNS; and [0514] wherein the C-terminus is, optionally, amidated; and [0515] wherein the N-terminus is, optionally, acylated; [0516] or functional fragments thereof, , and wherein residue designated f (position 2) is D-Phe.

[0517] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences.

TABLE-US-00006 HfDAVFTNSYZKVXKRLXARKLLQDIL HfDAVFTNSYRKVXKRLXARZLLQDIL HfDAVFTNSYRKVXKRLXARKLLQXIL HfDAVFTNSYZKVXKRLXARZLLQXIL HfDAVFTNSYRKVLZRLXARKLLQXIL HfDAVFTNSYZKVLZRLXARKLLQXIL HfDAVFTNSYRKVXKRLSARZLLXDIL HfDAVFTNSYRKVXKRXSARKLLXDIL HfDAVFTNSYRKVXKRXSARZLLXDIL
wherein residue designated f (position 2) is D-Phe, wherein each underlined residue is a beta amino acid, wherein X is a ACPC, wherein Z is APC, and wherein the analog interferes with the VPAC1 receptor signaling pathway. In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences:

TABLE-US-00007 HfDAVFTNSYZKVXKRLXARKLLQDIL HfDAVFTNSYRKVXKRLXARZLLQDIL HfDAVFTNSYRKVXKRLXARKLLQXIL HfDAVFTNSYZKVXKRLXARZLLQXIL HfDAVFTNSYRKVLZRLXARKLLQXIL HfDAVFTNSYZKVLZRLXARKLLQXIL HfDAVFTNSYRKVXKRLSARZLLXDIL HfDAVFTNSYRKVXKRXSARKLLXDIL HfDAVFTNSYRKVXKRXSARZLLXDIL
wherein residue designated f (position 2) is D-Phe, wherein each underlined residue is a beta amino acid, wherein X is a ACPC, wherein Z is APC, and wherein the analog is an antagonist of the VPAC1 receptor; or functional fragments thereof.

[0518] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences:

TABLE-US-00008 (SEQIDNO:1342) HSDAVFTDNYTRLRKQlAVKKYLNaILN (SEQIDNO:1342) HSDAVFTDNYtRLrKQLaVKkYLNaIln (SEQIDNO:1342) HSDAVFTDNYtRLRkQLaVKKyLNaILN (SEQIDNO:1342) HSDAVFTDNyTRLrKQlAVKkYLnAIln (SEQIDNO:1343) HSDAVFTDNYtRLzKQLxVKkYLNxILn (SEQIDNO:1344) HSDAVFTDNYtRLzKQLxVKzYLNxIln (SEQIDNO:1345) HSDAVFTDNYxRLzKQLxVKkYLNxIln (SEQIDNO:1346) HSDAVFTDNYxRLzKQLxVKzYLNxIln (SEQIDNO:1347) HSDAVFTDNYtRLRzQLxVKKyLNxILN (SEQIDNO:1348) HSDAVFTDNYxRLRzQLxVKKyLNxILN (SEQIDNO:1349) HSDAVFTDNyTRLzKQlAVKzYLxAIln (SEQIDNO:1350) HSDAVFTDNyTRLzKQxAVKkYLxAIln (SEQIDNO:1351) HSDAVFTDNyTRLzKQxAVKzYLxAIln
wherein each underlined residue is a beta amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof.

[0519] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433), and wherein the analog stimulates the VPAC2 receptor signaling pathway. In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433), wherein the analog is an agonist of the VPAC2 receptor. In some embodiments, the composition comprises a VIP analog is from about 80% to about 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is from about 80% to about 85% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is from about 85% to about 90% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is from about 90% to about 95% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is from about 95% to about 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is about 95%, 96%, 97%, 98%, or 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433).

[0520] In some embodiments, the composition or pharmaceutical composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=any beta amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=any beta amino acid; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY [0521] wherein the C-terminus is, optionally, amidated; and [0522] wherein the N-terminus is unmodified or modified; or functional fragments thereof.

[0523] In some embodiments, the composition or pharmaceutical composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=a beta-3 threonine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.2=a beta-3 arginine; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=an alpha leucine, .sub.3=a beta-3 alanine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=a beta-3 lysine; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 serine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=a beta-3 asparagine; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K. KR, or KRY [0524] wherein the C-terminus is, optionally, amidated; and [0525] wherein the N-terminus is unmodified or modified; or functional fragments thereof. [0526] wherein the VIP analog or functional fragment thereof is a VPAC2 agonist.

[0527] In some embodiments, the composition or pharmaceutical composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid, .sub.2=any beta amino acid; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid: .sub.4=any beta amino acid; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.6=any beta amino acid; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY [0528] wherein the C-terminus is, optionally, amidated; and [0529] wherein the N-terminus is unmodified or modified, or functional fragments thereof; and wherein the analog or functional fragment thereof is a VPAC2 agonist.

[0530] In some embodiments, the composition or pharmaceutical composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.2.sub.3.sub.4.sub.5.sub.3.sub.6.sub.7.sub.4.sub.8.sub.9.sub.10.sub.5.sub.11.sub.12.sub.6, wherein .sub.1=a beta-3 threonine; .sub.1=any alpha amino acid, .sub.2=any alpha amino acid; .sub.2=a beta-3 arginine; .sub.3=any alpha amino acid; .sub.4=any alpha amino acid: .sub.5=any alpha amino acid; .sub.3=a beta-3 alanine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.4=a beta-3 lysine; .sub.8=any alpha amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 serine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.3=a beta-3 asparagine; and wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY [0531] wherein the C-terminus is, optionally, amidated; and [0532] wherein the N-terminus is unmodified or modified; or functional fragments thereof.

[0533] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=any beta amino acid; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=any beta amino acid; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=any beta amino acid; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid, .sub.8=any alpha amino acid: .sub.4=any beta amino acid; .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=any beta amino acid; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid: .sub.13=any alpha amino acid; and .sub.6=any beta amino acid; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY [0534] wherein the C-terminus is, optionally, amidated; and [0535] wherein the N-terminus is unmodified or modified: or functional fragments thereof.

[0536] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=a beta-3 threonine or a beta-3 tyrosine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=a beta-3 lysine or a beta-3 arginine; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=a beta-3 alanine or a beta-3 valine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=a beta-3 tyrosine or a beta-3 lysine: .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 serine or a beta-3 glutamine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=a beta-3 lysine or a beta-3 asparagine; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY [0537] wherein the C-terminus is, optionally, amidated; and [0538] wherein the N-terminus is unmodified or modified: or functional fragments thereof.

[0539] In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential -amino acids from the amino-terminus: .sub.1.sub.1.sub.2.sub.3.sub.2.sub.4.sub.5.sub.3.sub.6.sub.7.sub.8.sub.4.sub.9.sub.10.sub.5.sub.11.sub.12.sub.13.sub.6; wherein .sub.1=a beta-3 threonine or a beta-3 tyrosine; .sub.1=any alpha amino acid; .sub.2=any alpha amino acid; .sub.3=an alpha amino acid; .sub.2=a beta-3 lysine or a beta-3 arginine; .sub.4=an alpha alpha amino acid; .sub.5=any alpha amino acid; .sub.3=a beta-3 alanine or a beta-3 valine; .sub.6=any alpha amino acid; .sub.7=any alpha amino acid; .sub.8=any alpha amino acid; .sub.4=a beta-3 tyrosine or a beta-3 lysine: .sub.9=any alpha amino acid; .sub.10=any alpha amino acid; .sub.5=a beta-3 serine or a beta-3 glutamine; .sub.11=any alpha amino acid; .sub.12=any alpha amino acid; .sub.13=any alpha amino acid; and .sub.6=a beta-3 lysine or a beta-3 asparagine; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY. [0540] wherein the C-terminus is, optionally, amidated; and [0541] wherein the N-terminus is unmodified or modified; or functional fragments thereof; [0542] and wherein the analog or functional fragment thereof is a VPAC2 agonist.

[0543] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences:

TABLE-US-00009 (SEQIDNO:1353) HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY (SEQIDNO:1354) HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQIDNO:1355) HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQIDNO:1356) HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQIDNO:1357) HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1358) HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1359) HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQIDNO:1360) HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQIDNO:1361) HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is a beta amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC: or functional fragments thereof; wherein the C-terminus is, optionally, amidated; and wherein the N-terminus is unmodified.

[0544] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences:

TABLE-US-00010 (SEQIDNO:1353) HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY (SEQIDNO:1354) HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQIDNO:1355) HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQIDNO:1356) HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQIDNO:1357) HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1358) HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1359) HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQIDNO:1360) HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQIDNO:1361) HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is a beta amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC: or functional fragments thereof; wherein the C-terminus is, optionally, amidated; and wherein the N-terminus is, optionally, modified.

[0545] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences:

TABLE-US-00011 (SEQIDNO:1353) HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY (SEQIDNO:1354) HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQIDNO:1355) HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQIDNO:1356) HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQIDNO:1357) HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1358) HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1359) HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQIDNO:1360) HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQIDNO:1361) HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is a beta amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof; wherein the C-terminus is, optionally, amidated; wherein the N-terminus is, optionally, modified; and wherein the VIP analog or functional fragment thereof is a VPAC2 agonist.

[0546] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences:

TABLE-US-00012 (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:1353) HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY (SEQIDNO:1354) HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQIDNO:1355) HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQIDNO:1356) HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQIDNO:1357) HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1358) HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1359) HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQIDNO:1360) HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQIDNO:1361) HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is an unnatural amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof; wherein the C-terminus is, optionally, amidated: wherein the N-terminus is, optionally, modified; and wherein the VIP analog or functional fragment thereof is a VPAC1 agonist.

[0547] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences:

TABLE-US-00013 (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:1353) HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY (SEQIDNO:1354) HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQIDNO:1355) HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQIDNO:1356) HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQIDNO:1357) HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1358) HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1359) HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQIDNO:1360) HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQIDNO:1361) HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is a beta amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof, wherein the C-terminus is, optionally, amidated; wherein the N-terminus is, optionally, modified; and wherein the VIP analog or functional fragment thereof is a VPAC1 agonist.

[0548] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences- G4.N

TABLE-US-00014 (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:1353) HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY (SEQIDNO:1354) HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQIDNO:1355) HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQIDNO:1356) HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQIDNO:1357) HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1358) HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1359) HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQIDNO:1360) HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQIDNO:1361) HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is a beta-3 homo amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof; wherein the C-terminus is, optionally, amidated: wherein the N-terminus is, optionally, modified; and wherein the VIP analog or functional fragment thereof is a VPAC1 agonist.

[0549] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog comprises an amino acid sequence that is between 75% and 100% homologous to one or more of the following sequences:

TABLE-US-00015 (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQIDNO:1353) HSDAVFTDNYXRLZKQVXAKKYLQSIKNKRY (SEQIDNO:1354) HSDAVFTDNYTRLZKQVXAKZYLQSIKNKRY (SEQIDNO:1355) HSDAVFTDNYTRLZKQVXAKKYLQXIKNKRY (SEQIDNO:1356) HSDAVFTDNYXRLZKQVXAKZYLQXIKXKRY (SEQIDNO:1357) HSDAVFTDNYTRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1358) HSDAVFTDNYXRLRZQVXAKKYLQXIKNKRY (SEQIDNO:1359) HSDAVFTDNYTRLZKQVSAKZYLXSIKNKRY (SEQIDNO:1360) HSDAVFTDNYTRLZKQXSAKKYLXSIKNKRY (SEQIDNO:1361) HSDAVFTDNYTRLZKQXSAKZYLXSIKNKRY
wherein each underlined residue is any unnatural amino acid: any beta-2 amino acid: any beta-3 amino acid; or a beta-3 homo amino acid corresponding to the single code amino acid upon which it is based; wherein X is a ACPC, and wherein Z is APC: or functional fragments thereof: wherein the C-terminus is, optionally, amidated; wherein the N-terminus is, optionally, modified; and wherein the VIP analog or functional fragment thereof is a VPAC1 or VPAC2 agonist.

[0550] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog comprises an amino acid sequence that is between 75% and 100% homologous to:

TABLE-US-00016 (SEQIDNO:433) HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY
or functional fragments thereof; and wherein the VIP analog or functional fragment thereof is a VPAC2 agonist.

[0551] In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid, and wherein the analog comprises an amino acid sequence that is between 75% and 100% homologous to any of the amino acid sequence provided in this application.

[0552] The invention relates to methods of manufacturing a composition comprising an analog, wherein the analog comprises an -amino acid and at least one -amino acid. In some embodiments, the invention relates to methods of manufacturing a composition comprising an analog, wherein the analog comprises an -amino acid, at least one -amino acid, and at least one modified amino acid residue comprising ACPC or APC. The invention relates to methods of manufacturing a composition comprising a secretin family analog, wherein the secretin family analog comprises an -amino acid and at least one -amino acid. The invention relates to methods of manufacturing a composition comprising a VIP analog, wherein the VIP analog comprises an -amino acid and at least one -amino acid. The method used to fabricate polypeptide compounds may be any means of polypeptide synthesis. Using methods of peptide synthesis, polypeptides fabricated according to the present method are generally less than about 100 residues long. In some embodiments, the invention relates to a method of manufacturing an analog (or fragments herein) comprising non-natural amino acids from about 5 total residues to about 50 total residues, from about 10 total residues to about 20 total residues, from about 20 total residues to about 30 total residues, from about 30 total residues to about 40 total residues, from about 40 total residues to about 50 total residues, from about 50 to about 60 total residues, from about 60 to about 70 total residues from about 70 to about 80 total residues, from about 80 to about 90 total residues, and from about 90 to about 100 total residues. Ranges above and below these stated ranges are within the scope of the invention. Many commercial services, such as Abgent (San Diego, California, USA) offer peptide synthesis services up to about 100 residues. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 100 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 90 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 80 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 70 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 60 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 50 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 40 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 30 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 20 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 10 non-natural amino acids. In some embodiments, the method of manufacturing the analog comprises synthesizing the analog using at least one, and, in some embodiments, a plurality of the following non-naturally occurring amino acid residues: (2S,3R)-3-(amino)-2-hydroxy-4-(4-nitrophenyl)butyric acid, (2R,3R)-3-(amino)-2-hydroxy-4-phenylbutyric acid, (R)-3-(amino)-5-phenylpentanoic acid, (R)-3-(amino)-4-(2-naphthyl)butyric acid, (R)-2-methyl--Phe-OH, (R)-3,4-dimethoxy--Phe-OH, (R)-(3-pyridyl)--Ala-OH, (R)-3-(trifluoromethyl)--Phe-OH, (R)-3-cyano--Phe-OH, (R)-3-methoxy--Phe-OH, (R)-3-methyl--Phe-OH, (R)-4-(4-pyridyl)--HomoAla-OH, (R)-4-(trifluoromethyl)--HomoPhe-OH, (R)-4-(trifluoromethyl)--Phe-OH, (R)-4-bromo--Phe-OH, (R)-4-chloro--HomoPhe-OH, (R)-4-chloro--Phe-OH, (R)-4-cyano--HomoPhe-OH, (R)-4-cyano--Phe-OH, (R)-4-fluoro--Phe-OH, (R)-4-methoxy--Phe-OH, (R)-4-methyl--Phe-OH, (R)--Tyr-OH, (R)-4-(3-pyridyl)--HomoAla-OH, (R)-4-fluoro--HomoPhe-OH, (S)-5-phenylpentanoic acid, (S)-5-hexenoic acid, (S)-5-phenyl-pentanoic acid, (S)-6-phenyl-5-hexenoic acid, (S)-2-(trifluoromethyl)--HomoPhe-OH, (S)-2-(trifluoromethyl)--Phe-OH, (S)-2-cyano--HomoPhe-OH, (S)-2-methyl--Phe-OH, (S)-3,4-dimethoxy--Phe-OH, (S)-3-(trifluoromethyl)--HomoPhe-OH, (S)-3-(trifluoromethyl)--Phe-OH, (S)-3-cyano--Phe-OH, (S)-3-methoxy--Phe-OH, (S)-3-methyl--Phe-OH, (S)-4-(4-pyridyl)--HomoAla-OH, (S)-4-(trifluoromethyl)--Phe-OH, (S)-4-bromo--Phe-OH, (S)-4-chloro--HomoPhe-OH, (S)-4-chloro--Phe-OH, (S)-4-cyano--HomoPhe-OH, (S)-4-cyano--Phe-OH, (S)-4-fluoro--Phe-OH, (S)-4-iodo--HomoPhe-OH, (S)-4-methyl--HomoPhe-OH, (S)-4-methyl--Phe-OH, (S)--Tyr-OH, (S)-,-diphenyl--HomoAla-OH, (S)-2-methyl--Homophe-OH, (S)-3,4-difluoro--HomoPhe-OH, (S)-3-(trifluoromethyl)--HomoPhe-OH, (S)-3-cyano--HomoPhe-OH, (S)-3-methyl--HomoPhe-OH, (S)-,-diphenyl-(i-HomoAla-OH, 3-Amino-3-(3-bromophenyl)propionic acid, and 3-Amino-4,4,4-trifluorobutyric acid.

[0553] In some embodiments, the fragment comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 amino acids of the wild type protein sequence.

[0554] In some embodiments, the fragment comprises any of the above-mentioned numbers of amino acids located anywhere within the peptide. Thus, one skilled in the art understands that a fragment of any of these lengths can be walked along the length of the peptide, thus providing any fragment of the peptide with the same or similar function as the native or wild-type amino acid sequence.

[0555] One of ordinary skill in the art would readily appreciate that the protecting groups would be removed from the final chemical structure of the analog which becomes administered to a subject. One of ordinary skill would be able to predict the final chemical structure of the analog by using the protecting groups selectively to create a polypeptide with a desirable chirality or secondary structure. For instance, if the analog of the composition is manufactured using (S)-Fmoc-3-methyl--HomoPhe-OH, the final yielded product should comprise at least one -amino acid residue of a 3-methyl--homophenylalanine.

[0556] In some embodiments, the method of manufacturing the analog comprises synthesizing the analog using at least one, and in some embodiments, a plurality of cyclic amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises the cyclic amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises at least one disulfide bridge that forms a cyclic chain of atoms along a side chain of two amino acid residues.

[0557] In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00017 (SEQIDNO:10) HSDAVFTDNYTRLRKQMAVKKYLNSILN;
wherein at least one of the amino acid residues is a -amino acid residue, and at least one of the amino acid residues is an -amino acid residue. In some embodiments, the at least one -amino acid residue is a non-natural amino acid residue. In some embodiments, the amino acid residues at positions 1, 3, 6, 7, 10, and 23 of the VIP analog are not alanine, glycine, or any amino acid residue with a methyl side chain.

[0558] In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00018 (SEQIDNO:1362) HSDAVFX.sub.1X.sub.2NYTRLRX.sub.3QX.sub.4AX.sub.5X.sub.6X.sub.7YLNX.sub.8IX.sub.9X.sub.10
wherein any of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 may be a beta-amino acid. In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00019 (SEQIDNO:1362) HSDAVFX.sub.1X.sub.2NYTRLRX.sub.3QX.sub.4AX.sub.5X.sub.6X.sub.7YLNX.sub.8IX.sub.9X.sub.10
wherein any of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 are a .sup.3-amino acid residue. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (R,S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.

[0559] In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00020 (SEQIDNO:1362) HSDAVFX.sub.1X.sub.2NYTRLRX.sub.3QX.sub.4AX.sub.5X.sub.6X.sub.7YLNX.sub.8IX.sub.9X.sub.10
wherein any one or more of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 is a beta-amino acid, and wherein X.sub.1=T; X.sub.2=D; X.sub.3=R or K; X.sub.4=M or L; X.sub.5=A or V; X.sub.6=R or K; X.sub.7=R or K; X.sub.8=S or A: X.sub.9=L or K; and X.sub.10=N or K In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00021 (SEQIDNO:1362) HSDAVFX.sub.1X.sub.2NYTRLRX.sub.3QX.sub.4AX.sub.5X.sub.6X.sub.7YLNX.sub.8IX.sub.9X.sub.10
wherein any one of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 is a .sup.3-amino acid residue. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (R,S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar: or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.

[0560] In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00022 (SEQIDNO:1362) HSDAVFX.sub.1X.sub.2NYTRLRX.sub.3QX.sub.4AX.sub.5X.sub.6X.sub.7YLNX.sub.8IX.sub.9X.sub.10
wherein any one or more of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 is a beta-amino acid, and wherein X.sub.1=T; X.sub.2=D; X.sub.3=R or K; X.sub.4=M or L; X.sub.5=A or V; X.sub.6=R or K; X.sub.7=R or K; X.sub.8=S or A; X.sub.9=L or K; and X.sub.10=N or K. In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00023 (SEQIDNO:1362) HSDAVFX.sub.1X.sub.2NYTRLRX.sub.3QX.sub.4AX.sub.5X.sub.6X.sub.7YLNX.sub.8IX.sub.9X.sub.10
wherein any one or more of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, or X.sub.10 is a .sup.3-amino acid residue. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (R,S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar: or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.

[0561] In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00024 (SEQIDNO:1363) HSDAVFX.sub.1X.sub.2NYX.sub.3RLX.sub.4X.sub.5QX.sub.6X.sub.7X.sub.8X.sub.9X.sub.10YLNX.sub.11IX.sub.12X.sub.13
wherein X.sub.3, X.sub.4, X.sub.7, X.sub.10, and X.sub.11 are beta-amino acid residues derived from the naturally occurring -amino acid residue at that position, and wherein X.sub.1=T; X.sub.2=D; X.sub.5=R or K: X.sub.6=M or L; X.sub.8=A or V; X.sub.9=R or K; X.sub.10=R or K; X.sub.11=S or A; X.sub.12=L or K; and X.sub.13=N or K. HSDAVFX.sub.1X.sub.2NYX.sub.3RLX.sub.4X.sub.5QX.sub.6X.sub.7X.sub.8X.sub.9X.sub.10YLNX.sub.11IX.sub.12X.sub.13 (SEQ ID NO: 1363) wherein X.sub.3, X.sub.4, X.sub.7, X.sub.10, and X.sub.11 are .sup.3-amino acid residues derived from the naturally occurring -amino acid residue at that position. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (R,S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar: or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.

[0562] In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00025 (SEQIDNO:1363) HSDAVFX.sub.1X.sub.2NYX.sub.3RLX.sub.4X.sub.5QX.sub.6X.sub.7X.sub.8X.sub.9X.sub.10YLNX.sub.11IX.sub.12X.sub.13
wherein at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10, X.sub.11, X.sub.12, or X.sub.13 is a beta-amino acid, and wherein X.sub.1=T; X.sub.2=D; X.sub.5=R or K; X.sub.6=M or L; X.sub.8=A or V; X.sub.9=R or K; X.sub.10=R or K: X.sub.11=S or A; X.sub.12=L or K; and X.sub.13=N or K. In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00026 (SEQIDNO:1363) HSDAVFX.sub.1X.sub.2NYX.sub.3RLX.sub.4X.sub.5QX.sub.6X.sub.7X.sub.8X.sub.9X.sub.10YLNX.sub.11IX.sub.12X.sub.13
wherein at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10, X.sub.11, X.sub.12, or X.sub.13 is a .sup.3-amino acid residue, and wherein X.sub.1=T; X.sub.2=D; X.sub.5=R or K; X.sub.6=M or L; X.sub.8=A or V; X.sub.9=R or K; X.sub.10=R or K; X.sub.11=S or A; X.sub.12=L or K; and X.sub.13=N or K. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (R,S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar: or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.

[0563] In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00027 (SEQIDNO:1364) X.sub.1TX.sub.2LRX.sub.3QLX.sub.4AX.sub.5X.sub.6YLQSIX.sub.7X.sub.8;
wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8 are non-natural amino acids and wherein the underlined residues are -amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00028 (SEQIDNO:1364) X.sub.1TX.sub.2LRX.sub.3QLX.sub.4AX.sub.5X.sub.6YLQSIX.sub.7X.sub.8;
wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, X.sub.8 are non-natural amino acids and wherein the underlined residues are .sup.3-amino acid residues. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar: or pyrrolidine analogue of (S,S)-ACPC, (R,S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.

[0564] In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00029 (SEQIDNO:1365) Y(OMe)TOrnLRAibQLUAAibOrnYLQSIOrnOrn,
wherein Om=omithine, Y(OMe)=O-methylated Tyrosine, Aib=-aminoisobutyric acid, U=amino butyric acid (i.e., side chain=ethyl), and wherein each underlined position is a -amino acid residue. In some embodiments at least one of the -amino acid residue are .sup.3-amino acid residues. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (R,S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.

[0565] In some embodiments, the VIP analog of the claimed invention comprises at least 17% -amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 15% to about 30% -amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 15% to about 30% -amino acid residues wherein the first ten amino acids of the amino acid sequence are alpha amino acids.

[0566] In some embodiments, the VIP analog of the claimed invention comprises from about 16% to about 29% -amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 17% to about 29% -amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 18% to about 29% -amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 19% to about 29% -amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 20% to about 29% -amino acid residues.

[0567] In some embodiments, the VIP analog of the claimed invention comprises -amino acid residues at residue positions 11, 14, 18, 21, and 25 of HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10). In some embodiments, the VIP analog of the claimed invention comprises -amino acid residues at positions 11, 14, 18, 21, and 25 of HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10), wherein the position 11 is .sup.3-homothreonine, position 14 is .sup.3-homoarginine, position 18 is .sup.3-homoalanine, position 21 is .sup.3-homolysine, and position 25 is .sup.3-homoserine. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar, or pyrrolidine analogue of (S,S)-ACPC, (R,S)-ACPC, (S,R)-ACPC, (R,R)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the .sup.3-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.

[0568] In some embodiments, the VIP analog of the claimed invention comprises the following sequence:

TABLE-US-00030 (SEQIDNO:1352) HSDAVFTDNYX.sub.1RLX.sub.2KQLX.sub.3VKX.sub.4YLNX.sub.5ILN
wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4, and X.sub.5 are -amino acid residues and wherein all other -amino residues are naturally-occurring or non-naturally occurring amino acid residues. In some embodiments, the VIP analog comprises a cyclic amino acid residue covalently bonded to one or more contiguous or non-contiguous amino acid sidechain residues via a lactam ring. In some embodiments, the VIP analog comprises a cyclic amino acid residue covalently bonded to one or more contiguous or non-contiguous amino acid sidechain residues via an amide bond. In some embodiments, the VIP analog of the claimed invention comprises one of the following sequences:

TABLE-US-00031 (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA
wherein each underlined residue is: a .sup.3-homoamino acid residue; or, if a non-polar (e.g., A, V), the underlined residues is/are (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC); or, if the underlined position is basic, (such as Lys or Arg), the underlined residue is a pyrrolidine analogue of (S,S)-ACPC, which is designated APC. (Note: Ac=acetyl; N.sup.le=norleucine; K*---D* indicates that the side chains of these two residues are linked via an amide bond.) In some embodiments, the sidechains of K and D are not linked via any bond. [0569] a/b-Peptide analogues will be synthesized:

TABLE-US-00032 (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK.sup.*YLND*LKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT
wherein each underlined residue is: a .sup.3-homoamino acid residue; or, if a non-polar (e.g., A, V), the underlined positions will be replaced by (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC): or if the underlined residue is basic, (such as Lys or Arg), the underlined residue is/are the pyrrolidine analogue of (S,S)-ACPC, which is designated APC; and wherein Ac=acetyl; N.sup.le=norleucine; K*---D* indicates that the side chains of these two residues are linked via an amide bond. In some embodiments, the sidechains of K and D are not linked via any bond. In some embodiments, the VIP analog comprises a cyclic amino acid residue covalently bonded to one or more contiguous or non-contiguous amino acid sidechain residues via the following synthetic linking structures:

##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018## ##STR00019##

[0570] In some embodiments, the analog does not comprise acyclic substituent in its side chain. In some embodiments, the cyclic amino acid residues are not covalently bonded to one or more contiguous or non-contiguous amino acid sidechain residues via the following synthetic linking structures:

##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028##

[0571] In some embodiments, the analogs of the present invention comprise at least one or a plurality of the following cyclic amino acid residues, some of which being described with a protecting group that becomes eliminated from the analog either during synthesis or when the analog is purified after synthesis: [0572] L--HomohydroxyProline hydrochloride [0573] (1R,2R)-Boc-2-aminocyclohexane carboxylic acid {(1R,2R)-ACHC} [0574] (1R,2R)-Fmoc-2-aminocyclohexane carboxylic acid {(1 R,2R)-ACHC} [0575] (1R,2S)-Boc-2-aminocyclohexane carboxylic acid {(1R,2S)-ACHC} [0576] (1R,2S)-Fmoc-2-aminocyclohexane carboxylic acid {(1 R,2S)-ACHC} [0577] (1S,2R)-Boc-2-aminocyclohexane carboxylic acid {(1S,2R)-ACHC} [0578] (1S,2R)-Fmoc-2-aminocyclohexane carboxylic acid (1S,2R)-ACHC} [0579] (1S,2S)-Boc-2-aminocyclohexane carboxylic acid {(1S,2S)-ACHC} [0580] (1S,2S)-Fmoc-2-aminocyclohexane carboxylic acid {(1S,2S)-ACHC} [0581] (1 R,2R)-Boc-2-aminocyclopentane carboxylic acid {(1 R,2R)-ACPC} [0582] (1R,2R)-Fmoc-2-aminocyclopentane carboxylic acid {(1R,2R)-ACPC} [0583] (1S,2S)-Boc-2-aminocyclopentane carboxylic acid {(1S,2S)-ACPC} [0584] (1S,2S)-Fmoc-2-aminocyclopentane carboxylic acid {(1S,2S)-ACPC} [0585] Boc-cis-2-aminocyclopentane carboxylic acid, cis-Acpc [0586] Fmoc-cis-2-aminocyclopentane carboxylic acid, cis-Acpc [0587] (R)-Boc-(2-carboxymethyl)-piperidine, (R)-(1-piperidin-2-yl)-acetic acid [0588] (R)-Fmoc-(2-carboxymethyl)-piperidine, (R)-(1-Fmoc-piperidin-2-yl)-acetic acid [0589] (S)-Boc-(2-carboxymethyl)-piperidine (S)-(1-Boc-piperidin-2-yl)-acetic acid [0590] (S)-Fmoc-(2-carboxymethyl)-piperidine (S)-(1-Fmoc-piperidin-2-yl)-acetic acid [0591] (R,S)-Boc-2-carboxymorpholine Boc-Cop [0592] (R,S)-Boc-2-carboxymorpholine Fmoc-Cop [0593] (R,S)-Boc-nipecotic acid Boc-Nip [0594] (R,S)-Boc-nipecotic acid Fmoc-Nip [0595] (R)-Fmoc-nipecotic acid (R)-Fmoc-Nip [0596] (R)-Fmoc-nipecotic acid (R)-Boc-Nip [0597] (3S)-Boc-1-pyrrolidine-3-carboxylic acid (3S)-Boc-beta-Pro-OH [0598] (3S)-Fmoc-1-pyrrolidine-3-carboxylic acid (3S)-Fmoc-beta-Pro-OH

[0599] In some embodiments, the analogs of the present invention comprise at least one or a plurality of non-natural amino acid residues that can modified by PEGylation. In some embodiments the analogs or fragments of the polypeptides related to this invention comprise PEG molecules which are covalently bound to the side chain of the , or amino acids in the polypeptide. In some embodiments, the polypeptides of this invention comprise the PEGylated cyclic amino acid residues or cyclic amino acid side chains. PEG molecule(s) may be covalently attached to any Lys, Cys, K(W) or K(CO(CH.sub.2).sub.2SH) residue at any position in the analog or fragment of analog. In some embodiments, the analog or a fragment thereof comprises a C-terminal extension may comprise one or more Cys residues which may be PEGylated. In some embodiment of the invention the polypeptides or fragments thereof may comprise one or more PEGylated residues in either or both sequences.

[0600] In some embodiments, the analog or fragment thereof comprises a PEG molecule covalently attached to one or all of the -residue within the analog. In some embodiments, the analog is at least one PEG molecule covalently attached to a residue in the C-terminal extension of the analog or fragment thereof. In some embodiments, the analog comprises more than one PEG molecule, there may be a combination of Lys, Cys, K(CO(CH.sub.2).sub.2SH), K(W) and carboxy-terminal amino acid PEGylation. For example, if there are two PEG molecules, one may be attached to a Lys residue and one may be attached to a Cys residue. In some embodiments, the polypeptide comprises one or more covalently bound PEG molecules, wherein at least one of the PEG molecules is branched. In some embodiments, one or more of the PEG molecules are linear. In some embodiments, the composition comprises one or more PEG molecule, wherein the PEG molecule is between about 200 daltons and about 100,000 daltons in molecular weight. In some embodiments, the PEG molecule is chosen from 10,000, 20,000, 30,000, 40,000, 50,000 and 60.000 daltons. In some embodiments, it is chosen from 20,000, 30,000, 40,000, or 60,000 daltons. Where there are two PEG molecules covalently attached to the analog or fragment thereof, each is 1,000 to 40,000 daltons and, they have molecular weights of 20,000 and 20,000 daltons, 10,000 and 30,000 daltons, 30,000 and 30,000 daltons, or 20,000 and 40,000 daltons. In some embodiments mini-PEGs are covalently bound to at least one residue or side chain of an , or -amino acid. In some embodiments, the mini-PEG is chosen from the following list of products: 8-Amino-3,6-Dioxaoctanoic Acid, 11-Amino-3,6,9-Trioxaundecanoic Acid, 8-Amino-3,6-Dioxaoctanoic Acid.Math.DCHA, 11-Amino-3,6,9-Trioxaundecanoic Acid.Math.DCHA.

[0601] In some embodiments the method of treatment or prevention of a human disorder depends upon the analog being synthesized. For instance: Peptides for triggering B and T cell activity can be used to treat autoimmune disease, including uveitis, collagen-induced, adjuvant and rheumatoid arthritis, thyroiditis, myasthenia gravis, multiple sclerosis and diabetes. Examples of these peptides are interleukins (referenced in Aulitzky, W E; Schuler, M; Peschel, C.; Huber, C.; Interleukins. Clinical pharmacology and therapeutic use. Drugs. 48(5):667-77, November 1994) and cytokines (referenced in Peters, M.; Actions of cytokines on the immune response and viral interactions: an overview. Hepatology. 23(4):909-16, April 1996).

[0602] Enkephlin analogs, agonist analogs and antagonist analogs can be used to treat AIDS, ARC, and cancer, pain modulation, Huntington's, Parkinson's diseases.

[0603] LHRH and analogs, agonists and antagonists can be used to treat prostatic tumors and reproductive physiopathology, including breast cancer, and infertility.

[0604] Peptides and peptidomimetics that target crucial enzymes, oncogenes or oncogene products, tumor-suppressor genes and their products, growth factors and their corresponding receptors can be used to treat cancer. Examples of these peptides are described in Unger, C. Current concepts of treatment in medical oncology: new anticancer drugs. Journal of Cancer Research & Clinical Oncology. 122(4):189-98, 1996.

[0605] Neuropeptide Y and other pancreatic polypeptides, and analogs, agonists and antagonists can be used to treat stress, anxiety, neurodegenerative diseases, depression and associated vasoconstrictive activities.

[0606] Gluco-incretins, including gastric inhibitory polypeptide, glucose-dependent insulinotropic polypeptide. PACAP/Glucagon and glucagon-like polypeptide-1 and 2 and analogs, agonists and antagonists can be used to treat Type I1 diabetic hyperglycaemia. Atrial natriuretic factor and analogs, agonists and antagonists can be used to treat congestive heart failure.

[0607] Integrin and analogs, agonists and antagonists can be used to treat osteoporosis, scar formation, bone synthesis, inhibition of vascular occlusion, and inhibition of tumor invasion and metastasis.

[0608] Glucagon, glucagon-like peptide 1, PACAP/Glucagon, and analogs, agonists and antagonists can be used to treat diabetes cardiovascular emergencies.

[0609] Antithrombotic peptides and analogs, agonists and antagonists can be used to treat cardiovascular and cerebrovascular diseases. Examples of these peptides RGD, D-Phe-Pro-Arg and others named are described in Ojima I.; Chakravarty S.; Dong Q. Antithrombotic agents: from RGD to peptide mimetics. Bioorganic & Medicinal Chemistry. 3(4):337-60, 1995.

[0610] Cytokines/interleukins and analogs, agonists and antagonists can be used to treat inflammatory disease, immune response dysfunction, hematopoiesis, mycosis fungoides, aplastic anemia, thrombocytopenia, and malignant melanoma. Examples of these peptides are Interleukins, referenced in Aulitzky et al. and Peters et al., which is herein incorporated by reference.

[0611] Endothelin and analogs, agonists and antagonists can be used to treat arterial hypertension, myocardial infarction, congestive heart failure, atherosclerosis, shock conditions, renal failure, asthma and vasospasm Natriuretic hormones and analogs, agonists and antagonists can be used to treat cardiovascular disease and acute renal failure. Examples of these peptides are named and described in Espiner, E. A. Richards, A. M.; Yandle. T. G.; Nicholls, M. G.; Natriuretic hormones. Endocrinology & Metabolism Clinics of North America. 24(3):481-509, 1995.

[0612] Peptides that activate or inhibit tyrosine kinase, or bind to TK-activating or inhibiting peptides and analogs, agonists and antagonists can be used to treat chronic myelogenous and acute lymphocytic leukemias, breast and ovarian cancers and other tyrosine kinase associated diseases. Examples of these peptides are described in Smithgall, T E.; SH2 and SH3 domains: potential targets for anti-cancer drug design. Journal of Pharmacological & Toxicological Methods. 34(3):125-32, 1995.

[0613] Renin inhibitors analogs, agonists and antagonists can be used to treat cardiovascular disease, including hypertension and congestive heart failure. Examples of these peptides are described in Rosenberg, S. H.; Renin inhibition. Cardiovascular Drugs & Therapy. 9(5):645-55, 1995.

[0614] Angiotensin-converting enzyme inhibitors, analogs, agonists and antagonists can be used to treat cardiovascular disease, including hypertension and congestive heart failure. Peptides that activate or inhibit tyrosine phosphorylases can be used to treat cardiovascular diseases. Examples of these peptides are described in Srivastava, A. K.; Protein tyrosine phosphorylation in cardiovascular system. Molecular & Cellular Biochemistry. 149-150:87-94, 1995.

[0615] Peptide based antivirals can be used to treat viral diseases. Examples of these peptides are described in Toes, R. E.; Feltkamp, M. C.; Ressing, M. E.; Vierboom, M. P.; Blom, R. J.; Brandt, R. M; Hartman, M.; Offringa, R; Melief, C. J.; Kast, W. M.; Cellular immunity against DNA tumour viruses: possibilities for peptide-based vaccines and immune escape. Biochemical Society Transactions. 23(3):692-6, 1995.

[0616] Corticotropin releasing factor and peptide analogs, agonist analogs and antagonist analogs can be used to treat disease associated with high CRF, i.e Alzheimer's disease, anorexia nervosa, depressive disorders, arthritis, and multiple sclerosis.

[0617] Peptide agonist analogs and antagonist analogs of platelet-derived wound-healing formula (PDWHF) can be used as a therapy for donor tissue limitations and wound-healing constraints in surgery. Examples of these peptides are described in Rudkin, G. H.; Miller, T. A.; Growth factors in surgery. Plastic & Reconstructive Surgery. 97(2):469-76, 1996. Fibronectin, fibrinopeptide inhibitors and analogs, agonists and antagonists can be used to treat metastasis (i.e. enzyme inhibition, tumor cell migration, invasion, and metastasis).

[0618] Chemokine (types of cytokine, including interleukin-8, RANTES, and monocyte chemotactic peptide) analogs, agonist analogs and antagonist analogs can be used to treat arthritis, hypersensitivity, angiogenesis, renal disease, glomerulonephritis, inflammation, and hematopoiesis.

[0619] Neutral endopeptidase inhibitors analogs, agonist analogs and antagonist analogs can be used to treat hypertension and inflammation. Examples of these peptides are described in Gregoire, J. R; Sheps, S. G: Newer antihypertensive drugs. Current Opinion in Cardiology. 10(5):445-9, 1995.

[0620] Substance P analogs, agonist analogs and antagonist analogs can be used to treat immune system dysfunction, pain transmission/perception and in autonomic reflexes and behaviors. Alpha-melanocyte-stimulating hormone analogs, agonist analogs and antagonist analogs can be used to treat AIDS, rheumatoid arthritis, and myocardial infarction.

[0621] Bradykinin (BK) analogs, agonist analogs and antagonist analogs can be used to treat inflammatory diseases (edema, etc), asthma, allergic reactions (rhinitis, etc), anesthetic uses, and septic shock.

[0622] Secretin analogs can be used to treat cardiovascular emergencies.

[0623] GnRH analogs, agonist analogs and antagonist analogs can be used to treat hormone-dependent breast and prostate tumors.

[0624] Somatostatin analogs, agonist analogs and antagonist analogs can be used to treat gut neuroendocrine tumors.

[0625] Gastrin, Gastrin Releasing Peptide analogs, agonist analogs and antagonist analogs can be used as an adjuvant to chemotherapy or surgery in small cell lung cancer and other malignancies, or to treat allergic respiratory diseases, asthma and allergic rhinitis.

[0626] Laminin analogs, agonist analogs and antagonist analogs, the Laminin derivative antimetastatic drug YIGSR analogs, Laminin-derived synthetic peptides analogs, agonist analogs and antagonist analogs can be used to treat tumor cell growth, angiogenesis, regeneration studies, vascularization of the eye with diabetes, and ischemia. The peptides of this category can inhibit the tumor growth and metastasis of leukemic cells and may be useful as a potential therapeutic reagent for leukaemic infiltrations. Peptides containing this sequence also inhibit experimental metastasis. Exemplary references include McGowan K A. Marinkovich M P. Laminins and human disease. Microscopy Research & Technique. 51(3):262-79, Nov. 1, 2000: Yoshida N. Ishii E. Nomizu M. Yamada Y. Mohri S. Kinukawa N. Matsuzaki A. Oshima K. Hara T. Miyazaki S. The laminin-derived peptide YIGSR (Tyr-Ile-Gly-Ser-Arg) inhibits human pre-B leukaemic cell growth and dissemination to organs in SCID mice. British Journal of Cancer. 80(12): 1898-904, 1999. Examples of these peptides are also described in Kleinman, H. K.; Weeks, B. S.; Schnaper, H. W.; Kibbey, M. C.; Yamamura, K.; Grant, D. S; The laminins: a family of basement membrane glycoproteins important in cell differentiation and tumor metastases. Vitamins & Hormones. 47:161-86, 1993.

[0627] Defensins, corticostatins, dermaseptins, mangainins, and other antibiotic (antibacterial and antimicrobial) peptides analogs, agonist analogs and antagonist analogs can be used to treat infections, tissue inflammation and endocrine regulation.

[0628] Vasopressin analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders, stress and Diabetes insipidus.

[0629] Oxytocin analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders and to induce labor.

[0630] ACTH-related peptides and analogs, agonist analogs and antagonist analogs can be used as neurotrophic, neuroprotective, and peripheral demyelinating neuropathy agents. Amyloid-beta peptide analogs, agonist analogs and antagonist analogs can be used to treat Alzheimer's disease.

[0631] Epidermal growth factor, receptor analogs, agonist analogs and antagonist analogs can be used to treat necrotizing enterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulceration, colitis, and congenital microvillus atrophycarcinomas.

[0632] Leukocyte adhesion molecule analogs, agonist analogs and antagonist analogs can be used to treat atherosclerosis, inflammation. Examples of these peptides are described in Barker, J. N.; Adhesion molecules in cutaneous inflammation. Ciba Foundation Symposium. 189:91-101.

[0633] Major histocompatibility complex (MHC) analogs, agonist analogs and antagonist analogs can be used to treat autoimmune, immunodysfunctional, immuno modulatory diseases and as well as used for their corresponding therapies. Examples of these peptides are described in Appella, E.; Padlan, E. A.; Hunt, D. F; Analysis of the structure of naturally processed peptides bound by class I and class 11 major histocompatibility complex molecules. EXS. 73:105-19, 1995.

[0634] Corticotropin releasing factor analogs can be used to treat neurological disorders.

[0635] Neurotrophins (including brain-derived neurotrophic factor (BDNF), nerve growth factor, and neurotrophin 3) analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders.

[0636] Cytotoxic T-cell activating peptide analogs, agonist analogs and antagonist analogs can be used to treat infectious diseases and cancer. Examples of these peptides are described in: Chesnut R. W.; Sette, A.; Celis, E.; Wentworth. P.; Kubo, R. T.; Alexander, J.; Ishioka, G.; Vitiello, A., Grey. H. M; Design and testing of peptide-based cytotoxic T-cell-mediated immunotherapeutics to treat infectious diseases and cancer. Pharmaceutical Biotechnology. 6:847-74, 1995.

[0637] Peptide immunogens for prevention of HIV-1 and HTLV-I retroviral infections can be used to treat AIDS. Examples of these peptides are described in Hart, M. K.; Palker, T. J.; Haynes, B F; Design of experimental synthetic peptide immunogens for prevention of HIV-1 and HTLV-1 retroviral infections. Pharmaceutical Biotechnology. 6:821-45, 1995.

[0638] Galanin analogs, agonist analogs and antagonist analogs can be used to treat Alzheimer's disease, depression, eating disorders, chronic pain, prevention of ischemic damage, and growth hormone modulation.

[0639] Tachykinins (neurokinin A and neurokinin B) analogs, agonist analogs and antagonist analogs can be used to treat pain transmission/perception and in autonomic reflexes and behaviors.

[0640] RGD containing peptide analogs can be used to treat various diseases involved with cell adhesion, antithrombotics, and acute renal failure.

[0641] Osteogenic growth peptide analogs, agonist analogs and antagonist analogs can be used as treatment of systemic bone loss. Examples of these peptides are described in Bab I A. Regulatory role of osteogenic growth peptide in proliferation, osteogenesis, and hemopoiesis. Clinical Orthopaedics & Related Research. (313):64-8, 1995.

[0642] Parathyroid hormone, parathyroid hormone related-peptide analogs, agonist analogs and antagonist analogs can be used to treat diseases affecting calcium homeostasis (hypercalcemia), bone metabolism, vascular disease, and atherosclerosis.

[0643] Kallidin analogs, agonist analogs and antagonist analogs can be used to treat tissue injury or inflammation and pain signaling pathological conditions of the CNS.

[0644] T cell receptor peptide analogs, agonist analogs and antagonist analogs can be used in immunotherapy. Examples of these peptides are described in Brostoff, S W: T cell receptor peptide vaccines as immunotherapy. Agents & ActionsSupplements. 47:53-8, 1995.

[0645] Platelet-derived growth factor (PDGF) analogs, agonist analogs and antagonist analogs can be used to treat non-neoplastic hyperproliferative disorders, therapy for donor tissue limitations and wound-healing constraints in surgery.

[0646] Amylin, calcitonin gene related peptides (CGRP) analogs, agonist analogs and antagonist analogs can be used to treat insulin-dependent diabetes.

[0647] VIP analogs, agonist analogs and antagonist analogs can be used to treat allergic respiratory diseases, asthma and allergic rhinitis, and nervous control of reproductive functions.

[0648] Growth hormone-releasing hormone (GHRH) analogs, agonist analogs and antagonist analogs can be used to treat growth hormone deficiency and immunomodulation.

[0649] HIV protease inhibiting peptide analogs, agonist analogs and antagonist analogs can be used to treat AIDS. Examples of these peptides are described in Bugelski, P. J.; Kirsh, R.; Hart, T. K; HIV protease inhibitors: effects on viral maturation and physiologic function in macrophages. Journal of Leukocyte Biology. 56(3):374-80, 1994.

[0650] Thymopoietin active fragment peptides analogs, agonist analogs and antagonist analogs can be used to treat rheumatoid arthritis and virus infections.

[0651] Cecropins analogs, agonist analogs and antagonist analogs can be used as antibacterials.

[0652] Thyroid releasing hormone (TRH) analogs, agonist analogs and antagonist analogs can be used to treat spinal cord injury and shock.

[0653] Erythropoietin (EPO) analogs, agonist analogs and antagonist analogs can be used to treat anemia.

[0654] Fibroblast growth factor (FGF), receptor analogs, agonist analogs and antagonist analogs can be as stimulation of bone formation, as well as used as a treatment for Kaposi's sarcoma, neuron regeneration, prostate growth, tumor growth inhibition, and angiogenesis.

[0655] Stem cell factor analogs, agonist analogs and antagonist analogs can be used to treat anemias. GP120, GP60, CD4 fragment peptides analogs, agonist analogs and antagonist analogs can be used to treat HIV and AIDS.

[0656] Insulin-like growth factor (IGF) analogs, agonist analogs and antagonist analogs, and IGF receptor analogs, agonist analogs and antagonist analogs can be used to treat breast and other cancers, noninsulin-dependent diabetes mellitus, cell proliferation, apoptosis, hematopoiesis, HIV, AIDS, growth disorders, osteoporosis, and insulin resistance.

[0657] Colony stimulating factors (granulocyte-macrophage colony-stimulating factor (GMCSF), granulocyte colony-stimulating factor (GCSF), and macrophage colony-stimulating factor (MCSF) analogs, agonist analogs and antagonist analogs can be used to treat anemias.

[0658] Kentsin analogs, agonist analogs and antagonist analogs can be used for immunomodulation.

[0659] Lymphocyte activating peptide (LAP) analogs, agonist analogs and antagonist analogs can be used for immunomodulation. Examples of these peptides are described in Loleit, M.; Deres, K.; Wiesmuller, K. H.; Jung, G.; Eckert, M.; Bessler, W. G; Biological activity of the Escherichia coli lipoprotein: detection of novel lymphocyte activating peptide segments of the molecule and their conformational characterization. Biological Chemistry Hoppe-Seyler. 375(6):407-12, June 1994.

[0660] Tuftsin analogs, agonist analogs and antagonist analogs can be used for immunomodulation.

[0661] Prolactin analogs, agonist analogs and antagonist analogs can be used to treat rheumatic diseases, systemic lupus erythematosus, and hyperprolactemia.

[0662] Angiotensin II analogs, agonist analogs and antagonist analogs and Angiotensin II receptor(s) analogs, agonist analogs and antagonist analogs can be used to treat hypertension, hemodynamic regulation, neurological disorders, diabetic nephropathies, aortoarterities induced RVH, hyperaldosteronism, heavy metal induced cardiovascular effects, diabetes mellitus and thyroid dysfunction.

[0663] Dynorphin analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders, pain management, algesia, spinal cord injury and epilepsy.

[0664] Calcitonin analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders, immune system dysfunction, calcium homeostasis, and osteoporosis.

[0665] Pituitary adenylate cyclase activating polypeptide analogs, agonist analogs and antagonist analogs may modulate growth, signal transduction vasoactivity roles.

[0666] Cholecystokinin analogs, agonist analogs and antagonist analogs can be used to treat feeding disorders, panic disorders, and anti-opioid properties.

[0667] Pepstatin analogs, agonist analogs and antagonist analogs can be used as pepsin and HIV protease inhibitors (AIDS).

[0668] Bestatin analogs, agonist analogs and antagonist analogs can be used to treat muscular dystrophy, anticancer, antileukemia, immune response modulator, and acute non-lymphocytic leukemia.

[0669] Leupeptin analogs, agonist analogs and antagonist analogs can be used as a protease inhibitor, exact role in diseases not determined yet.

[0670] Luteinizing hormone and releasing hormone analogs, agonist analogs and antagonist analogs can be used as a infertility male contraceptive.

[0671] Neurotensin analogs, agonist analogs and antagonist analogs can be used, e.g., as antipsychotic, analgesic, anti-cancer, and/or neuroprotective agents, e.g., for treating stroke victims, e.g., by inducing hypothermia so as to provide neuroprotection.

[0672] Motilin analogs, agonist analogs and antagonist analogs can be used for the control of gastric emptying.

[0673] Insulin analogs, agonist analogs and antagonist analogs can be used to treat diabetes.

[0674] Transforming growth factor (TGF) analogs, agonist analogs and antagonist analogs can be used for cell proliferation and differentiation, cancer treatment, immunoregulation, therapy for donor tissue limitations, and wound-healing constraints in surgery.

[0675] Bone morphogenetic proteins (BMPs) analogs, agonist analogs and antagonist analogs can be used as therapy for donor tissue limitations, osteogenesis, and wound-healing constraints in surgery.

[0676] Bombesin and Enterostatin analogs, agonist analogs and antagonist analogs can be used to prevent the proliferation of tumor cells, modulation of feeding, and neuroendocrine functions. These peptides fall within a supercategory of the neuromedins described above. These peptides are described in such exemplary references as Yamada K. Wada E. Wada K. Bombesin-like peptides: studies on food intake and social behaviour with receptor knock-out mice. Annals of Medicine. 32(8):519-29, November 2000: Ohki-Hamazaki H. Neuromedin B. Progress in Neurobiology. 62(3):297-312, October 2000; Still CD. Future trends in weight management. Journal of the American Osteopathic Association. 99(10 Su Pt 2):S18-9, 1999; Martinez V. Tache Y. Bombesin and the brain-gut axis. Peptides. 21(11):1617-25, 2000: Afferent signals regulating food intake. Proceedings of the Nutrition Society. 59(3):373-84, 2000; Takenaka Y. Nakamura F. Jinsmaa Y. Lipkowski A W. Yoshikawa M. Enterostatin (VPDPR) has anti-analgesic and anti-amnesic activities. Bioscience Biotechnology & Biochemistry. 65(1):236-8, 2001 J.

[0677] Glucagon, glucagon-like peptide 1 analogs, agonist analogs and antagonist analogs can be used to treat diabetes cardiovascular emergencies.

[0678] Pancreastatin, chromogranins A, B and C analogs, agonist analogs and antagonist analogsconditions associated with inhibition of insulin secretion, exocrine pancreatic secretion and gastric acid secretion, and stimulation of secretion.

[0679] Endorphins analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders, alleviating pain, treatment of opioid abuse, obesity, and diabetes. Examples of these peptides are named and described in Dalayeun, J. F.; Nores, J. M.; Bergal, S.; Physiology of beta-endorphins. A close-up view and a review of the literature. Biomedicine & Pharmacotherapy. 47(8):311-20, 1993.

[0680] Miscellaneous opioid peptides analogs, agonist analogs and antagonist analogs, including (but not limited to) adrenal peptide E analogs, alpha casein fragment analogs, beta casomorphin analogs, dermorphin analogs, kyotorphin analogs, metophamide neuropeptide FF (NPFF) analogs, melanocyte inhibiting factor analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders, alleviating pain, as well as for the treatment of opioid abuse.

[0681] Vasotocin analogs, agonist analogs and antagonist analogs can be used for sleep disorders including but not limited to insomnia.

[0682] Protein kinase C and inhibitors analogs, agonist analogs and antagonist analogs can be used to treat cancer, apoptosis, smooth muscle function, and Alzheimer's disease. Examples of these peptides are named and described in Philip, P. A.; Harris, A. L: Potential for protein kinase C inhibitors in cancer therapy. Cancer Treatment & Research. 78:3-27, 1995.

[0683] Amyloid, amyloid fibrin, analogs, agonist analogs and antagonist analogs can be used to treat neurodegenerative diseases and diabetes.

[0684] Calpain and other calmodulin-inhibitory protein analogs, agonist analogs and antagonist analogs can be used to treat neurodegenerative disorders, cerebral ischaemia, cataracts, myocardial ischaemia, muscular dystrophy and platelet aggregation.

[0685] Charybdotoxin and Apamin analogs, agonist analogs and antagonist analogs can be used for treatment of neurodegenerative diseases and pain and cerebral ischemia.

[0686] Phospholipase A2 analogs, agonist analogs and antagonist analogs and Phospholipase A2 receptor inhibiting/activating peptides analogs, agonist analogs and antagonist analogs can be used to treat acute pancreatitis, pancreatic cancer, abdominal trauma, and inflammation, e.g., sepsis, infections, acute pancreatitis, various forms of arthritis, cancer, complications of pregnancy, and postoperative states.

[0687] Potassium channel activating and inhibiting analogs, agonist analogs and antagonist analogs can be used to treat various diseases. Examples of these peptides are described in Edwards, G.; Weston, A. H; Pharmacology of the potassium channel openers. Cardiovascular Drugs & Therapy. 9 Suppl 2:185-93, March 1995.

[0688] IgG activators, inhibitors analogs, agonist analogs and antagonist analogs can be used to treat autoimmune diseases and immune dysfunctions. Examples of these peptides are described in Mouthon, L; Kaveri, S. V.; Spalter. S. H.; Lacroix-Desmazes. S.; Lefranc, C.; Desai, R.; Kazatchkine, M. D; Mechanisms of action of intravenous immune globulin in immune-mediated diseases. Clinical & Experimental Immunology. 104 Suppl 1:3-9, 1996.

[0689] Endotoxin and inhibitor analogs, agonist analogs and antagonist analogs can be used for decreasing cardiac output, systemic hypotension, decreased blood flow and O.sub.2 delivery to tissues, intense pulmonary vasoconstriction and hypertension, bronchoconstriction, increased permeability, pulmonary oedema, ventilation-to-perfusion inequalities, hypoxaemia, and haemoconcentration. Examples of these peptides are named and described in Burrell, R; Human responses to bacterial endotoxin. Circulatory Shock. 43(3):137-53, July 1994.

[0690] Orphan receptor ligand analogs, agonist analogs and antagonist analogs (including but not limited to ADNF, Adrenomedullin, Apelin, Ghrelin, Mastoparan (MCD peptides), Melanin concentrating hormone, Nociceptin/Nocistatin, Orexin, Receptor activity modulating protein, Urotensin) can be used to treat obesity, weight problems, neuropathy, sleep deprivation, sleep disorder inclusing insomnia, and lung cell repair. These orphan receptor ligands are described in such references as In D S. Orphan G protein-coupled receptor s and beyond. Japanese Journal of Pharmacology. 90(2): 101-6, 2002; Maguire J J. Discovering orphan receptor function using human in vitro pharmacology. Current Opinion in Pharmacology. 3(2):135-9, 2003: Szekeres P G. Functional assays for identifying ligands at orphan G protein-coupled receptor s. Receptor s & Channels. 8(5-6):297-308, 2002; Shiau A K. Coward P. Schwarz M. Lehmann J M. Orphan nuclear receptor s: from new ligand discovery technologies to novel signaling pathways. Current Opinion in Drug Discovery & Development. 4(5):575-90, 2001; Civelli O. Nothacker H P. Saito Y. Wang Z. Lin S H. Reinscheid R K. Novel neurotransmitters as natural ligands of orphan G-protein-coupled receptor s. Trends in Neurosciences. 24(4):230-7, 2001: Darland T. Heinricher M M. Grandy D K. Orphan in F Q/nociceptin: a role in pain and analgesia, but so much more. Trends in Neurosciences. 21(5):215-21, 1998, the disclosures of which are incorporated herein by reference.

[0691] Another embodiment of the invention includes analogs of Glycoprotein IIb/IIIa inhibitors. The central role of platelet-rich thrombus in the pathogenesis of acute coronary syndromes (ACSs) is well-known. Glycoprotein IIb/IIIa (Gp IIb/IIIa) receptor analogs, agonist analogs and antagonist analogs can be used as potent modulators of platelet function that may be expected to affect favorably the natural history of ACSs. Exemplary references for this category include Bhatt D L. Topol E J. Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. JAMA. 284(12):1549-58, 2000; Kereiakes D J. Oral blockade of the platelet glycoprotein IIb/IIIa receptor: fact or fancy?American Heart Journal. 138(1 Pt 2):S39-46, 1999; Bassand J P. Low-molecular-weight heparin and other antithrombotic agents in the setting of a fast-track revascularization in unstable coronary artery disease. Haemostasis. 30 Suppl 2:114-21: discussion 106-7, 2000.

[0692] Apo-lipoprotein A-I analogs, agonist analogs and antagonist analogs may increase the HDL levels of subjects upon administration. Analogs of the present invention that are homolgous to Apo-lipoprotein A-I may be useful to treat or prevent liver disease and inflammatory diseases including but not limited to artherosclerosis. Analogs of the present invention that are homolgous to Apo-lipoprotein A-1 may be useful to increase the amount of formation of pre-1 HDL in human plasma.

[0693] The cytokine analogs of the present invention may treat or prevent autoimmune disease, inflammatory disease, and dysfunctional growth or differentiation of cells such as cellular proliferative disorders, the development of neoplasia, tumors, and cancer.

[0694] The present invention provides for the use of an antibody or binding composition which specifically binds to a specified analog. in some embodiments the antibody specifically binds the analog derived from a mammalian polypeptide, e.g., a polypeptide derived from a primate, human, cat, dog, rat, or mouse. Antibodies can be raised to various analogs, including individual, polymorphic, allelic, strain, or species variants, and fragments thereof, both in their naturally occurring (full-length) forms or in their synthetic forms. Additionally, antibodies can be raised to the analogs in their inactive state or active state. Anti-idiotypic antibodies may also be used.

[0695] A number of immunogens may be selected to produce antibodies specifically reactive with ligand or receptor proteins. Synthetic analogs may serve as an immunogen for the production of monoclonal or polyclonal antibodies. Such antibodies may be used as antagonists or agonists for their targets modulating the disease state associated with the naturally occurring proteins and analogs listed above. Synthetic polypeptides of the claimed invention may also be used either in pure or impure form. Synthetic peptides, made using the appropriate protein sequences, may also be used as an immunogen for the production of antibodies. Naturally folded or denatured material can be used, as appropriate, for producing antibodies. Either monoclonal or polyclonal antibodies may be generated, e.g., for subsequent use in immunoassays to measure the protein, or for immunopurification methods. Methods of producing polyclonal antibodies are well known to those of skill in the art.

[0696] Typically, an immunogen, such as a purified analog of the invention, is mixed with an adjuvant and animals are immunized with the mixture. The animal's immune response to the immunogen preparation is monitored by taking test bleeds and determining the titer of reactivity to the protein of interest. For example, when appropriately high titers of antibody to the immunogen are obtained, usually after repeated immunizations, blood is collected from the animal and antisera are prepared. Further fractionation of the antisera to enrich for antibodies reactive to the protein can be performed if desired. See, e.g., Harlow and Lane; or Coligan. Immunization can also be performed through other methods, e.g., DNA vector immunization. See, e.g., Wang, et al. (1997) Virology 228:278-284.

[0697] Monoclonal antibodies may be obtained by various techniques familiar to researchers skilled in the art. Typically, spleen cells from an animal immunized with a desired analog are immortalized, commonly by fusion with a myeloma cell. See, Kohler and Milstein (1976) Eur. J. Immunol. 6:511-519. Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods known in the art. See, e.g., Doyle, et al. (eds. 1994 and periodic supplements) Cell and Tissue Culture: Laboratory Procedures, John Wiley and Sons, New York, N.Y. Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, one may isolate DNA sequences which encode a monoclonal antibody or a binding fragment thereof by screening a DNA library from human B cells according, e.g., to the general protocol outlined by Huse, et al. (1989) Science 246:1275-1281.

[0698] Antibodies or binding compositions, including binding fragments, single chain antibodies, F.sub.v, F.sub.ab, single domain V.sub.H, disulfide-bridged F.sub.v, single-chain F.sub.v or F(.sub.ab).sub.2 fragments of antibodies, diabodies, and triabodies against predetermined fragments of the analogs can be raised by immunization of animals with analogs or conjugates of analogs or receptor proteins with carrier proteins. Monoclonal antibodies are prepared from cells secreting the desired antibody. These antibodies can be screened for binding to analogs described herein. These monoclonal antibodies will usually bind with at least a K.sub.D of about 1 mM, usually at least about 300 M, typically at least about 10 M, at least about 30 M, at least about 10 M, and at least about 3 M or more. These antibodies can be screened for binding to the naturally occurring polypeptides upon which the analogs are derived.

[0699] In some instances, it is desirable to prepare monoclonal antibodies (mAbs) from various mammalian hosts, such as mice, rodents, primates, humans, etc. Description of techniques for preparing such monoclonal antibodies may be found in, e.g., Stites, et al. (eds.) Basic and Clinical Immunology, 4th ed., Lange Medical Publications, Los Altos, Calif, and references cited therein; Harlow and Lane (1988) Antibodies: A Laboratory Manual CSH Press; Goding (1986) Monoclonal Antibodies: Principles and Practice, 2nd ed., Academic Press, New York, N.Y.; and particularly in Kohler and Milstein (1975) Nature 256:495497, which discusses one method of generating monoclonal antibodies. Summarized briefly, this method involves injecting an animal with an analog described herein. The animal is then sacrificed and cells taken from its spleen, which are then fused with myeloma cells. The result is a hybrid cell or hybridoma that is capable of reproducing in vitro. The population of hybridomas is then screened to isolate individual clones, each of which secrete a single antibody species to the analog. In this manner, the individual antibody species obtained are the products of immortalized and cloned single B cells from the immune animal generated in response to a specific site recognized on the immunogenic substance.

[0700] Other suitable techniques involve selection of libraries of antibodies in phage or similar vectors. See, e.g., Huse, et al. (1989) Science 246:1275-1281; and Ward, et al. (1989) Nature 341:544-546. The polypeptides and antibodies of the present invention may be used with or without modification, including chimeric or humanized antibodies. Frequently, the polypeptides and antibodies will be labeled by joining, either covalently or non-covalently, a substance which provides for a detectable signal. A wide variety of labels and conjugation techniques are known and are reported extensively in both the scientific and patent literature. Suitable labels include radionuclides, enzymes, substrates, cofactors, inhibitors, fluorescent moieties, chemiluminescent moieties, magnetic particles, and the like. Patents teaching the use of such labels include U.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241. Also, recombinant immunoglobulins may be produced, see, Cabilly, U.S. Pat. No. 4,816,567; and Queen, et al. (1989) Proc. Nat'l Acad. Sci. USA 86:10029-10033; or made in transgenic mice, see Mendez, et al. (1997) Nature Genetics 15:146-156: also see Abgenix and Medarex technologies.

[0701] The instant invention is related to pharmaceutical compositions of the instant invention or the pharmaceutical acceptable salts derived therefrom that comprise analogs that comprise isotopes. In some embodiments, the compositions of the claimed invention may contain any isotope described in Cyr and Pearson (Stabilization of radiopharmaceutical compositions using hydrophilic thioethers and hydrophilic 6-hydroxy chromans. Cyr, John E.; Pearson, Daniel A. (Diatide, Inc., USA). PCT Int. Appl. (2002). WO 200260491 A2 20020808), which is herein incorporated by reference. In some embodiments the compositions of the invention comprise analog that comprise one or more of the following isotopes: .sup.125I, .sup.131I, .sup.211At, .sup.47Sc, .sup.67Cu, .sup.72Ga, .sup.90Y, .sup.153Sm, .sup.159Gd, .sup.165Dy, .sup.166Ho, .sup.175Yb, .sup.177Lu, .sup.212Bi, .sup.213Bi, .sup.68Ga, .sup.99Tc, .sup.111In, .sup.123I, and .sup.3H.

[0702] The pharmaceutical compositions of the instant invention or the pharmaceutical acceptable salts derived therefrom may be in a liquid or solid dosage form. Such compositions may include any type of dosage form such as tablets, capsules, powders, liquid formulations, delayed or sustained release, patches, snuffs, nasal sprays and the like. The formulations may additionally include other ingredients such as dyes, preservatives, buffers and anti-oxidants, for example. The physical form and content of the pharmaceutical formulations contemplated are conventional preparations that can be formulated by those skilled in the pharmaceutical formulation field and are based on well established principles and compositions described in, for example, Remington: The Science and Practice of Pharmacy, 19th Edition, 1995; British Pharmacopoeia 2000, each of which is incorporated herein by reference. The compositions of the present invention may also include other active agents useful in the treatment of cardiovascular conditions. Solid forms can be prepared according to any means suitable in the art. For example, capsules are prepared by mixing the analog composition with a suitable diluent and filling the proper amount of the mixture in capsules. Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Diluents, but are not limited to, include various types of starch, cellulose, crystalline cellulose, microcrystalline cellulose, lactose, fructose, sucrose, mannitol or other sugar alcohols, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Non-limiting examples of tablet binders include, but are not limited to, starches, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including, but are not limited to, acacia, alginates, methylcellulose, polyvinylpyrrolidone and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[0703] A lubricant can be used in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant include, but are not limited to, such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

[0704] Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compounds may also be formulated as chewable tablets, by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well-established in the art.

[0705] Also contemplated are liquid formulations and solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. Such liquid forms include, but are not limited to, solutions, suspensions, syrups, slurries, and emulsions. Liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats or oils); emulsifying agents (e.g., lecithin or acacia): non-aqueous vehicles (e.g., almond oil, oily esters, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl--hydroxybenzoates or sorbic acid). These preparations may contain, in addition to the active agent, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The compositions may be in powder form for constitution with a suitable vehicle such as sterile water, saline solution, or alcohol, before use. Preparations may also contain mucosal enhancers.

[0706] In some embodiments, the oral transmucosal solid dosage further comprises a permeation enhancer. In some embodiments, the permeation enhancer is chosen from: a bile salt, sodium dodecyl sulfate, dimethyl sulfoxide, sodium lauryl sulfate, a derivative of a saturated or a unsaturated fatty acid, a surfactant, a bile salt analog, and a derivative of a bile salt. In some embodiments the oral transmucosal dosage form is chosen from: a chewing gum, a patch, a lozenge, a lozenge-on-a-handle, a tablet, a troche, a pastille, a sachet, a sublingual tablet, and a rapid disintegrating tablet. In some embodiments, the oral transmucosal solid dosage form of wherein the composition further comprises at least one flavoring agent, artificial coloring, sweetener, lubricating agent, disintegration agent, lubricating agent, diluent, base, or buffering agent. In some embodiments, the oral transmucosal solid dosage form further comprises a sustained release agent. The invention is directed to an oral transmucosal solid dosage form comprising from wherein the concentration of analog is from about 0.01% to about 90% of the dry matter weight of the composition.

[0707] Solid dosage forms such as lozenges and tablets may also be used for oral transmucosal delivery of pharmaceuticals. For example, nitroglycerin sublingual tablets have been on the market for many years. The sublingual tablets are designed to deliver small amounts of the potent nitroglycerin, which is almost immediately dissolved and absorbed. On the other hand, most lozenges or tablets are typically designed to dissolve in the mouth over a period of at least several minutes which allows extended dissolution of the lozenge and absorption of the drug.

[0708] Administration of lozenges or sublingual tablets generally utilize an open delivery system, in which the drug delivery conditions are influenced by the conditions of the surrounding environment, such as rate of saliva secretion, pH of the saliva, or other conditions beyond the control of the formulation.

[0709] A lozenge-on-a-handle (similar to a lollipop) is another dosage form suitable for transmucosal drug delivery. In addition to being non-invasive and providing a particularly easy method of delivery, the lozenge-on-a-handle (or lozenge with an integrated oral transmucosal applicator) dosage form allows a patient or caregiver to move the dosage form in and out of the mouth to titrate the dose. This practice is called dose-to-effect, in which a patient or caregiver controls the administration of the dose until the expected therapeutic effect is achieved. This is particularly important for certain symptoms, such as pain, nausea, motion sickness, and premedication prior to anesthesia because each patient needs a different amount of medication to treat these symptoms. For these types of treatments, the patient is the only one who knows how much medication is enough. Once the appropriate amount of drug is delivered, the patient or caregiver can remove the lozenge-on-a-handle, thus, stopping delivery of the drug. This feature is especially important for particularly potent drugs, which may present a significant advantage of terminating drug administration once the desired effect is achieved.

[0710] As used herein, the term oral transmucosal delivery (OTD) refers to the delivery of a pharmaceutical agent across a mucous membrane in the oral cavity, pharyngeal cavity, or esophagus, and may be contrasted, for example, with traditional oral delivery, in which absorption of the drug occurs in the intestines. Accordingly, routes of administration in which the pharmaceutical agent is absorbed through the buccal, sublingual, gingival, pharyngeal, and/or esophageal mucosa are all encompassed within oral transmucosal delivery, as that term is used herein. Oral transmucosal delivery involves the administration of an oral transmucosal solid dosage form to the oral cavity of a patient, which is held in the oral cavity and dissolved, thereby releasing the pharmaceutical agent for oral transmucosal delivery. Of course, as the solid dosage form dissolves in the oral cavity, some of the saliva containing the pharmaceutical agent may be swallowed, and a portion of the drug may ultimately be absorbed from the intestines.

[0711] The compositions of the invention can be administered in a sustained release composition, such as those described in, for example, U.S. Pat. Nos. 5,672,659 and 5,595,760, and herein incorporate by reference. The use of immediate or sustained release compositions depends on the type of condition being treated.

[0712] The pharmaceutical compositions of the instant invention or the pharmaceutical acceptable salts derived therefrom may be in a dosage amount in an effective amount for inducing or increasing the naturally occurring biological activity of the wild-type polypeptide upon which the analog is derived. The pharmaceutical compositions of the instant invention or the pharmaceutical acceptable salts derived therefrom may be in a dosage amount in an effective amount for inducing or increasing the naturally occurring biological activity of the wild-type secretin polypeptide upon which the analog is derived. The pharmaceutical compositions of the instant invention or the pharmaceutical acceptable salts derived therefrom may be in a dosage amount in an effective amount for increasing the half-life of the composition when administered to a human being or other subject. In some embodiments the secretin analog is VIP.

[0713] The present invention also encompasses methods of using the compositions comprising a VIP analog. Any of these methods may involve the administration of a pharmaceutical composition comprising a VIP analog wherein the VIP analog is in a therapeutically effective dose. Any of these methods may involve the administration of a pharmaceutical composition comprising a VIP analog wherein the VIP analog is selective for VPAC1, VPAC2, PAC1, VIPR1, or VIPR2. The composition comprising an analog of the invention produces a broad range of activities, depending on the dosage administered. The present invention encompasses methods of treating or preventing pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndromeCalcinosis, Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction comprising administering to at least one patient in need thereof, mammal in need thereof or human in need thereof a composition or pharmaceutical composition comprising a secretin family analog in a therapeutically effective amount. The compositions of the invention may also be used at lower doses in order to prevent pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndromeCalcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof. The compositions of the invention may also be used to prevent pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndromeCalcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject susceptible to those indications. In some embodiments, the method of prevention comprising administering the composition or pharmaceutical compositions of the invention after the subject is tested for susceptibility or genetic propensity for developing the disease, indication or disorder.

[0714] The pharmaceutical composition comprising a pharmaceutically acceptable carrier/diluent and an analog comprising an -amino acid and at least one -amino acid may be formulated by one having ordinary skill in the art with compositions selected depending upon the chosen mode of administration. Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field, which is incorporated herein in its entirety.

[0715] For parenteral administration, analog can be, for example, formulated as a solution, suspension, emulsion or lyophilized powder in association with a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Liposomes and nonaqueous vehicles such as fixed oils may also be used. The vehicle or lyophilized powder may contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives). The formulation is sterilized by commonly used techniques. For example, a parenteral composition suitable for administration by injection is prepared by dissolving 1.5% by weight of analog in 0.9% sodium chloride solution.

[0716] The present invention relates to routes of administration include intramuscular, sublingual, intravenous, intraperitoneal, intrathecal, intravaginal, intraurethral, intradermal, intrabuccal, via inhalation, via nebulizer and via subcutaneous injection. Alternatively, the pharmaceutical composition may be introduced by various means into cells that are removed from the individual. Such means include, for example, microprojectile bombardment and liposome or other nanoparticle device.

[0717] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In solid dosage forms, the analogs are generally admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, starch, or other generally regarded as safe (GRAS) additives. Such dosage forms can also comprise, as is normal practice, an additional substance other than an inert diluent, e.g., lubricating agent such as magnesium state. With capsules, tablets, and pills, the dosage forms may also comprise a buffering agent. Tablets and pills can additionally be prepared with enteric coatings, or in a controlled release form, using techniques know in the art.

[0718] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions and syrups, with the elixirs containing an inert diluent commonly used in the art, such as water. These compositions can also include one or more adjuvants, such as wetting agent, an emulsifying agent, a suspending agent, a sweetening agent, a flavoring agent or a perfuming agent.

[0719] In another embodiment of the invention the composition of the invention is used to treat a patient suffering from, or susceptible to, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndromeCalcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction due to administration of a medication that causes onset of or exacerbates symptoms of pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension. CREST syndromeCalcinosis; Raynaud's disease: loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject. In some embodiments, the invention relates to compositions comprising a secretin family analog for treatment or prevention of pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndromeCalcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity. Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments, the secretin family analog of the invention comprises an analog of VIP.

[0720] One of skill in the art will recognize that the appropriate dosage of the compositions and pharmaceutical compositions may vary depending on the individual being treated and the purpose. For example, the age, body weight, and medical history of the individual patient may affect the therapeutic efficacy of the therapy. Further, a lower dosage of the composition may be needed to produce a transient cessation of symptoms, while a larger dose may be needed to produce a complete cessation of symptoms associated with the disease, disorder, or indication. A competent physician can consider these factors and adjust the dosing regimen to ensure the dose is achieving the desired therapeutic outcome without undue experimentation. It is also noted that the clinician and/or treating physician will know how and when to interrupt, adjust, and/or terminate therapy in conjunction with individual patient response. Dosages may also depend on the strength of the particular analog chosen for the pharmaceutical composition.

[0721] The dose of the composition or pharmaceutical compositions may vary. The dose of the composition may be once per day. In some embodiments, multiple doses may be administered to the subject per day. In some embodiments, the total dosage is administered in at least two application periods. In some embodiments, the period can be an hour, a day, a month, a year, a week, or a two-week period. In an additional embodiment of the invention, the total dosage is administered in two or more separate application periods, or separate doses.

[0722] In some embodiments, subjects can be administered the composition in which the composition is provided in a daily dose range of about 0.0001 mg/kg to about 5000 mg/kg of the weight of the subject. The dose administered to the subject can also be measured in terms of total amount of analog administered per day. In some embodiments, a subject is administered from about 0.001 to about 3000 milligrams of analog per day. In some embodiments, a subject is administered up to about 2000 milligrams of analog per day. In some embodiments, a subject is administered up to about 1800 milligrams of analog per day. In some embodiments, a subject is administered up to about 1600 milligrams of analog per day. In some embodiments, a subject is administered up to about 1400 milligrams of analog per day. In some embodiments, a subject is administered up to about 1200 milligrams of analog per day. In some embodiments, a subject is administered up to about 1000 milligrams of analog per day. In some embodiments, a subject is administered up to about 800 milligrams of analog per day. In some embodiments, a subject is administered from about 0.001 milligrams to about 700 milligrams of analog per dose. In some embodiments, a subject is administered up to about 700 milligrams of analog per dose. In some embodiments, a subject is administered up to about 600 milligrams of analog per dose. In some embodiments, a subject is administered up to about 500 milligrams of analog per dose. In some embodiments, a subject is administered up to about 400 milligrams of analog per dose. In some embodiments, a subject is administered up to about 300 milligrams of secretin analog per dose. In some embodiments, a subject is administered up to about 200 milligrams of analog per dose. In some embodiments, a subject is administered up to about 100 milligrams of analog per dose. In some embodiments, a subject is administered up to about 50 milligrams of analog per dose.

[0723] In some embodiments, subjects can be administered the composition in which the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dose range of about 0.0001 mg/kg to about 5000 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 450 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 400 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 350 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 300 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 250 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 200 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 150 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 100 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 50 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 25 mg/kg of the weight of the subject.

[0724] In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 10 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 5 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 1 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 0.1 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 0.01 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 0.001 mg/kg of the weight of the subject. The dose administered to the subject can also be measured in terms of total amount of VIP analog administered per day.

[0725] In some embodiments, a subject in need thereof is administered from about 1 ng to about 500 g of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 1 ng to about 10 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 10 ng to about 20 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 10 ng to about 100 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 100 ng to about 200 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 200 ng to about 300 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 300 ng to about 400 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 400 ng to about 500 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 500 ng to about 600 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 600 ng to about 700 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 800 ng to about 900 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 900 ng to about 1 g of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 1 g to about 100 g of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 100 g to about 200 g of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 200 g to about 300 g of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 300 g to about 400 g of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 400 g to about 500 g of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 500 g to about 600 g of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 600 g to about 700 g of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 800 g to about 900 g of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 900 g to about 1 mg of analog or pharmaceutically salt thereof per day.

[0726] In some embodiments, a subject in need thereof is administered from about 0.0001 to about 3000 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 2000 milligrams of VIP analog or pharmaceutically salt thereof day. In some embodiments, a subject is administered up to about 1800 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 1600 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 1400 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 1200 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 1000 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 800 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered from about 0.0001 milligrams to about 700 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 700 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 600 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 500 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 400 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 300 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 200 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 100 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 50 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 25 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 15 milligrams of VIP analog or pharmaceutically salt thereof per dose.

[0727] In some embodiments, a subject is administered up to about 10 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 5 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 1 milligram of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 0.1 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 0.001 milligrams of VIP analog or pharmaceutically salt thereof per dose.

[0728] The dose administered to the subject can also be measured in terms of total amount of VIP analog or pharmaceutically salt thereof administered per ounce of liquid prepared. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 2.5 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 2.25 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 2.25 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 2.0 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.9 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.8 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.7 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.6 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.5 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.4 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.3 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.2 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.1 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.0 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.9 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.8 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.7 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.6 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.5 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.4 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.3 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.2 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.1 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.01 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.001 grams per ounce of solution prepared. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.0001 grams per ounce of solution prepared. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.00001 grams per ounce of solution prepared. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.000001 grams per ounce of solution prepared.

[0729] Dosage may be measured in terms of mass amount of analog per liter of liquid formulation prepared. One skilled in the art can increase or decrease the concentration of the analog in the dose depending upon the strength of biological activity desired to treat or prevent any above-mentioned disorders associated with the treatment of subjects in need thereof. For instance, one embodiment of the invention can include up to 0.00001 grams of analog per 5 mL of liquid formulation and up to about 10 grams of analog per 5 mL of liquid formulation.

[0730] In some embodiments the pharmaceutical compositions of the claimed invention comprise at least one other active agent. in some embodiments, the active agent is a vasoactive agent. In some embodiments the vasoactive agent is chosen from the naturally occurring prostaglandins prostaglandin E0 (PGE0, also referred to 13,14-dihydro-PGE1; hereinafter, the abbreviation PG is used for prostaglandin), PGE1, 19-hydroxy-PGE1, PGE2, 19-hydroxy-PGE2, PGA1, 19-hydroxy-PGA1, PGA2, 19-hydroxy-PGA2, PGB1, 19-hydroxy-PGB1, PGB2, 19-hydroxy-PGB2, PGB3, PGD2, PGF1, PGF2(dinoprost), PGE3, PGF3, PGI2 (prostacyclin), and combinations thereof. PGE0, PGE1, PGE2, and the hydrolyzable lower alkyl esters thereof (e.g., the methyl, ethyl and isopropyl esters) are, however, particularly suitable. Other suitable prostaglandins are exemplified, without limitation, by arboprostil, carbaprostacyclin, carboprost tromethamine, dinoprost tromethamine, dinoprostone, enprostil, iloprost, lipoprost, gemeprost, metenoprost, sulprostone, tiaprost, viprostil (CL 115,347), viprostil methyl ester, 16,16-dimethyl-A2-PGE1 methyl ester, 15-deoxy-16-hydroxy-16-methyl-PGE1 methyl ester (misoprostol), 16,16-dimethyl-PGE1, 11-deoxy-15-methyl-PGE1, 16-methyl-18,18,19,19-tetrahydrocarbacyclin, 16(R,S)-15-deoxy-16-hydroxy-16-methyl-PGE1 methyl ester, (+)-4,5-didehydro-16-phenoxy--tetranor-PGE2 methyl ester, 11-deoxy-11,16,16-trimethyl-PGE2. (+)-11,16,16 -dihydroxy-1-(hydroxymethyl)-16-methyl-trans-prostene, 9-chloro-16,16-dimethyl-PGE2, 16,16-dimethyl-PGE2, 15(S)-15-methyl-PGE2, 9-deoxy-9-methylene-16,16-dimethyl-PGE2, potassium salt, 19(R)-hydroxy-PGE2, and 11-deoxy-16,16-dimethyl-PGE2. Additional vasoactive agents useful as secondary active agents herein include endothelin-derived relaxation factors (EDRFs) such as nitric oxide releasing agents, e.g., sodium nitroprusside and diazenium diolates, or NONOates. NONOates include, but are not limited to, (Z)-1-{N-methyl-N-{6-(N-methyl-ammoniohexyl)amino}}diazen-1-ium-1,2-diolate (MAHMA/NO), (Z)-1-{N-(3-ammoniopropyl)-N-(n-propyl)amino}-diazen-1-ium-1,2-diolate (PAPA/NO), (Z)-1-{N-{3-aminopropyl}-N-{4-(3-aminopropylammonio)butyl}amino}diazen-1-ium-1,2-diolate (spermine NONOate or SPER/NO) and sodium (Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate (diethylamine NONOate or DEA/NO) and derivatives thereof). Still other vasoactive agents include vasoactive intestinal polypeptide analogs and derivatives thereof (particularly derivatives in the form of hydrolyzable lower alkyl esters), smooth muscle relaxants, leukotriene inhibitors, calcium channel blockers, P2-adrenergic agonists, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and phosphodiesterase inhibitors. Still other suitable vasoactive agents include, but are not limited to: nitrates and like compounds such as nitroglycerin, isosorbide dinitrate, erythrityl tetranitrate, amyl nitrate, molsidomine, linsidomine chlorhydrate (SIN-1), S-nitroso-N-acetyl-d,l-penicillamine (SNAP) and S-nitroso-N-glutathione (SNO-GLU): long and short acting -blockers such as phenoxybenzamine, dibenamine, doxazosin, terazosin, phentolamine, tolazoline, prazosin, trimazosin, alfuzosin, tamsulosin and indoramin; ergot alkaloids such as ergotamine and ergotamine analogs, e.g., acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride: antihypertensive agents such as diazoxide, hydralazine and minoxidil; nimodepine; pinacidil; cyclandelate: dipyridamole; isoxsuprine; chlorpromazine: haloperidol: yohimbine; and trazodone.

[0731] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is an inhibitor of rho kinase, an enzyme belonging to the rhoA/rho associated kinase pathway, which regulates the state of phosphorylation of myosin phosphatase, in turn leading to the control of smooth muscle contraction. One example of a suitable rho kinase inhibitor has the following structural formula and is identified as Y-27632. Other suitable rho kinase inhibitors are disclosed, for example, in U.S. Pat. No. 6,218,410, which is herein incorporated by reference.

[0732] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that are peptide analogs of -melanocyte-stimulating hormone (-MSH), also referred to as melanocortin peptides. Such peptides include the sequence His-Phe-Arg-Trp, His-D-Phe-Arg-Trp, or are homologs thereof, and can be cyclic. A suitable melanocortin peptide is Ac-Nle-cyclo-(-Asp-His-D-Phe-Arg-Trp-Lys)-OH. See U.S. Pat. No. 6,051,555 to Hadley and International Patent Publication No. WO 01/00224 to Blood et al., assigned to Palatin Technologies, Inc. The aforementioned amino acid residues have their conventional meaning as given in Chapter 2422 of the Manual of Patent Examining Procedure (2000). Thus, Arg is arginine, Nle is norleucine, His is histamine, Phe is phenylalanine. D-Phe is D-phenylalanine, Trp is tryptophan, and Ac refers to an acetyl moiety, i.e., an acetyl moiety present in a peptide or amino acid sequence that is acetylated.

[0733] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is an endothelin antagonists, including antagonists of any or all of the three isoforms of endothelin, i.e., ET-1, ET-2, and ET-3, and are exemplified by: phenoxyphenylacetic acids and derivatives thereof, such as N-(4-isopropylbenzene-sulfonyl)--(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenyl acetamide dipotassium salt, 2-{(2,6-dipropyl-4-hydroxymethyl)-phenoxy}-2-(4-phenoxyphenyl)-acetic acid, 2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(4-phenylphenyl)acetic acid, 2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3-carboxyphenyl)-acetic acid, 2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3,4-ethylenedioxyphenyl)acetic acid, 2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3,4,5-trimethoxyphenyl)acetic acid, 2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3,4-methylenedioxyphenyl)acetic acid, N-(4-dimethylaminobenzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl) acetamide, N-(2-methylbenzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetamide, N-(2-methoxycarbonyl-benzenesulfonyl)-2-(4-methoxy-carbonyl-2-propylphenoxy)-2-(3,4-methylenedioxy-phenyl)acetamide, N-(2-chlorobenzene-sulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetamide, and others, as described in U.S. Pat. No. 5,565,485; and certain isooxazoles, oxazoles, thiazoles, isothiazoles and imidazoles, as described, for example, in U.S. Pat. No. 6,136,828.

[0734] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a peptidyl drug including the peptidyl hormones activin, amylin, angiotensin, atrial natriuretic peptide (ANP), calcitonin, calcitonin gene-related peptide, calcitonin N-terminal flanking peptide, ciliary neurotrophic factor (CNTF), corticotropin (adrenocorticotropin hormone, ACTH), corticotropin-releasing factor (CRF or CRH), epidermal growth factor (EGF), follicle-stimulating hormone (FSH), gastrin, gastrin inhibitory peptide (GIP), gastrin-releasing peptide, gonadotropin-releasing factor (GnRF or GNRH), growth hormone releasing factor (GRF, GRH), human chorionic gonadotropin (hCH), inhibin A, inhibin B, insulin, luteinizing hormone (LH), luteinizing hormone-releasing hormone (LHRH), -melanocyte-stimulating hormone, -melanocyte-stimulating hormone, -melanocyte-stimulating hormone, melatonin, motilin, oxytocin (pitocin), pancreatic polypeptide, parathyroid hormone (PTH), placental lactogen, prolactin (PRL), prolactin-release inhibiting factor (PIF), prolactin-releasing factor (PRF), secretin, somatotropin (growth hormone, GH), somatostatin (SIF, growth hormone-release inhibiting factor, GIF), thyrotropin (thyroid-stimulating hormone, TSH), thyrotropin-releasing factor (TRH or TRF), thyroxine, and vasopressin. Other peptidyl drugs are the cytokines, e.g., colony stimulating factor 4, heparin binding neurotrophic factor (HBNF), interferon-, interferon -2a, interferon -2b, interferon -n3, interferon-, etc., interleukin-1, interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, etc., tumor necrosis factor, tumor necrosis factor-, granuloycte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor, midkine (MD), and thymopoietin.

[0735] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a selective androgen receptor modulators (SARMs) include LGD2226 and/or LGD1331, both available from Ligand Pharmaceuticals (San Diego, Calif.). See Negro-Villar et al. J. Clin. Endocrinol. & Metabol. 84(10):3459-62 (1999).

[0736] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a suitable neuropeptide including bradykinin, kallidin, des-Arg9-bradykinin, des-Arg10-kallidin, des-Arg9-{Leu8}-bradykinin, {D-Phe7}-bradykinin, HOE 140, neuropeptide Y, calcitonin gene-related peptide (cGRP), enkaphalins and related opioid peptides such as Met5-enkaphalin, Leu5-enkephalin, -, - and -endorphin, - and -neo-endorphin, and dynorphin, as well as the neurotransmitters GABA (-aminobutyric acid), glycine, glutamate, acetylcholine, dopamine, epinephrine, 5-hydroxytryptamine, substance P, serotonin, and catecholamines.

[0737] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a suitable serotonin agonists include, but are not limited to 2-methyl serotonin, buspirone, ipsaperone, tiaspirone, gepirone, ergot alkaloids, 8-hydroxy-(2-N,N-dipropyl-amino)-tetraline, 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride, sumatriptan, m-chlorophenylpiperazine, trazodone, zacopride, mezacopride, and combinations thereof. Suitable serotonin antagonists include, for example, ondansetron, granisetron, metoclopramide, tropisetron, dolasetron, palonosetron, trimethobenzamide, methysergide, risperidone, ketanserin, ritanserin, clozapine, amitriptyline, MDL 100,907 (R(+)--(2,3-dimethoxyphenyl)-1-{2-(4-fluorophenyl)ethyl}-4-piperidine-methanol) (Marion Merrell Dow), azatadine, cyproheptadine, fenclonine, chlorpromazine, mianserin and combinations thereof.

[0738] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is an ergot alkaloids include ergotamine and ergotamine analogs, e.g., acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, dihydroergotamine, disulergine, ergonovine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride.

[0739] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a calcium channel blockers that are suitable for use according to the present invention include, without limitation, amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, bepridil, diltiazem, verapamil, and combinations thereof. In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a potassium channel openers include, but are not limited to, pinacidil, diazoxide, cromakalim, nicorandil, minoxidil, (N-cyano-N-(1,1-dimethylpropyl)-N-3-pyridyl-guanidine (P-1075), and N-cyano-N-(2-nitroxyethyl)-3-pridinecarboximidamide monomethanesulfonate (KRN 2391).

[0740] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a potassium channel blockers include tedisamil, agitoxin-2, apamin, BDS-I, BDS-II, charybdotoxin, -dendrotoxin, -dendrotoxin, -dendrotoxin, -dendrotoxin, dendrotoxin-I, dendrotoxin-K, E-4031, iberiotoxin, kaliotoxin, MCD-peptide, margatoxin, noxiustoxin, paxilline, penitrem A, stichodactyla, tertiapin, tityustoxin K alpha, verruculogen, and combinations thereof. Although all of the active agents are available commercially, most of the listed potassium channel blockers are available from Alomone Labs (Jerusalem, Israel).

[0741] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a dopamine agonist including, for example, levodopa, bromocriptine, pergolide, apomorphine, piribedil, pramipexole, ropinirole, and combinations thereof. Dopamine antagonists include, without limitation, spiroperidol, benperidol, trifluperidol, pimozide, fluphenazine, droperidol, haloperidol, thiothixene, trifluperazine, moperone, prochlorperazine, molindone, thioridazine, clozapine, chlorpromazine, promazine, sulpiride, clebopride, chlorpromazine, spiperone, flupenthixol, and combinations thereof.

[0742] In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a non-androgenic steroid including progestins and estrogens. Suitable estrogens include synthetic and natural estrogens such as: estradiol (i.e., 1,3,5-estratriene-3,17-diol, or 17-estradiol) and its esters, including estradiol benzoate, valerate, cypionate, heptanoate, decanoate, acetate and diacetate; 17-estradiol; ethinylestradiol (i.e., 17-ethinylestradiol) and esters and ethers thereof, including ethinylestradiol 3-acetate and ethinylestradiol 3-benzoate; estriol and estriol succinate; polyestrol phosphate; estrone and its esters and derivatives, including estrone acetate, estrone sulfate, and piperazine estrone sulfate; quinestrol; mestranol; and conjugated equine estrogens. Suitable progestins include acetoxypregnenolone, allylestrenol, anagestone acetate, chlormadinone acetate, cyproterone, cyproterone acetate, desogestrel, dihydrogesterone, dimethisterone, ethisterone (17-ethinyltestosterone), ethynodiol diacetate, flurogestone acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone, hydroxymethylprogesterone acetate, 3-ketodesogestrel, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol, megestrol acetate, melengestrol acetate, norethindrone, norethindrone acetate, norethisterone, norethisterone acetate, norethynodrel, norgestimate, norgestrel, norgestrienone, normethisterone, and progesterone. It is generally desirable to co-administer a progestin along with an estrogen so that the estrogen is not unopposed. As is well known in the art, estrogen-based therapies are known to increase the risk of endometrial hyperplasia and cancer, as well as the risk of breast cancer, in treated individuals. Co-administration of estrogenic agents with a progestin has been found to decrease the aforementioned risks.

[0743] The pharmaceutical compositions of the present invention may also include one or more chemotherapeutic agents. Suitable chemotherapeutic agents include, but are not limited to, platinum coordination compounds, topoisomerase inhibitors, antibiotics, antimitotic alkaloids and difluoronucleosides.

[0744] In one embodiment of the present invention, the chemotherapeutic agent is a platinum coordination compound. The term platinum coordination compound refers to any tumor cell growth inhibiting platinum coordination compound that provides the platinum in the form of an ion. Suitable platinum coordination compounds include, but are not limited to, cis-diamminediaquoplatinum (II)-ion; chloro (diethylenetriamine)-platinum (II) chloride; dichloro (ethylenediamine)-platinum (II); diammine (1,1-cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin; iproplatin; diammine (2-ethylmalonato)-platinum (II); ethylenediaminemalonatoplatinum (II); aqua (1,2-diaminodyclohexane)-sulfatoplatinum (II); (1,2-diaminocyclohexane) malonatoplatinum (II); (4-caroxyphthalato) (1,2-diaminocyclohexane) platinum (II); (1,2-diaminocyclohexane)-(isocitrato) platinum (II); (1,2-diaminocyclohexane) cis (pyruvato) platinum (II); (1,2-diaminocyclohexane) oxalatoplatinum (II); ormaplatin; and tetraplatin

[0745] In some embodiments, the secretin analog and the additional active agent or agents may be incorporated into a single formulation, or they may be administered separately, either simultaneously or sequentially. In one embodiment, an androgenic agent is administered prior to administration of VIP or a VIP agonist, i.e., the androgenic agent is administered as a pretreatment. In some embodiments, such a method involves administration of an androgenic agent, e.g., via oral or topical (vulvar and/or vaginal) administration, followed by topical (again, vulvar and/or vaginal) administration of VIP or a VIP agonist.

[0746] In some embodiments, the formulations herein are administered by topical application to the vulvar region and/or by vaginal drug administration. These pharmaceutical formulations may typically contain one or more pharmaceutically acceptable carriers suited to the particular type of formulation, i.e., gel, ointment, suppository, or the like. The vehicles are comprised of materials of naturally occurring or synthetic origin that do not adversely affect the active agent or other components of the formulation. Suitable carriers for use herein include water, silicone, waxes, petroleum jelly, polyethylene glycol, propylene glycol, liposomes, sugars such as mannitol and lactose, and a variety of other materials, again depending, on the specific type of formulation used. As described in Section IV, infra, dosage forms used for administration to the vulvar region and/or vagina may be used to deliver drug on an as-needed, on-demand basis, and/or throughout an extended, sustained release profile.

[0747] The pharmaceutical compositions may also include a chemical compound to enhance permeation of the active agent through the mucosal tissue, i.e., a permeation enhancer. Suitable permeation enhancers include those generally useful in conjunction with topical, transdermal or transmucosal drug delivery. Examples of suitable permeation enhancers include the following: sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C10MSO); ethers such as diethylene glycol monoethyl ether (available commercially as TRANSCUTOL (Gattefosse S. A., Saint-Priest, France) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), TWEEN (20, 40, 60, 80) (ICI Chemicals, Bridgewater, N.J.), and lecithin (U.S. Pat. No. 4,783,450); the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclaz-cycloheptan-2-one (available under the trademark AZONE (Durham Pharmaceuticals, LLC, Durham, N.C.); see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); alcohols such as ethanol, propanol, octanol, decanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid and valeric acid: fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate; polyols and esters thereof such as propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid. Mixtures of two or more enhancers may also be used.

[0748] In some embodiments, the pharmaceutical compositions may include an enzyme inhibitor, i.e., a compound effective to inhibit enzymes present in the vagina or vulvar area that could degrade or metabolize the active agent. That is, inhibitors of enzymes that decrease or eliminate the activity of the active agent may be included in the formulation so as to effectively inhibit the action of those enzymes. Such compounds include, for example, fatty acids, fatty acid esters, and NAD inhibitors.

[0749] In some embodiments, the pharmaceutical composition may be in the form of an ointment, cream, emulsion, lotion, gel, solid, solution, suspension, foam or liposomal formulation. Alternatively, the formulations may be contained within a vaginal ring (e.g., as disclosed in U.S. Pat. No. 5,188,835 to Lindskog et al., assigned to Kabi Pharmacia AB), or within a tampon, suppository, sponge, pillow, puff, or osmotic pump system; these platforms are useful solely for vaginal delivery. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery. As with other carriers or vehicles, an ointment base should be inert, stable, non irritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, supra. at pages 1034-1038, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases, emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Suitable water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight; again, reference may be had to Remington: The Science and Practice of Pharmacy for further information.

[0750] In one aspect of the invention, a method is provided for treating sexual dysfunction in a female individual comprising administering to the vagina and/or vulvar area a pharmaceutical formulation comprising a secretin family analog. In some embodiments, the secretin family analog is a vasodilator, with vasodilators selected from the group consisting of VIP and vasoactive intestinal polypeptide analogs and combinations of any of the foregoing. Any number of drug delivery platforms may be used, e.g., suppositories, ointments, creams, gels, solutions and the like. Also, one or more additional types of drugs, i.e., pharmacologically active agents may be incorporated into the pharmaceutical formulations. In other aspects of the invention, vaginal administration of a vasoactive agent as just described is used to improve vaginal muscle tone and tissue health, to enhance vaginal lubrication, or to minimize collagen misdeposition resulting from hypoxia as well as the associated lack of elasticity resulting from the collagen misdeposition.

[0751] In another embodiment of the invention, a method is provided for improving memory by administering a secretin family analog.

[0752] In another aspect of the invention, pharmaceutical compositions and dosage forms are provided for carrying out the aforementioned methods. The compositions and dosage forms contain a vasoactive agent as described above, a pharmaceutically acceptable vehicle, and, optionally, one or more additional pharmacologically active agents. The formulations contain a therapeutically effective amount of the active agent, or a therapeutically effective concentration of the active agent, i.e., a concentration that provides a therapeutically effective amount of active agent upon administration of a selected volume of composition.

[0753] The subject can be any animal, including but not necessarily limited to mammals such as a human, mouse, rat, hamster, guinea pig, rabbit, cat, dog, monkey, cow, horse, pig, and the like. In some embodiments, the subject is a human.

[0754] According to some embodiments of the invention, the formulation may be supplied as part of a kit. The kit comprise comprising an analog, wherein the analog comprises an -amino acid and at least one -amino acid. In another embodiment, the kit comprises a pharmaceutically acceptable salt of an analog with a rehydration mixture. In another embodiment, the pharmaceutically acceptable salt of an analog are in one container while the rehydration mixture is in a second container. The rehydration mixture may be supplied in dry form, to which water or other liquid solvent may be added to form a suspension or solution prior to administration. Rehydration mixtures are mixtures designed to solubilize a lyophilized, insoluble salt of the invention prior to administration of the composition to a subject takes at least one dose of a purgative. In another embodiment, the kit comprises a pharmaceutically acceptable salt in orally available pill form.

[0755] The kit may contain two or more containers, packs, or dispensers together with instructions for preparation and administration. In some embodiments, the kit comprises at least one container comprising the pharmaceutical composition or compositions described herein and a second container comprising a means for delivery of the compositions such as a syringe. In some embodiments, the kit comprises a composition comprising an analog in solution or lyophilized or dried and accompanied by a rehydration mixture. In some embodiments, the analog and rehydration mixture may be in one or more additional containers.

[0756] The compositions included in the kit may be supplied in containers of any sort such that the shelf-life of the different components are preserved, and are not adsorbed or altered by the materials of the container. For example, suitable containers include simple bottles that may be fabricated from glass, organic polymers, such as polycarbonate, polystyrene, polypropylene, polyethylene, ceramic, metal or any other material typically employed to hold reagents or food; envelopes, that may consist of foil-lined interiors, such as aluminum or an alloy. Other containers include test tubes, vials, flasks, and syringes. The containers may have two compartments that are separated by a readily removable membrane that upon removal permits the components of the compositions to mix. Removable membranes may be glass, plastic, rubber, or other inert material.

[0757] Kits may also be supplied with instructional materials. Instructions may be printed on paper or other substrates, and/or may be supplied as an electronic-readable medium, such as a floppy disc, CD-ROM, DVD-ROM, zip disc, videotape, audio tape, or other readable memory storage device. Detailed instructions may not be physically associated with the kit; instead, a user may be directed to an internet web site specified by the manufacturer or distributor of the kit, or supplied as electronic mail.

[0758] In another embodiment, a packaged kit is provided that contains the pharmaceutical formulation to be administered, i.e., a pharmaceutical formulation containing VIP analog or a for enhancing female sexual desire and responsiveness, a container (e.g., a vial, a bottle, a pouch, an envelope, a can, a tube, an atomizer, an aerosol can, etc.), optionally sealed, for housing the formulation during storage and prior to use, and instructions for carrying out drug administration in a manner effective to enhance sexual desire and responsiveness. The instructions will typically be written instructions on a package insert, a label, and/or on other components of the kit.

[0759] Depending on the type of formulation and the intended mode of administration, the kit may also include a device for administering the formulation (e.g., a transdermal delivery device). The administration device may be a dropper, a swab, a stick, or the nozzle or outlet of an atomizer or aerosol can. The formulation may be any suitable formulation as described herein. For example, the formulation may be an oral dosage form containing a unit dosage of the active agent, or a gel or ointment contained within a tube. The kit may contain multiple formulations of different dosages of the same agent. The kit may also contain multiple formulations of different active agents.

[0760] The present kits will also typically include means for packaging the individual kit components, i.e., the pharmaceutical dosage forms, the administration device (if included), and the written instructions for use. Such packaging means may take the form of a cardboard or paper box, a plastic or foil pouch, etc.

[0761] The invention relates to the use of an analog in the preparation of a medicament for treating or preventing chronic obstructive pulmonary disease, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndromeCalcinosis; Raynaud's disease: loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction due to administration of a medication that causes onset of or exacerbates symptoms of pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndromeCalcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly: Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof. In some embodiments, the invention relates to compositions comprising a secretin family analog for treatment or prevention of chronic obstructive pulmonary disease, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndromeCalcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof.

[0762] The present invention relates to inhibiting secretion of TNF- in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to inhibiting binding of VIP to a VIP receptor in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to inhibiting biological effect of GHRH in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to inhibiting chemotaxis of T cells in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to inhibiting expression of LPS in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to modulating the amount of cyclic cAMP in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to increasing the activity or expression of adenylate cyclase in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a secretin family analog and a VPAC1 antagonist. In some embodiments the analog is a secretin family analog, and a VPAC2 agonist. In some embodiments the analog is a VIP analog. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a VIPR1 agonist, and has substantially reduced selectivity or no selectivity for VIPR2 or PAC1 receptors. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a PAC1 agonist, and has substantially reduced selectivity or no selectivity for VIPR2 or VIPR1 receptors. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a VIPR2 agonist, and has substantially reduced selectivity or no selectivity for VIPR1 or PAC1 receptors. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a VIPR2 antagonist, but does not antagonize VIPR1 or PAC1 receptors. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a VIPR1 antagonist, but does not antagonize VIPR2 or PAC1 receptors. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a PAC1 antagonist, but does not antagonize VIPR2 or VIPR1 receptors. Any of the above-mentioned selective agonist or antagonists may be used in any of the method claims provided herein.

[0763] The present invention relates to modulating the amount of PLD in the nervous system of a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog.

[0764] The present invention relates to modulating the amount of antibody production of a B cell in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog.

[0765] The present invention relates to modulating the amount of antibody production of a B cell or a B cell hybridoma cell in vitro comprising treating a culture containing B cells or a hybridoma with a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog.

[0766] The present invention relates to modulating the immune response of a subject comprising administering a subject with a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog.

[0767] The present invention relates to modulating the activation of cystic fibrosis transmembrane conductance regulator (CFTR) in a subject comprising administering a subject with a composition comprising an analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog.

[0768] The present invention also relates measuring the modulation of activity of a secretin receptor molecule by measuring receptor activity comprising: [0769] a) contacting a human secretin family receptor with a secretin family analog, wherein the analog comprises an -amino acid and at least one -amino acid; [0770] b) measuring the association of the secretin family analog to the secretin receptor in the presence and absence of an unknown compound; and [0771] c) comparing the rate of association of the secretin family analog to the human secretin receptor in the presence of an unknown compound to the rate of association of the secretin analog to the human secretin receptor in the absence of an unknown compound.

[0772] The present invention also relates identifying a modulator of activity of a secretin receptor molecule by measuring receptor activity comprising: [0773] a) contacting a human secretin family receptor with a secretin family analog, wherein said analog comprises an -amino acid and at least one -amino acid; [0774] b) measuring the association of the secretin family analog to the secretin receptor in the presence and absence of an unknown compound; and [0775] c) comparing the rate of association of the secretin family analog to the human secretin receptor in the presence of an unknown compound to the rate of association of the secretin analog to the human secretin receptor in the absence of an unknown compound.

[0776] The present invention also relates to a method of measuring the modulation of activity of a human VIP receptor molecule by measuring receptor activity comprising: [0777] a) contacting a human VIP family receptor with a VIP analog, wherein the analog comprises an -amino acid and at least one -amino acid; [0778] b) measuring the association of the VIP analog to the VIP receptor in the presence and absence of an unknown compound; and [0779] c) comparing the rate of association of the VIP analog to the human VIP receptor in the presence of an unknown compound to the rate of association of the VIP analog to the human VIP receptor in the absence of an unknown compound.

[0780] The present invention also relates identifying a modulator of activity of a VIP family receptor molecule by measuring receptor activity comprising: [0781] a) contacting a human VIP family receptor with a VIP analog, wherein said analog comprises an -amino acid and at least one -amino acid; [0782] b) measuring the association of the VIP analog to the VIP receptor in the presence and absence of an unknown compound; and [0783] c) comparing the rate of association of the VIP analog to the human VIP receptor in the presence of an unknown compound to the rate of association of the VIP analog to the human VIP receptor in the absence of an unknown compound. In some embodiments, the VIP family receptor is chosen from VIPR1, VIPR2, VPAC.sub.1, VPAC.sub.2 or PAC.sub.1.

[0784] The present invention also relates identifying a modulator of activity of a VIP family receptor molecule by measuring receptor activity comprising: [0785] a) contacting a VIP family receptor with a VIP analog in a known concentration, wherein said analog comprises an -amino acid and at least one -amino acid; [0786] b) measuring the binding affinity of the VIP analog to the VIP family receptor in the presence and absence of a compound that binds to the VIP family receptor; and [0787] c) comparing the binding affinity of the VIP analog to the VIP receptor in the presence of a compound that binds to the VIP family receptor to the binding affinity of the VIP analog to the VIP receptor in the absence of a compound that binds to the VIP family receptor. In some embodiments, the VIP family receptor is chosen from VIPR1, VIPR2, VPAC.sub.1, VPAC.sub.2 or PAC.sub.1.

[0788] The invention also relates to the use of an analog with selectivity for VPAC1, PAC1, or VPAC2 in the preparation of a medicament for treating or preventing chronic obstructive pulmonary disease, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension. CREST syndromeCalcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia. Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood glucose levels, elevated blood pressure, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction due to administration of a medication that causes onset of or exacerbates symptoms of pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndromeCalcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity. Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof. In some embodiments, the invention relates to compositions comprising a secretin family analog with selectivity for VPAC1, PAC1, or VPAC2 for treatment or prevention of chronic obstructive pulmonary disease, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndromeCalcinosis; Raynaud's disease, loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type I1 diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof.

[0789] The present invention also relates to a method of treating or preventing cancer in a subject in need thereof comprising administering a VIP analog to the subject, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for the VPAC1, VPAC2, or PAC1 receptor as compared to the other receptors. In some embodiments, the cancer is chosen from the following: non-small cell lung carcinoma, small cell lung carcinoma, colorectal carcinoma, breast carcinoma, gastric carcinoma, prostate carcinoma, liver carcinoma, ductal pancreatic carcinoma, bladder carcinoma. Non-Hodgkin's lymphoma, maningioma, leiomyoma, endometrial carcinoma, pheochromocytoma, paraganglioma. The present invention also relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for the VPAC1, VPAC2, or PAC1 receptor as compared to the other receptors. In some embodiments the inflammatory disease is rheumatoid arthritis. In some embodiments, the VIP analog is administered at a therapeutically effective dose.

[0790] The present invention also relates to a method of treating or preventing cancer in a subject in need thereof comprising administering a VIP analog to the subject, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1 receptor antagonist with increased selectivity for the VPAC1 receptor. The present invention also relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1 receptor antagonist with increased selectivity for the VPAC1 receptor. In some embodiments the inflammatory disease is rheumatoid arthritis. In some embodiments, the VIP analog is administered at a therapeutically effective dose.

[0791] The present invention also relates to a method of treating or preventing small cell lung carcinoma comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for at least one VPAC1, VPAC2, or PAC1 receptor. The present invention also relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for at least one of the following: VPAC1, VPAC2, or PAC1 receptors. In some embodiments, the VIP analog is administered at a therapeutically effective dose.

[0792] The present invention also relates to a method of treating or preventing primary arterial hypertension (PAH) comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for at least one VPAC1, VPAC2, or PAC1 receptor. The present invention relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for at least one of the following: VPAC1, VPAC2, or PAC1 receptors as compared to its selectivity for the other receptors. In some embodiments, the VIP analog is administered at a therapeutically effective dose.

[0793] The present invention also relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1 receptor agonist with increased selectivity for the VPAC1 receptor. The present invention relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1 receptor agonist with increased selectivity for the VPAC1 receptor. In some embodiments the inflammatory disease is rheumatoid arthritis. In some embodiments, the VIP analog is administered at a therapeutically effective dose.

[0794] The present invention also relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity for the VPAC2 receptor. The present invention relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity for the VPAC2 receptor. In some embodiments the inflammatory disease is rheumatoid arthritis. In some embodiments, the VIP analog is administered at a therapeutically effective dose.

[0795] The present invention also relates to a method of treating or preventing chronic obstructive pulmonary disease, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension comprising administering a VIP analog with selectivity for VPAC2 to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity to VPAC2 receptor. In all methods of treatment or prevention, analogs of the present invention may be administered in therapeutically effective doses.

[0796] The present invention relates to a method of treating or preventing chronic obstructive pulmonary disease (COPD) comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1 receptor antagonist or agonist with increased selectivity for the VPAC1 receptor. The present invention relates to a method of treating or preventing COPD comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1 receptor antagonist or agonist with increased selectivity for the VPAC1 receptor. In some embodiments, the VIP analog is administered at a therapeutically effective dose via nebulizer or inhaler.

[0797] The invention also relates to a method of preventing or inhibiting activation of alveolar macrophages comprising administering a VIP analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC1 receptor antagonist or agonist with increased selectivity for the VPAC1 receptor. In some embodiments, the VIP analog is administered at a therapeutically effective dose via nebulizer or inhaler.

[0798] The present invention relates to a method of treating or preventing chronic obstructive pulmonary disease (COPD) comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity for the VPAC2 receptor. The present invention relates to a method of treating or preventing COPD comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity for the VPAC2 receptor. In some embodiments, the VIP analog is administered at a therapeutically effective dose via nebulizer or inhaler. The invention relates to a method of preventing or inhibiting activation of alveolar macrophages comprising administering a VIP analog to a subject, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity for the VPAC2 receptor. In some embodiments, the VIP analog is administered at a therapeutically effective dose via nebulizer or inhaler.

[0799] The present invention also relates to methods of identifying a selective modulator of activity of a VIP family receptor molecule by measuring receptor activity comprising: [0800] a) contacting a human VIP family receptor with a VIP analog, wherein said analog comprises an -amino acid and at least one -amino acid; [0801] b) measuring the association of the VIP analog to the VIP receptor in the presence and absence of an unknown compound; and [0802] c) comparing the rate of association of the VIP analog to the human VIP receptor in the presence of an unknown compound to the rate of association of the VIP analog to the human VIP receptor in the absence of an unknown compound.

[0803] The present invention also relates to methods of identifying a selective modulator of activity of a VIP family receptor molecule by measuring receptor activity comprising: [0804] a) contacting a first and a second VIP family receptor with a VIP analog in a known concentration, wherein said analog comprises an -amino acid and at least one -amino acid; [0805] b) measuring the rate association of the VIP analog to the first and second VIP receptors in the presence and absence of an unknown compound; and [0806] c) comparing the rate of association of the VIP analog to the first VIP receptor in the presence of an unknown compound to the rate of association of the VIP analog to the second VIP receptor in the absence of an unknown compound.

[0807] The present invention also relates to methods of identifying a selective modulator of activity of a VIP family receptor molecule by measuring receptor activity comprising: [0808] a) contacting a first and a second VIP family receptor with a VIP analog in a known concentration, wherein said analog comprises an -amino acid and at least one -amino acid; [0809] b) measuring the binding affinity of the VIP analog to the first and second VIP receptors in the presence and absence of an unknown compound; and [0810] c) comparing the binding affinity of the VIP analog to the first VIP receptor in the presence of an unknown compound to the binding affinity of the VIP analog to the second VIP receptor in the absence of an unknown compound. In some embodiments, the VIP family receptor is chosen from VIPR1, VIPR2, VPAC.sub.1, VPAC.sub.2 or PAC.sub.1.

[0811] The present invention also relates to methods of inhibiting the immune response against a transplanted organ in a subject, wherein the subject is an organ donor recipient, in some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a human experiencing organ rejection after transplantation.

[0812] In another embodiment, the present invention also relates to a method for inhibiting the growth of a tumor cell, the method comprising: contacting the tumor cell with an effective amount of a secretin family analog, wherein the secretin family analog or functional fragment thereof comprises at least one -amino acid. In some embodiments, the method comprises contacting the tumor cell with an effective amount of a combination of a chemotherapeutic agent and a secretin family analog. In some embodiments, the secretin analog is a VIP analog. Suitable chemotherapeutic agents include, but are not limited to, platinum coordination compounds, topoisomerase inhibitors, antibiotics, antimitotic alkaloids and difluoronucleosides. In some embodiments, the secretin analog is a VPAC1 antagonist with selectivity for VPAC1. In some embodiments, the tumor cell is a tumor cell derived from a breast cancer, a lung cancer, a colon cancer, a prostate cancer, or a pancreatic cancer.

[0813] In another embodiment, the present invention also relates to a method of inhibiting the growth of a tumor cell in a mammalian subject in need thereof, the method comprising, administering to the subject an effective amount of a secretin family analog or functional fragment thereof, wherein the secretin family analog or functional fragment thereof comprises at least one -amino acid. In some embodiments, the method comprises administering to the subject an effective amount of a combination of a chemotherapeutic agent and a secretin family analog. In some embodiments, the secretin analog is a VIP analog. In some embodiments, the tumor cell is a tumor cell derived from a breast cancer, a lung cancer, a colon cancer, a prostate cancer, hepatic cancer (HCC) or a pancreatic cancer. Suitable chemotherapeutic agents include, but are not limited to, platinum coordination compounds, topoisomerase inhibitors, antibiotics, antimitotic alkaloids and difluoronucleosides.

[0814] The present invention also relates to a method of treating or preventing cancer cell growth in a subject in need thereof comprising the steps of: administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one -amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to VPAC1; wherein the VIP analog is a VPAC1 antagonist; and wherein the cancer cell is a bladder, breast, colon, liver, lung, prostate, stomach, thyroid or uterine cancer cell. The present invention relates to a method of treating or preventing cancer in a subject in need thereof comprising the steps of; administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one -amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to VPAC.sub.1; wherein the VIP analog is a VPAC.sub.1 antagonist; and wherein the cancer is a bladder, breast, colon, liver, lung, prostate, stomach, thyroid, hepatocellular, or uterine cancer. In some embodiments, the cancer has been diagnosed as being malignant. In some embodiments, the subject may have an increased risk or increased susceptibility to contracting a malignant cancer.

[0815] The present invention also relates to a method of treating or preventing cancer cell growth in a subject in need thereof comprising the steps of: administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one -amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to VPAC.sub.2; wherein the VIP analog is a VPAC.sub.2 antagonist; and wherein the cancer cell is a lung, breast, stomach cancer cell. In some embodiments the cancer cell is derived from a stomach leiomyoma.

[0816] The present invention also relates to a method of treating or preventing cancer in a subject in need thereof comprising the steps of: administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one -amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to VPAC.sub.2; wherein the VIP analog is a VPAC.sub.2 antagonist; and wherein the cancer a lung, breast, stomach, or heptocellular cancer. In some embodiments, the cancer has been diagnosed as being malignant. In some embodiments, the subject may have an increased risk or increased susceptibility to contracting a malignant cancer.

[0817] The present invention also relates to a method of treating or preventing airway constriction comprising administering a VIP analog or functional fragment thereof to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC2 receptor agonist. In some embodiments, the VIP analog or functional fragment thereof has increased selectivity to VPAC2 receptor. In all methods of treatment or prevention, analogs of the present invention may be administered in therapeutically effective doses.

[0818] The present invention also relates to a method of treating or preventing asthma, comprising administering a VIP analog or functional fragment thereof to a subject in need thereof, wherein said analog comprises an -amino acid and at least one -amino acid and wherein said analog is a VPAC2 receptor agonist. In some embodiments, the VIP analog or functional fragment thereof has increased selectivity to VPAC2 receptor. In all methods of treatment or prevention, analogs of the present invention may be administered in therapeutically effective doses. In some embodiments, the VIP analog or functional fragment thereof may be administered via an inhaler or nebulizer.

[0819] The present invention also relates to a method of treating or preventing cancer cell growth in a subject in need thereof comprising the steps of: administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one -amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to PAC.sub.1: wherein the VIP analog is a PAC.sub.1 antagonist; and wherein the cancer cell is a nerve cell, adrenal cell, pituitary cell, or breast cell. The present invention also relates to a method of treating or preventing cancer in a subject in need thereof comprising the steps of: administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one -amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to PAC.sub.1; wherein the VIP analog is a PAC.sub.1 antagonist; and wherein the cancer is a glioblastoma, neuroblastoma, adrenal, pituitary, catecholamine-secreting tumors, pheochromocytomas, paragangliomas, endometrial cancers, or breast cancer. In some embodiments, the cancer has been diagnosed as being malignant. In some embodiments, the subject may have an increased risk or increased susceptibility to contracting a malignant cancer.

[0820] The invention also relates to methods of treating or preventing the aforementioned diseases using the analogs of the present invention. Any analog described in the present invention may or may not have preferred selectivity of one of its receptors versus another. The invention relates to analogs based upon the polypeptide sequences identified in Tables 1, 2, 3, and 4. All modified and unmodified variants of the sequences listed in Table 4 are contemplated as being part of the invention. For instance, the sequence of Biotin-Bombesin is listed in Table 4 as BiotinEQRLGNQWAVGHLMNH.sub.2 (SEQ ID NO:67). Not only do analogs of the claimed invention include biotinylated sequence above with an amidated methionine, but the analogs of the present invention also relate to the unmodified or modified polypeptide backbone EQRLGNQWAVGHLM as well as functional fragments thereof. In some embodiments the polypeptide analog is derived from one of the following amino acid sequences of Table 4:

TABLE-US-00033 TABLE 4 Targets from which the Analogs are derived 1. Galanin 2. neurokinin A 3. neurokinin B 4. RGD 5. Osteogenic growth peptide 6. Parathyroid hormone 7. Kallidin 8. T cell receptor peptide 9. PDGF 10. Amylin 11. Calcitonin 12. GHRH 13. Thymopoietin 14. cecropin 15. TRH 16. EPO 17. FGF 18. Stem Cell Factor 19. Gp120 20. Gp160 21. CD4 22. IGF 23. IGF receptor 24. Insulin 25. GMCSF 26. GCSF 27. MCSF 28. Kentsin 29. LAP 30. Tuftsin 31. Prolactin 32. Angiotensin II 33. Angiotensin II receptor 34. Dynorphin 35. Calcitonin 36. Cholecystokinin 37. Pepstatin 38. Bestatin 39. Leupeptin 40. Luteinizing hormone 41. Neurotensin 42. Motilin 43. TGF-alpha 44. TGF-beta 45. BMP-1 46. BMP-2 47. BMP-3 48. BMP-4 49. BMP-5 50. BMP-7 51. BMP-8 52. BMP-9 53. Bombesin 54. Enterostatin 55. Glucagon 56. GLP-1 57. Beta-Endorphin 58. ACTH 59. Alpha-MSH 60. -MSH 61. adrenal peptide E 62. alpha casein fragment 63. beta casomorphin 64. dermorphin 65. kyotorphin 66. metophamide 67. neuropeptide FF (NPFF) 68. melanocyte inhibiting factor 69. vasotocin 70. Protein kinase C 71. Amyloid 72. Amyloid fibrin 73. Calpain 74. Charybdotoxin 75. Apamin 76. Phospholipase A2 77. Phospholipase A2 receptor 78. ENaC-alpha 79. ENaC-beta 80. ENaC-gamma 81. IgG subunit 82. Endotoxin 83. ADNF 84. Adrenomedullin 85. Apelin 86. Ghrelin 87. Mastoparan (MCD peptides) 88. Melanin concentrating hormone 89. Nociceptin 90. Nocistatin 91. Orexin 92. Receptor activity modulating protein, 93. Urotensin 94. Glycoprotein IIb/IIIa inhibitors 95. c7E3 Fab 96. Apo-lipoprotein A-I 97. IL-1 98. IL-2 99. IL-3 100. IL-4 101. IL-5 102. IL-6 103. IL-7 104. IL-8 105. IL-9 106. IL-10 107. IL-12 108. IL-15 109. IL-18 110. IL-22 111. IL-23 112. IL-24 113. IL-26 114. IL-27 115. IL-28 116. brain-derived neurotrophic 117. nerve growth factor factor (BDNF) 118. neurotrophin 3 119. Corticotropin releasing factor 120. MHC I bind protei 121. P-selectin 122. LFA-1 123. LFA-3 124. EPGF 125. EPGF receptor 126. Oxytocin 127. Vasopressin 128. Defensin, alpha 1 129. Neutrophil defensin 3 130. Neutrophil defensin 4 131. Defensin-5 132. Defesin-6 133. Beta-defensin 1 134. Beta-defensin-3 135. Beta defensin 103 136. Beta-defensin 107 137. Beta-defensin 110 138. Beta-defensin 136 139. RK-1 (MPCSCKKYCDPWEVIDGSCGLFNSKYICCREK) 140. dermaseptin S4 141. magainin 1 142. magainin 2 143. magainin A 144. magainin B 145. magainin G 146. MSI-78 147. MSI-99 148. MSI-130 149. MSI-511 150. Myp30 151. Pexiganan 152. Laminin 153. YIGSR 154. Gastrin 155. Gastrin releasing peptide 156. GnRH 157. Secretin 158. Bradykinin 159. Substance P 160. RANTES 161. MCP-1 162. MIP-1alpha 163. MIP-1beta 164. PDWHF 165. CRF 166. Endothelin 167. Integrin 168. Neuropeptide Y 169. LHRH 170. Enkephilin 171. alpha-neo-endorphin, porcine 172. beta-neoendorphin 173. Ac-beta-endorphin, camel, bovine, ovine 174. Ac-beta-endorphin 1-27, camel, 175. Ac-beta-endorphin, human bovine, ovine 176. Ac-beta-endorphin 1-26, human 177. Ac-beta-endorphin 1-27, human 178. Ac-gamma-endorphin (Ac-beta- 179. acetyl-alpha-endorphin lipotropin 61-77) 180. alpha-endorphin (beta-lipotropin 61- 181. alpha-neo-endorphin analog 76) 182. alpha-neo-endorphin 1-7 183. {Arg.sup.8}-alpha-neoendorphin 1-8 184. beta-endorphin (beta-lipotropin 61- 185. beta-endorphin 1-27, camel, bovine, 91), camel, bovine, ovine ovine 186. beta-endorphin, equine 187. beta-endorphin (beta-lipotropin 61-91), human 188. beta-endorphin (1-5) + (16-31), human 189. beta-endorphin 1-26, human 190. beta-endorphin 1-27, human 191. beta-endorphin 6-31, human 192. beta-endorphin 18-31, human 193. beta-endorphin, porcine 194. beta-endorphin, rat 195. beta-lipotropin 1-10, porcine 196. beta-lipotropin 60-65 197. beta-lipotropin 61-64 198. beta-lipotropin 61-69 199. beta-lipotropin 88-91 200. biotinyl-beta-endorphin (biotinyl- 201. biocytin-beta-endorphin, human bets-lipotropin 61-91) 202. gamma-endorphin (beta-lipotropin 203. {DAla.sup.2}-alpha-neo-endorphin 1-2, amide 61-77) 204. {DAla.sup.2}-beta-lipotropin 61-69 205. {DAla.sup.2}-gamma-endorphin 206. {Des-Tyr.sup.1}-beta-endorphin, human 207. {Des-Tyr.sup.1}-gamma-endorphin (beta- lipotropin 62-77) 208. {Leu.sup.5}-beta-endorphin, camel, 209. {Met.sup.5, Lys.sup.6}-alpha-neo-endorphin 1-6 bovine, ovine 210. {Met.sup.5, Lys.sup.6, 7}-alpha-neo-endorphin 211. {Met.sup.5, Lys.sup.6, Arg.sup.7}-alpha-neo-endorphin 1-7 1-7 212. endothelin-1 (ET-1) 213. endothelin-1 {Biotin-Lys.sup.9} 214. endothelin-1 (1-15), human 215. endothelin-1 (1-15), amide, human 216. Ac-endothelin-1 (16-21), human 217. Ac-{DTrp.sup.16}-endothelin-1 (16-21), human 218. {Ala.sup.3, 11}-endothelin-1 219. {Dpr1, Asp.sup.15}-endothelin-1 220. {Ala.sup.2}-endothelin-3, human 221. {Ala.sup.18}-endothelin-1, human 222. {Asn.sup.18}-endothelin-1, human 223 224. {Res-701-1}-endothelin B receptor 225. Suc-{Glu.sup.9, Ala.sup.11, 15}-endothelin-1 (8-21), antagonist IRL-1620 226. endothelin-C-terminal hexapeptide 227. {D-Val.sup.22}-big endothelin-1 (16-38), human 228. endothelin-2 (ET-2), human, canine 229. endothelin-3 (ET-3), human, rat, porcine, rabbit 230. biotinyl-endothelin-3 (biotinyl-ET-3) 231. prepro-endothelin-1 (94-109), porcine 232. BQ-518 233. BQ-610 234. BQ-788 235. endothelium-dependent relaxation antagonist 236. FR139317 237. IRL-1038 238. JKC-30 1 239. JKC-302 240. PD-145065 241. PD-142893 242. sarafotoxin S6a (atractaspis 243. sarafotoxin S6b (atractaspis engaddensis) engaddensis) 244. sarafotoxin S6c (atractaspis 245. {Lys.sup.4}-sarafotoxin S6c engaddensis) 246. sarafotoxin S6d 247. big endothelin-1, human 248. biotinyl-big endothelin-1, human 249. big endothelin-1 (1-39), porcine 250. big endothelin-3 (22-41), amide, 251. big endothelin-1 (22-39), rat human 252. big endothelin-1 (1-39), bovine 253. big endothelin-1 (22-39), bovine 254. big endothelin-1 (19-38), human 255. big endothelin-1 (22-38), human 256. big endothelin-2, human 257. big endothelin-2 (22-37), human 258. big endothelin-3, human 259. big endothelin-1, porcine 260. big endothelin-1 (22-39) 261. big endothelin-1, rat (prepro-endothelin-1 (74-91)) 262. big endothelin-2 (1-38), human 263. big endothelin-2 (22-38), human 264. big endothelin-3, rat 265. biotinyl-big endothelin-1, human 266. {Tyr.sup.123}-prepro-endothelin (110- 267. {BQ-123} 130), amide, human 268. {BE18257B} 269. {BE-18257A}/{W-7338A} 270. {BQ-485} 271. FR139317 272. PD-151242 and TTA-386 273. {BQ-3020} {RES-701-3} and {IRL- 1720} 274. adrenorphin 275. free acid amidorphin (proenkephalin A (104-129)-NII2) 276. bovine BAM-12P 277. bovine adrenal medulla enkephalin 278. {D-Ala.sup.2, D-Leu.sup.5}-enkephalin 279. {D-Ala.sup.2, D-Met.sup.5}-enkephalin 280. {DAla.sup.2}-Leu-enkephalin 281. amide {DAla.sup.2, Leu.sup.5, Arg.sup.6}-enkephalin 282. {Des-Tyr.sup.1, DPen.sup.2, 5}-enkephalin 283. {Des-Tyr.sup.1, DPen.sup.2, Pen.sup.5}-enkephalin 284. {Des-Tyr.sup.1}-Leu-enkephalin 285. {D-Pen.sup.2, 5}-enkephalin 286. {DPen.sup.2, Pen.sup.5}-enkephalin 287. enkephalinase substrate 288. {D-Pen.sup.2, pCI-Phe.sup.4, D-Pen.sup.5}- 289. Leu-enkephalin enkephalin 290. amide biotinyl-Leu-enkephalin 291. {D-Ser.sup.2}-Leu-enkephalin-Thr (delta- receptor peptide) (DSLET) 292. {D-Thr.sup.2}-Leu-enkephalin-Thr 293. {Lys.sup.6}-Leu-enkephalin (DTLET) 294. {Met.sup.5, Arg.sup.6}-enkephalin 295. {Met.sup.5, Arg.sup.6-enkephalin-Arg {Met.sup.5, Arg.sup.6, Phe.sup.7}-enkephalin 296. amide Met-enkephalin biotinyl-Met- 297. {D-Ala.sup.2}-Met-enkephalin enkephalin 298. amide Met-enkephalin-Arg-Phe Met- 299. amide {Ala.sup.2}-Met-enkephalin enkephalin 300. amide {DMet.sup.2, Pro.sup.5}-enkephalin 301. amide {DTrp.sup.2}-Met-enkephalin, amide, metorphinamide (adrenorphin) peptide B 302. bovine 3200-Dalton adrenal peptide E 303. bovine peptide F 304. bovine preproenkephalin B 186-204 305. human spinorphin 306. bovine and thiorphan (D, L, 3- 307. platelet factor-4 (58-70) mercapto-2-benzylpropanoyl-glycine) 308. human echistatin (Echis carinatus) E 309. human echistatin (Echis carinatus) P 310. L selectin conserved region 311. fibrinopeptide A fibronectin 312. human {Tyr.sup.0}-fibrinopeptide A 313. human fibrinopeptide B 314. human {Glu.sup.1}-fibrinopeptide B 315. human {Tyr.sup.15}-fibrinopeptide B 316. human fibrinogen beta-chain 317. fibrinolysis inhibiting factor FNC/H-1 fragment of 24-42 fibrinogen binding (fibronectin heparin-binding fragment) inhibitor peptide 318. FNC/HV (fibronectin heparin- 319. heparin-binding peptide laminin penta binding fragment) peptide, amide Leu-Asp-Val-NH.sub.2 (LDV-NH.sub.2), 320. human, bovine, rat, 321. chicken necrofibrin 322. human necrofibrin, rat 323. platelet membrane glycoprotein IIB peptide 296-306 324. human galanin 1-19 325. human preprogalanin 1-30 326. human preprogalanin 65-88 327. human preprogalanin 89-123 328. human galanin 329. porcine galanin 1-16 330. porcine, rat galanin 331. rat biotinyl-galanin 332. rat preprogalanin 28-67 333. rat galanin 1-13-bradykinin 2-9 334. amide M40 335. galanin 1-13-Pro-Pro-(Ala-Leu) 2-Ala- amide C7 336. galanin 1-13-spantide-amide GMAP 337. amide GMAP 16-41 1-41 338. amide GMAP 25-41 339. amide galantide and entero-kassinin 340. gastrin 341. chicken gastric inhibitory peptide (GIP) 342. human gastrin I 343. human biotinyl-gastrin I 344. human big gastrin-1 345. human gastrin releasing peptide 346. human gastrin releasing 347. human gastric inhibitory polypeptide peptide 1-16 (GIP) 348. porcine gastrin releasing peptide 349. porcine biotinyl-gastrin releasing peptide 350. porcine gastrin releasing 351. porcine, buman little gastrin peptide 14-27 352. rat pentagastrin gastric inhibitory 353. porcine gastric inhibitory peptide 1-30, peptide 1-30 amide 354. porcine {Tyr.sup.0-gastric inhibitory 355. human and gastric inhibitory peptide, rat peptide 23-42 356. {Des-His-Glu.sup.9}-glucagon 357. exendin-4 358. glucagon 359. human biotinyl-glucagon 360. human glucagon 19-29 361. human glucagon 22-29 362. human {Des-His.sup.1-Glu.sup.9}-glucagon 363. amide glucagon-like peptide 1 364. amide glucagon-like peptide 1 365. human glucagon-like peptide 1 (7-36) glucagon-like peptide 2 366. rat biotinyl-glucagon-like peptide-1 367. (biofinyl-preproglucagon 78-107, amide) (7-36) 368. glucagon-like peptide 2 369. human intervening peptide-2 oxyntomodulin/glucagon 37 370. valosin (peptide VQY), porcine 371. Gn-RH associated peptide 25-53 372. human Gn-RH associated 373. human Gn-RH associated peptide 1-13 peptide 1-24 374. human Gn-RH associated 375. rat gonadotropin releasing peptide peptide 1-13 376. human {Tyr.sup.0}-GAP ({Tyr.sup.0}-Gn-RH 377. proopiomelanocortin (POMC) precursor Precursor Peptide 14-69) 27-52, porcine 378. TGF-d 379. TGF beta 380. TF alpha 381. TGF 34-43 382. EGF, any mammalian version 383. human acidic fibroblast growth factor basic 384. fibroblast growth factor 385. basic fibroblast growth factor 13-18 386. basic fibroblast growth 387. brain derived acidic fibroblast growth factor 120-125 factor 1-11 388. brain derived basic fibroblast growth 389. brain derived acidic fibroblast growth factor 1-24 factor 102-111 390. {Cys(Acm.sup.20, 31)}-epidermal growth 391. epidermal growth factor receptor peptide factor 20-31 985-996 392. insulin-like growth factor (IGF)-I 393. chicken IGF-I 394. rat IGF-I 395. human Des (1-3) IGF-I 396. human R3 IGF-I 397. human R3 IGF-I 398. human long R3 IGF-I 399. human adjuvant peptide analog 400. anorexigenic peptide Des (1-6) 401. IGF-II 402. human R6 IGF-II 403. human IGF-I analogue IGF 1 (24-41) 404. IGF 1 (57-70) 405. IGF I (30-41) 406. IGF II IGF II (33-40) 407. {Tyr.sup.0}-IGF II (33-40) 408. liver cell growth factor midkine 409. midkine 60-121 410. alpha-TGF 34-43 411. human alpha-TGF 34-43 412. human alpha-TGF 34-43 413. rat nerve growth factor (NGF) 414. mouse platelet-derived growth factor 415. platelet-derived growth factor 416. transforming growth factor- 417. human and rat transforming growth factor-I 418. growth hormone (hGH) 419. human growth hormone 1-43 420. human growth hormone 6-13 421. human growth hormone releasing factor 422. murine growth hormone releasing 423. bovine growth hormone releasing factor factor 424. porcine growth hormone releasing 425. rat growth hormone pro-releasing factor factor 1-29, amide 426. human biotinyl-growth hormone 427. human growth hormone releasing factor releasing factor 1-29, amide 428. human {D-Ala.sup.2}-growth hormone 429. human {N-Ac-Tyr.sup.1, D-Arg.sup.2}-GRF 1-29, releasing factor 1-29, amide amide 430. {His.sup.1, Nle.sup.27}-growth hormone 431. growth hormone releasing factor 1-37 releasing factor 1-32, amide 432. human growth hormone releasing 433. human growth hormone releasing factor factor 140 1-40, amide 434. human growth hormone releasing 435. human growth hormone releasing factor factor 30-44, amide 436. mouse growth hormone releasing 437. ovine growth hormone releasing factor factor 438. rat biotinyl-growth hormone releasing 439. rat GHRP-6 ({His.sup.1, Lys.sup.6}-GHRP) factor 440. hexarelin (growth hormone releasing 441. {D-Lys.sup.3}-GHRP-6 hexapeptide) 442. {Arg.sup.8}-GTP-binding protein 443. Gs alpha GTP-binding protein fragment fragment 445. G beta GTP-binding protein fragment 446. GAlpha GTP-binding protein fragment 447. Go Alpha GTP-binding protein 448. Gs Alpha and GTP-binding protein fragment fragment 449. G Alpha i2 450. guanylin 451. human guanylin 452. rat uroguanylin 453. human uroguanylin 454. inhibin 455. bovine inhibin 456. alpha-subunit 1-32 457. human {Tyr.sup.0}-inhibin, alpha-subunit 458. human seminal plasma inhibin-like 1-32 peptide 459. human {Tyr.sup.0}-seminal plasma 460. human inhibin inhibin-like peptide 461. alpha-subunit 1-32 462. porcine and {Tyr.sup.0}-inhibin, alpha-subunit 1-32, porcine 463. human insulin 464. porcine IGF-I 465. human insulin-like growth factor II 466. pro-insulin-like growth (69-84) factor 11 (68-102) 467. human pro-insulin-like growth factor 468. human {Asp.sup.B28}-insulin II (105-128) 469. human {Lys.sup.B28}-insulin 470. human {Leu.sup.B28}-insulin 471. human {Val.sup.B28}-insulin 472. human {Ala.sup.B28}-insulin 473. human {Asp.sup.B28, Pro.sup.B29}-insulin 474. human {Lys.sup.B28, Pro.sup.B29}-insulin 475. human {Leu.sup.B28 Pro.sup.B29}-insulin 476. human {Val.sup.B28, Pro.sup.B29}-insulin 477. human {Ala.sup.B28, Pro.sup.B29}-insulin 478. human {Gly.sup.A21}-insulin 479. human {Gly.sup.A21 Gln.sup.B30}-insulin 480. human {Ala.sup.A21}-insulin 481. human {Ala.sup.A21 Gln.sup.B30} insulin 482. human {Gln.sup.B30}-insulin 483. human {Gln.sup.B30}-insulin 484. human {Gly.sup.A21 Glu.sup.B30}-insulin 485. human {Gly.sup.A21 Gln.sup.B3 Glu.sup.B30}-insulin 486. human {Gln.sup.B3 Glu.sup.B30}-insulin 487. human B22-B30 insulin 488. human B23-B30 insulin 489. human B25-B30 insulin 490. human B26-B30 insulin 491. human B27-B30 insulin 492. human B29-B30 insulin 493. A chain of human insulin 494. B chain of human insulin 495. interleukin-1 beta 165-181, rat 496. rat IL-8 497. laminin alphal (I)-CB3 435-438, rat 498. laminin binding inhibitor 499. leptin 93-105 500. human leptin 22-56, rat 501. Tyr-leptin 26-39, human 502. leptin 116-130, amide, mouse 503. leucomyosuppressin (LMS) 504. leucopyrokinin (LPK) 505. leucokinin I 506. leucokinin II 507. leucokinin III 508. leucokinin IV 509. leucokinin VI 510. leucokinin VII 511. leucokinin VIII 512. antide Gn-RH II 513. chicken luteinizing hormone- 514. (GnRH) biotinyl-LH-RH releasing hormone (LH-RH) 515. cetrorelix (D-20761) 516. {D-Ala.sup.6}-LH-RH 517. {Gln.sup.8}-LH-RH (Chicken LH-RH) 518. {DLeu.sup.6, Val.sup.7} LH-RH 1-9 519. ethyl amide {D-Lys.sup.6}-LH-RH 520. {D-Phe.sup.2, Pro.sup.3, D-Phe.sup.6}-LH-RH 521. {DPhe.sup.2, DAla.sup.6} LH-RH 522. {Des-Gly.sup.10}-LH-RH, ethyl amide 523. {D-Ala.sup.6, Des-Gly.sup.10}-LH-RH, ethyl 524. {DTrp.sup.6}-LH-RH, ethyl amide amide 525. {D-Trp.sup.6, Des-Gly.sup.10}-LH-RH, ethyl 526. {DSer(But).sub.6, Des-Gly.sup.10}-LH-RH, ethyl amide (Deslorelin) amide ethyl amide leuprolide 527. LH-RH 4-10 528. LH-RH 7-10 LH-RH 529. free acid LH-RH 530. lanprey LH-RH 531. salmon {Lys.sup.8}-LH-RH 532. {Trp.sup.7, Leu.sup.8} LH-RH, free acid 533. {(t-Bu)DSer.sup.6, (Aza)Gly.sup.10}-LH-RH 534. {(t-Bu)DSer.sup.6, (Aza)Gly.sup.10}-LH-RH free acid 535. mastoparan 536. mas7 537. mas8 538. mas17 539. mastoparan X 540. mast cell degranulating peptide HR-1 541. mast cell degranulating peptide HR-2 542. {Ac-Cys.sup.4, DPhe.sup.7, Cys.sup.10} alpha-MSH 4-13 543. amide alpha-melanocyte stimulating 544. free acid beta-MSH, porcine hormone alpha-MSH 545. biotinyl-alpha-melanocyte 546. biotinyl-{Nle.sup.4, D-Phe.sup.7} stimulating hormone 547. alpha-melanocyte stimulating 548. {Des-Acetyl}-alpha-MSH {DPhe.sup.7}- hormone alpha-MSH, amide 549. gamma-1-MSH, amide 550. {Lys.sup.0}-gamma-1-MSH, amide 551. MSH release inhibiting factor, amide 552. {Nle.sup.4}-alpha-MSH, amide 553. {Nle.sup.4, D-Phe.sup.7}-alpha-MSH N-Acetyl 554. {Nle.sup.4, DPhe.sup.7} alpha-MSH 4-10, amide 555. beta-MSH, human 556. gamma-MSH 557. morphiceptin (beta-casomorphin 14 558. {D-Pro.sup.4}-morphiceptin amide) 559. {N-MePhe.sup.3, D-Pro.sup.4}-morphiceptin 560. motilin 561. canine motilin 562. porcine biotinyl-motilin 563. porcine {Leu.sup.13}-motilin 564. Ac-Asp-Glu achatina cardio-excitatory peptide-1 (ACEP-1) (Achatina fulica) 565. adipokinetic hormone (AKH) 566. adipokinetic hormone (Heliothis zea and (Locust) Manduca sexta) 567. alytesin Tabanus atratus 568. adipokinetic hormone (Taa-AKH) 569. adipokinetic hormone II (Locusta 570. adipokinetic hormone II (Schistocera migratoria) gregaria) 571. adipokinetic hormone III (AKH-3) 572. adipokinetic hormone G (AKH-G) (Gryllus bimaculatus) 573. allatotropin (AT) (Manduca sexta) 574. allatotropin 6-13 (Manduca sexta) 575. APGW amide (Lymnaea stagnalis) 576. buccalin 577. {Des-Ser.sup.1}-cerebellin corazonin 578. crustacean cardioactive peptide (CCAP) (American Cockroach Periplaneta americana) 579. crustacean erythrophore DF2 580. diazepam-binding inhibitor fragment (Procambarus clarkii) 581. human diazepam binding inhibitor 582. eledoisin related peptide FMRF amide fragment (ODN) (molluscan cardioexcitatory neuropeptide) 583. cerebellin 584. human granuliberin R head activator neuropeptide {His.sup.7}-corazonin 585. stick insect hypertrehalosaemic factor 586. Tabanus atratus hypotrehalosemic II hormone (Taa-HoTH) 587. rat NGE (prepro-MCH 110-128) 588. methiodide piperidine-4-sulphonic acid neuropeptide joining peptide of proopiomelanocortin 589. (POMC) 590. bovine joining peptide 591. rat KSAYMRF amide (P. redivivus) 592. kassinin kinetensin levitide 593. litorin LUQ 81-91 (Aplysia 594. LUQ 83-91 (Aplysia californica) californica) 595. myoactive peptide I (Periplanetin CC- 596. myoactive peptide II (Periplanetin CC-2) 1) 597. myomodulin neuron specific peptide 598. neuron specific enolase 404-443 599. rat neuropeptide FF neuropeptide K 600. porcine NEI (prepro-MCH 131-143) neuropeptide 601. rat NGE (prepro-MCH 110-128) 602. rat NFI (Procambarus clarkii) neuropeptide 603. PBAN-1 (Bombyx mori) 604. Hez-PBAN (Heliothis zea) 605. SCPB (cardioactive peptide from 606. secretoneurin, rat uperolein aplysia) 607. urechistachykinin I 608. urechistachykinin II 609. xenopsin-related peptide I 610. xenopsin-related peptide II 611. pedal peptide (Pep) 612. aplysia peptide F1 613. lobster, phyllomedusin 614. polistes mastoparan 615. proctolin 616. ranatensin Ro I (Lubber Grasshopper, Romalea microptera) 617. Ro II (Lubber Grasshopper, Romalea 618. SALMF amide 1 (S1) microptera) 619. SALMF amide 2 (S2) 620. SCPA 621. {Leu.sup.31, Pro.sup.34} neuropeptide Y, 622. B1BP3226 NPY antagonist Bis (31/31) human neuropeptide F (Moniezia expansa) {{Cys.sup.31, Trp.sup.32, Nva.sup.34} NPY 31-36}. neuropeptide Y, human 623. rat neuropeptide Y 1-24 amide 624. human biotinyl-neuropeptide Y 625. {D-Tyr.sup.27, 36, D-Thr.sup.32}-NPY 27-36 626. Des 10-17 (cyclo 7-21) {Cys.sup.7, 21, Pro.sup.34}- NPY C2-NPY 627. {Leu.sup.31, Pro.sup.34} neuropeptide Y 628. human neuropeptide Y 629. porcine prepro NPY 68-97 630. human N-acetyl-{Leu.sup.28, Leu.sup.31} NPY 24- 36 neuropeptide Y 631. porcine {D-Trp.sup.32}-neuropeptide Y 632. porcine {D-Trp.sup.32} NPY 1-36 633. human {Leu.sup.17, DTrp.sup.32} neuropeptide Y 634. human {Leu.sup.31, Pro.sup.34}-NPY 635. porcine NPY 2-36 636. porcine NPY 3-36 637. human NPY 3-36 638. porcine NPY 13-36 639. human NPY 13-36 640. porcine NPY 16-36 641. porcine NPY 18-36 642. porcine NPY 20-36 643. FY 22-36 NPY 26-36 644. Pro.sup.34}-NPY 1-36 645. human {Pro.sup.34}-neuropeptide Y 646. porcine PYX-1 647. PYX-2 648. T4-{NPY(33-36)}4 649. Tyr(OMe).sup.21}-neuropeptide Y, human 650. glial derived neurotropic factor (GDNF) 651. brain derived neurotropic factor 652. ciliary neurotropic factor (CNTF) (BDNF) 653. orexin A 654. human orexin B 655. rat orexin B 656. mouse orexin B 657. alpha-casein fragment 90-95 658. BAM-18P 659. casomokinin L 660. casoxin D 661. crystalline DALDA 662. dermenkephalin (deltorphin) (Phylomedusa sauvagei) 663. {D-Ala.sup.2}-deltorphin 1 664. {D-Ala.sup.2}-deltorphin II 665. endomorphin-1 666. endomorphin-2 667. kyotorphin 668. {DArg.sup.2}-kyotorphin 669. morphine tolerance peptide 670. morphine modulating peptide 671. C-terminal fragment morphine 672. nociceptin {orphanin FQ} (ORL1 modulating neuropeptide (A-18-FNH2) agonist) 673. TIPP 674. Tyr-MIF-1 675. Tyr-W-MIF-1 676. valorphin LW-hemorphin-6 677. human Leu-valorphin-Arg 678. Z-Pro-D-Leu 679. {Asu.sup.6}-oxytocin 680. oxytocin 681. biotinyl-oxytocin 682. {Thr.sup.4, Gly.sup.7}-oxytocin 683. tocinoic acid ({Ile.sup.3}-pressinoic acid) 684. PACAP 1-27, human, ovine, rat 685. PACAP (1-27)-Gly-Lys-Arg-NH.sub.2 686. human {Des-Gln.sup.16}-PACAP 6-27 687. human, ovine, rat PACAP38 688. frog PACAP27-NH.sub.2 689. human, ovine, rat biotinyl-PACAP27- 690. human, ovine, rat PACAP 6-27 NH2 691. human, ovine, rat PACAP38 692. human, ovine, rat biotinyl-PACAP38 693. human, ovine, rat PACAP 6-38 694. human, ovine, rat PACAP27-NH.sub.2 695. human, ovine, rat biotinyl-PACAP27- 696. human, ovine, rat PACAP 6-27 NH2 697. human, ovine, rat PACAP38 698. human, ovine, rat biotinyl-PACAP38 699. human, ovine, rat PACAP 6-38 700. human, ovine, rat PACAP38 16-38 701. human, ovine, rat PACAP38 31-38 702. human, ovine, rat PACAP38 31-38 703. human, ovine, rat PACAP-related 704. human peptide (PRP) 705. PACAP-related peptide (PRP), rat 706. chromostatin 707. bovine pancreastatin (hPST-52) 708. pancreastatin 24-52 (hPST-29) (chromogranin A 250-301, amide) 709. human chromogranin A 286-301, 710. human pancreastatin amide 711. porcine biotinyl-pancreastatin 712. porcine {Nle.sup.8}-pancreastatin 713. porcine {Tyr.sup.0, Nle.sup.8}-pancreastatin 714. porcine {Tyr.sup.0}-pancreastatin 715. porcine parastatin 1-19 716. porcine pancreastatin (chromogranin A 347-365) 717. chromogranin A 264-314-amide 718. rat biotinyl-pancreastatin 719. biotinyl-chromogranin A 264-314- 720. {Tyr.sup.0}-pancreastatin amide 721. rat pancreastatin 26-51 722. pancreastatin 33-49, porcine 723. pancreatic polypeptide 724. avian pancreatic polypeptide 725. human C-fragment pancreatic 726. human C-fragment pancreatic polypeptide acid polypeptide amide 727. human pancreatic polypeptide (Rana 728. ancreatic polypeptide temporaria) 729. salmon pancreatic polypeptide 730. {Asp.sup.76-parathyroid hormone 39-84 731. human {Asp.sup.76}-parathyroid hormone 732. human {Asn.sup.76}-parathyroid hormone 1- 53-84 84 733. hormone {Asn.sup.76}-parathyroid 734. human {Asn.sup.8, Leu.sup.18}-parathyroid hormone 64-84 hormone 1-34 735. human {Cys.sup.5, 28}-parathyroid 736. human hypercalcemia malignancy factor hormone 1-34 1-40 737. {Leu.sup.18}-parathyroid hormone 1-34 738. human {Lys(biotinyl).sup.13 739. {Nle.sup.8, 18, Tyr.sup.34}-parathyroid hormone 740. {Nle.sup.8, 18, Tyr.sup.34}-parathyroid hormone 3- 1-34 amide 34 amide 741. bovine {Nle.sup.8, 18, Tyr.sup.34}-parathyroid 742. human {Nle.sup.8, 18, Tyr.sup.34}-parathyroid hormone 1-34 hormone 1-34 amide 743. human {Nle.sup.8, 18, Tyr.sup.34}-parathyroid 744. human {Nle.sup.8, 18, Tyr.sup.34}-parathyroid hormone 3-34 amide hormone 7-34 amide 745. bovine {Nle.sup.8, 21, Tyr.sup.34}-parathyroid 746. rat parathyroid hormone 44-68 hormone 1-34 amide 747. human parathyroid hormone 1-34 748. bovine parathyroid hormone 3-34 749. bovine parathyroid hormone 1-31 750. human parathyroid hormone 1-34 amide 751. human parathyroid hormone 13-34 752. human parathyroid hormone 1-34 753. rat parathyroid hormone 1-38 754. human parathyroid hormone 1-44 755. human parathyroid hormone 28-48 756. human parathyroid hormone 39-68 757. human parathyroid hormone 39-84 758. human parathyroid hormone 53-84 759. human parathyroid hormone 69-84 760. human parathyroid hormone 70-84 761. human {Pro.sup.34} -peptide YY (PYY) 762. human {Tyr.sup.0}-hypercalcemia malignancy factor 1-40 763. {Tyr.sup.0}-parathyroid hormone 1-44 764. human {Tyr.sup.0}-parathyroid hormone 1-34 765. human {Tyr.sup.1}-parathyroid hormone 766. human (Tyr.sup.27}-parathyroid hormone 27- 1-34 48 767. human {Tyr.sup.34}-parathyroid hormone 768. bovine {Tyr.sup.43}-parathyroid hormone 43- 7-34 amide 68 769. human {Tyr.sup.52, Asn.sup.76}-parathyroid 770. {Tyr.sup.63}-parathyroid hormone 63-84, hormone 52-84 human 771. PTHrP ({Tyr.sup.36}-PTHrP 1-36 amide) 772. chicken hHCF-(1-34)--NH2 (humoral hypercalcemic factor) 773. human PTH-related protein 1-34 774. human biotinyl-PTH-related protein 1-34 775. human {Tyr.sup.0}-PTH-related protein 1- 776. human {Tyr.sup.34}-PTH-related protein 1-34 34 amide 777. human PTH-related protein 1-37 778. human PTH-related protein 7-34 amide 779. human PTH-related protein 38-64 780. human PTH-related protein 67-86 amide amide 781. human PTH-related protein 107-111 782. human, rat, mouse PTH-related protein 107-111 free acid 783. PTH-related protein 107-138 784. human and PTH-related protein 109-111 785. peptide T {D-Ala.sup.1}-peptide T 786. {D-Ala.sup.1}-peptide T amide 787. prolactin-releasing peptide 31 788. human prolactin-releasing peptide 20 789. human prolactin-releasing peptide 31 790. rat prolactin-releasing peptide 20 791. rat prolactin-releasing peptide 31 792. bovine prolactin-releasing peptide 20 793. human PYY 3-36 794. human biotinyl-PYY 795. human PYY 796. human {Leu.sup.31, Pro.sup.34}-PYY 797. porcine PYY 798. rat PYY 799. acetyl 800. angiotensinogen 1-14 801. human angiotensinogen 1-14 802. porcine renin substrate tetradecapeptide 803. rat {Cys.sup.8}-renin substrate 804. rat {Leu.sup.8}-renin substrate tetradecapeptide tetradecapeptide 805. rat {Val.sup.8}-renin substrate 806. canine secretin tetradecapeptide, rat. 807. chicken secretin 808. human biotinyl-secretin 809. human secretin 810. porcine secretin 811. rat secretin 812. BIM-23027 813. biotinyl-somatostatin biotinylated 814. human cortistatin 14 cortistatin 17 815. rat cortistatin 17 816. human {Tyr.sup.0}-cortistatin 17 817. human cortistatin 29 818. rat {D-Trp.sup.3}-somatostatin 819. {DTrp.sup.8, DCys.sup.14}-somatostatin 820. {DTrp.sup.8, Tyr.sup.11}-somatostatin 821. {D-Trp.sup.11}-somatostatin NTB 822. {Nle.sup.8}-somatostatin 1-28 (Naltriben) 823. octreotide (SMS 201-995) 824. prosomatostatin 1-32 825. porcine {Tyr.sup.0}-somatostatin 826. {Tyr.sup.0}-somatostatin 827. {Tyr.sup.1}-somatostatin 28 (1-14) 828. {Tyr.sup.11}-somatostatin {Tyr.sup.0} 829. {D-Trp.sup.8}-somatostatin 830. somatostatin 831. somatostatin antagonist 832. somatostatin-25 833. somatostatin-28 834. somatostatin 28 (1-12) 835. biotinyl-somatostatin-28 836. {Tyr.sup.0}-somatostatin-28 837. {Leu.sup.8, D-Trp.sup.22, Tyr.sup.25}-somatostatin- 838. biotinyl-{Leu.sup.8, D-Trp.sup.22, Tyr.sup.25}- 28 somatostatin-28 839. somatostatin-28 (1-14) 840. RC-160 841. G protein antagonist-2 Ac-{Arg.sup.6, 842. Ac-Trp-3,5-bis(trifluoromethyl)benzyl Sar.sup.9, Met(02).sup.11}-substance P 6-11 {Arg.sup.3}- ester Ac-{Arg.sup.6, Sar.sup.9, Met(O2).sup.11}-substance P substance P 843. 6-11 {D-Ala.sup.4}-substance P 844. 4-11 {Tyr.sup.6, D-Phe.sup.7, D-His.sup.9}-substance P 845. 6-11 (sendide) biotinyl-substance P 846. {Tyr.sup.8}-substance P biotinyl-NTE{Arg.sup.3}-substance P 847. {Sar.sup.9, Met(O2) .sup.11}-substance P 848. {D-Pro.sup.2, DTrp.sup.7, 9}-substance P 849. {D-Pro.sup.4, O-Trp.sup.7, 9}-substance P 850. 4-11 substance P 851. 4-11 {DTrp.sup.2, 7, 9}-substance P 852. {(Dehydro)Pro.sup.2, 4, Pro.sup.9}-substance P 853. {Dehydro-Pro.sup.4}-substance P 854. 4-11 {Glp.sup.5, (Me)Phe.sup.8, Sar.sup.9} -substance P 855. 5-11 {Glp.sup.5, Sar.sup.9}-substance P 856. 5-11 {Glp.sup.5}-substance P 857. 5-11 hepta-substance P (substance P 858. {MePhe.sup.8, Sar.sup.9}-substance P 5-11) hexa-substance P(substance P 6-11) 859. {Nle.sup.11}-substance P 860. Octa-substance P(substance P 4-11) 861. (pGlu.sup.1}-hexa-substance P 862. ({pGlu.sup.6}-substance P 6-11) 863. {pGlu.sup.6, D-Pro.sup.9}-substance P 6-11 864. {(pNO.sub.2)Phe.sup.7 Nle.sup.11}-substance P 865. penta-substance P (substance P 7-11) 866. {Pro.sup.9}-substance P GR73632 867. substance P 7-11 868. {Sar.sup.4}-substance P 4-11 869. {Sar.sup.9}-substance P septide 870. ({pGlu.sup.6, Pro.sup.9}-substance P 6-11) 871. spantide I 872. spantide II 873. cod substance P 874. trout substance P 875. antagonist substance P-Gly-Lys-Arg 876. substance P 1-4 877. substance P 1-6 878. substance P 1-7 879. substance P 1-9 880. deca-substance P (substance P 2-11) 881. nona-substance P (substance P 3-11) 882. substance P tetrapeptide (substance P 8- 11) 883. substance P tripeptide (substance P 9- 884. substance P, free acid 11) 885. substance P methyl ester 886. {Tyr.sup.8, Nle.sup.11} substance P 887. {Ala.sup.5, beta-Ala.sup.3} neurokinin A 888. 4-10 eledoisin 889. locustatachykinin I (Lom-TK-I) 890. locustatachykinin II (Lom-TK-II) (Locusta migratoria) (Locusta migratoria) 891. neurokinin A 4-10 892. neurokinin A (neuromedin L, substance K) 893. cod neurokinin A 894. biotinyl-neurokinin A (biotinyl- neuromedin L, biotinyl-substance K) 895. {Tyr.sup.0}-neurokinin A 896. {Tyr.sup.6}-substance K 897. FR64349 898. {Lys.sup.3, Gly.sup.8-(R)-gamma-lactam-Leu.sup.9}- neurokinin A 3-10 899. GR83074 900. GR87389 901. GR94800 902. {Beta-Ala.sup.8}-neurokinin A 4-10 903. {Nle.sup.10}-neurokinin A 4-10 904. {Trp.sup.7, beta-Ala.sup.8}-neurokinin A 4-10 905. neurokinin B (neuromedin K) 906. biotinyl-neurokinin B (biotinyl- neuromedin K) 907. {MePhe.sup.7}-neurokinin B 908. {Pro.sup.7}-neurokinin B 909. {Tyr.sup.0}-neurokinin B 910. neuromedin B 911. porcine biotinyl-neuromedin B 912. porcine neuromedin B-30 913. porcine neuromedin B-32 914. porcine neuromedin B 915. receptor antagonist neuromedin C 916. porcine neuromedin N 917. porcine neuromedin (U-8) 918. porcine neuromedin (U-25) 919. porcine neuromedin U 920. rat neuropeptide-gamma (gamma- preprotachykinin 72-92) 921. PG-KII phyllolitorin 922. {Leu.sup.8}-phyllolitorin (Phyllomedusa sauvagei) 923. physalaemin 924. physalaemin 1-11 925. scyliorhinin II, amide 926. dogfish senktide 927. selective neurokinin B receptor 928. {Ser.sup.2}-neuromedin C peptide 929. beta-preprotachykinin 69-91 930. human beta-preprotachykinin 111-129 931. human tachyplesin I 932. xenopsin 933. human xenopsin 25 (xenin 25) 934. biotinyl-thyrotropin-releasing hormone 935. {Glu.sup.1}-TRH 936. His-Pro-diketopiperazine 937. {3-Me-His.sup.2}-TRH 938. pGlu-Gln-Pro-amide pGlu-His {Phe.sup.2}- TRH 939. prepro TRH 53-74 940. prepro TRH 83-106 941. prepro-TRH 160-169 942. Ps4, TRH-potentiating peptide 943. prepro-TRH 178-199 944. thyrotropin-releasing hormone (TRH) 945. TRH, free acid 946. TRH--SH Pro 947. TRH precursor peptide 948. omega-agatoxin TK agelenin, (spider, Agelena opulenta) 949. apamin (honeybee, Apis mellifera) 950. calcicudine (CaC) (green mamba, Dedroaspis angusticeps) 951. calciseptine (black mamba, 952. charybdotoxin (ChTX) (scorpion, Leiurus Dendroaspis polylepis polylepis) quinquestriatus var. hebraeus) 953. chlorotoxin conotoxin GI (marine 954. conotoxin GS (marine snail, Conus snail, Conus geographus) geographus) 955. conotoxin MI (Marine Conus magus) 956. alpha-conotoxin EI, Conus ermineus 957. alpha-conotoxin SIA 958. alpha-conotoxin ImI alpha-conotoxin SI (cone snail, Conus striatus) 959. micro-conotoxin GIIIB (marine snail, 960. omega-conotoxin GVIA (marine snail, Conus geographus) Conus geographus) 961. omega-conotoxin MVIIA (Conus 962. omega-conotoxin MVIIC (Conus magus) magus) 963. omega-conotoxin SVIB, (cone snail, 964. endotoxin inhibitor geographutoxin I Conus striatus) (GTX-I) (.mu.- Conotoxin GIIIA) 965. iberiotoxin (IbTX) (scorpion, Buthus 967. kaliotoxin 1-37 kaliotoxin (scorpion, tamulus) Androctonus mauretanicus mauretanicus) 968. mast cell-degranulating peptide 969. margatoxin (MgTX) (scorpion, (MCD-peptide, peptide 401) Centruriodes Margaritatus) 970. neurotoxin NSTX-3 (Papua New 971. PLTX-II (spider, Plectreurys tristes) Guinean spider, Nephilia maculata) 972. scyllatoxin (leiurotoxin I) 973. stichodactyla sheep VIP toxin (ShK) 974. stichodactyla porcine VIP toxin 975. stichodactyla rat VIP toxin (ShK) (ShK) 976. VIP-Gly-Lys-Arg-NH.sub.2 biotinyl-PHI 977. porcine {Glp.sup.16} VIP 16-28 (biotinyl-PHI-27) 978. porcine PHI (PHI-27) 979. porcine PHI (PHI-27) 980. rat PHM-27 (PHI) 981. human prepro VIP 81-122 982. human preproVIP/PHM 111-122 983. prepro VIP/PHM 156-170 984. biotinyl-PHM-27 (biotinyl-PHI) 985. human vasoactive intestinal contractor (endothelin-beta) 986. vasoactive intestinal octacosa-peptide 987. chicken vasoactive intestinal peptide 988. guinea pig biotinyl-VIP 989. human VIP peptide 1-12 990. porcine VIP peptide 1-12 991. rat VIP peptide 1-12 992. sheep VIP peptide 1-12 993. human VIP peptide 10-28 994. porcine VIP peptide 10-28 995. rat VIP peptide 10-28 996. sheep VIP peptide 10-28 997. human VIP peptide 11-28 998. porcine VIP peptide 11-28 999. rat VIP peptide 11-28 1000. sheep VIP peptide 11-28 1001. human VIP peptide 6-28 1002. porcine VIP peptide 6-28 1003. rat VIP peptide 6-28 1004. sheep VIP peptide 6-28 1005. vasoactive intestinal peptide antagonist 1006. vasoactive intestinal peptide 1007. vasoactive intestinal peptide receptor antagonist ({Ac-Tyr.sup.1, D-Phe.sup.2}-GHRF 1-29 antagonist (4-Cl-D-Phe.sup.6, Leu.sup.17}-VIP) amide) 1008. vasoactive intestinal peptide 1009. Ala{.sup.11, 22, 28}VIP receptor binding inhibitor, L-8-K 1010. Ala{.sup.2, 8, 9, 11, 19, 22, 24, 25, 27, 28} VIP 1011. {K.sup.15, R.sup.16, L.sup.27}-VIP(1-7)/GRF(8-27) 1012. Ro25-1553 1013. Ro25-1392 1014. BAY55-9837 1015. R3P65 1016. Maxadilan 1017. PG97-269 1018. PG99-465 1019. Max.d.4. 1020. M65 (Dickson & Finlayson, 1021. {Asu.sup.1, 6, Arg.sup.8}-vasopressin Pharmacology & Therapeutics, Volume 121, Issue 3, March 2009, Pages 294-316). 1022. vasotocin 1023. {Asu.sup.1, 6, Arg.sup.8}-vasotocin 1024. {Lys.sup.8}-vasopressin 1025. {Arg.sup.8}-desamino vasopressin 1026. desglycinamide 1027. {Arg.sup.8}-vasopressin (AVP) 1028. {Arg.sup.8}-vasopressin desglycinamide 1029. biotinyl-{Arg.sup.8}-vasopressin (biotinyl- AVP) 1030. {D-Arg}-vasopressin 1031. desamino-{Arg.sup.8}-vasopressin 1032. desamino-{D-Arg.sup.8}-vasopressin 1033. {deamino-{D-3-(3-pyridyl-Ala)}- (DDAVP) {Arg.sup.8}-vasopressin 1034. {1-(beta-Mercapto-beta, beta- 1035. vasopressin metabolite neuropeptide cyclopentamethylene propionic acid), 2-(O- methyl)tyrosine}-{ Arg.sup.8}-vasopressin 1036. {pGlu.sup.4, Cys.sup.6} vasopressin 1037. {pGlu.sup.4, Cys.sup.6} {Lys.sup.8}-deamino metabolite neuropeptide vasopressin desglycinamide 1038. {Lys.sup.8}-vasopressin 1039. {Mpr.sup.1, Val.sup.4, DArg.sup.8}-vasopressin 1040. {Phe.sup.2, Ile.sup.3, Orn.sup.8}-vasopressin 1041. ({Phe.sup.2, Orn.sup.8}-vasotocin) 1042. {Arg.sup.8}-vasotocin 1043. {d(CH.sub.2).sub.5, Tyr(Me).sub.2, Orn.sup.8}-vasotocin 1044. human CMV protease substrate 1045. HCV core protein 59-68 1046. HCV NS4A 1047. protein 1840 (JT strain) 1048. HCV NS4A protein 21-34 (JT 1049. hepatitis B virus receptor binding strain) fragment 1050. hepatitis B virus pre-S region 120- 1051. {Ala.sup.127}-hepatitis B virus pre-S region 145 120-131 1052. herpes virus inhibitor 2 1053. HIV envelope protein fragment 254-274 1054. HIV gag fragment 129-135 1055. HIV substrate P 18 peptide 1056. peptide T 1057. {3,5 diiodo-Tyr.sup.7} peptide T 1058. R15K 1059. HIV-1 inhibitory peptide T20 1060. T21 1061. V3 1062. decapeptide P 18-110 1063. virus replication inhibiting peptide 1064. buforin I 1065. buforin II 1066. cecropin A 1067. cecropin B 1068. cecropin P1 1069. porcine gaegurin 2 (Rana rugosa) 1070. gaegurin 5 (Rana rugosa) 1071. indolicidin 1072. protegrin-(PG)-1 1073. magainin 1 1074. magainin 2 1075. T-22 1076. {Tyr.sup.5, 12, Lys.sup.7}-poly-phemusin II 1077. Alzheimer's disease beta-protein (SP28) peptide 1078. calpain inhibitor peptide 1079. capsase-1 inhibitor V 1080. capsase-3 1081. substrate IV caspase-1 inhibitor I 1082. cell-permeable caspase-1 inhibitor 1083. caspase-3 substrate III VI 1084. caspase-1 substrate V 1085. fluorogenic caspase-3 inhibitor I 1086. cell-permeable caspase-6 1087. ICE inhibitor III 1088. {Des-Ac, biotin}-ICE inhibitor III 1089. IL-1B converting enzyme (ICE) inhibitor II 1090. IL-1 B converting enzyme (ICE) 1091. MDL 28170 substrate IV 1092. MG-132 1093. alpha-ANP (alpha-chANP) 1094. chicken anantin ANP 1-11 1095. rat ANP 8-30 1096. frog ANP 11-30 1097. frog ANP-21 (fANP-21) 1098. frog ANP-24 (fANP-24) 1099. frog ANP-30 1100. frog ANP fragment 5-28 1101. human ANP 7-23 1102. canine ANP 7-23 1103. human ANP fragment 7-28 1104. human alpha-atrial natriuretic 1105. canine alpha-atrial natriuretic polypeptide 1-28 polypeptide 1-28 1106. human A71915 1107. canine A71915 1108. rat atrial natriuretic factor 8-33 1109. rat atrial natriuretic polypeptide 3-28 1110. human atrial natriuretic polypeptide 1111. human atrial natriuretic polypeptide 5- 4-28 27 1112. canine atrial natriuretic polypeptide 1113. human atrial natriuretic aeptide (ANP) 5-27 1114. eel atriopeptin I 1115. rat atriopeptin II 1116. rabbit atriopeptin II 1117. mouse atriopeptin II 1118. rat atriopeptin III 1119. rabbit atriopeptin III 1120. mouse atriopeptin III 1121. rat atrial natriuretic factor (rANF), 1122. rabbit atrial natriuretic factor 1123. mouse atrial natriuretic factor (rANF), (rANF), 1124. rat, auriculin A (rat ANF 126-149) 1125. auriculin B (rat ANF 126-150) 1126. beta-ANP (1-28, dimer, antiparallel) 1127. biotinyl-alpha-ANP 1-28 beta-rANF 17-48 1128. human biotinyl-atrial natriuretic 1129. canine biotinyl-atrial natriuretic factor factor (biotinyl-rANF) (biotinyl-rANF) 1130. rat cardiodilatin 1-16 1131. human C-ANF 4-23 1132. rat Des-{Cys.sup.105, Cys.sup.121}-atrial 1133. rat {Met(O).sup.12} ANP 1-28 natriuretic factor 104-126 1134. human {Mpr.sup.7, DAla.sup.9} ANP 7-28, 1135. rat prepro-ANF 104-116 amide 1136. human prepro-ANF 26-55 (proANF 1137. human prepro-ANF 56-92 (proANF 31- 1-30) 67) 1138. human prepro-ANF 104-123 1139. human {Tyr.sup.0}-atriopeptin I 1140. rat {Tyr.sup.0}-atriopeptin II 1141. rabbit {Tyr.sup.0}-atriopeptin II 1142. mouse {Tyr.sup.0}-atriopeptin II 1143. rat {Tyr.sup.0-prepro ANF 104-123} 1144. rabbit {Tyr.sup.0-prepro ANF 104-123} 1145. mouse {Tyr.sup.0-prepro ANF 104-123} 1146. human urodilatin (CDD/ANP 95- 1147. ventricular natriuretic peptide (VNP), 126) eel 1148. ventricular natriuretic peptide 1149. alpha bag cell peptide (VNP), rainbow trout 1150. alpha-bag cell peptide 1-9 1151. alpha-bag cell peptide 1-8 1152. alpba-bag cell peptide 1-7 1153. beta-bag cell factor 1154. gamma-bag cell factor 1155. alpha-s1 1156. casein 101-123 (bovine milk) 1157. biotinyl-bombesin 1158. bombesin 8-14 1159. {Leu.sup.13-psi (CH.sub.2NH)Leu.sup.14}-bombesin 1160. {D-Phe.sup.6, Des-Met.sup.14}-bombesin 1161. 6-14 ethylamide {DPhe.sup.12} bombesin 1162. {DPhe.sup.12, Leu.sup.14}-bombesin 1163. {Tyr.sup.4}-bombesin 1164. {Tyr.sup.4, DPhe.sup.12}-bombesin 1165. bone GLA protein 1166. bone GLA protein 45-49 1167. {Glu.sup.17, Gla.sup.21, 24}-osteocalcin 1-49 1168. human myclopeptide-2 (MP-2) 1169. osteocalcin 1-49 1170. human osteocalcin 37-49 1171. {Tyr.sup.38, Phe.sup.42, 46} bone GLA protein 38- 49 1172. {Ala.sup.2, 6, des-Pro.sup.3}-bradykinin 1173. bradykinin bradykinin (Bowfin. Gar) 1174. bradykinin potentiating peptide 1175. bradykinin 1-3 1176. bradykinin 1-5 1177. bradykinin 1-6 1178. bradykinin 1-7 1179. bradykinin 2-7 1180. bradykinin 2-9 1181. {DPhe.sup.7} bradykinin 1182. {Des-Arg.sup.9}-bradykinin 1183. (Des-Arg.sup.10}-Lys-bradykinin 1184. ({Des-Arg.sup.10}-kallidin) 1185. {D-NMe-Phe.sup.7}-bradykinin 1186. {Des-Arg.sup.9, Leu.sup.8}-bradykinin 1187. Lys-bradykinin (kallidin) 1188. Lys-(Des- Arg.sup.9, Leu.sup.8}-bradykinin 1189. ({Des-Arg.sup.10, Leu.sup.9}-kallidin) 1190. (Lys.sup.0-Hyp.sup.3}-bradykinin 1191. ovokinin 1192. {Lys.sup.0, Ala.sup.3}-bradykinin 1193. Met-Lys-bradykinin 1194. peptide K12 1195. bradykinin potentiating peptide 1196. {(pCl)Phe.sup.5, 8}-bradykinin 1197. T-kinin (Ile-Ser-bradykinin) 1198. {Thi..sup.5, 8, D-Phe.sup.7}-bradykinin 1199. {Tyr.sup.0}-bradykinin {Tyr.sup.5}-bradykinin 1200. {Tyr.sup.8}-bradykinin 1201. kallikrein 1202. BNP 32 1203. canine BNP-like Peptide 1204. eel BNP-32 1205. human BNP-45 1206. mouse BNP-26 1207. porcine BNP-32 1208. porcine biotinyl-BNP-32 1209. porcine BNP-32 1210. rat biotinyl-BNP-32 1211. rat BNP45 (BNP 51-95, 5K cardiac natriuretic peptide) 1212. human {Tyr.sup.0}-BNP 1-32 1213. C-peptide 1214. human {Tyr.sup.0}-C-peptide 1215. C-type natriuretic peptide 1216. chicken C-type natriuretic peptide- 1217. porcine C-type natriuretic peptide-53 22 (CNP-22) (CNP-53) 1218. rat C-type natriuretic peptide-53 1219. human C-type natriuretic peptide-53 (CNP-53) (CNP-53) 1220. porcine C-type natriuretic peptide- 1221. rat C-type natriuretic peptide-53 53 1222. (porcine) 1-29 (CNP-531-29) 1223. (rat) 1-29 (CNP-531-29) 1224. prepro-CNP 1-27 1225. rat prepro-CNP 30-50 1226. porcine vasonatrin peptide (VNP) 1227. rat vasonatrin peptide (VNP) 1228. {Tyr.sup.0}-C-type natriuretic peptide-22 1229. biotinyl-calcitonin ({Tyr.sup.0}-CNP-22) 1230. human biotinyl-calcitonin 1231. rat biotinyl-calcitonin 1232. salmon calcitonin 1233. chicken calcitonin 1234. eel calcitonin 1235. human calcitonin 1236. porcine calcitonin 1237. rat calcitonin 1238. salmon calcitonin 1-7 1239. human calcitonin 8-32 1240. salmon katacalcin (PDN-21) (C- 1241. human N-proCT (amino-terminal procalcitonin) procalcitonin cleavage peptide) 1242. acetyl-alpha-CGRP 19-37 1243. human alpha-CGRP 19-37 1244. human alpha-CGRP 23-37 1245. human biotinyl-CGRP 1246. human biotinyl-CGRP II 1247. human biotinyl-CGRP 1248. rat beta-CGRP 1249. rat biotinyl-beta-CGRP 1250. rat CGRP 1251. human calcitonin C-terminal adjacent peptide CGRP 1-19 1252. human CGRP 20-37 1253. human CGRP 8-37 1254. human CGRP II 1255. human CGRP 1256. rat CGRP 8-37 1257. rat CGRP 29-37 1258. rat CGRP 30-37 1259. rat CGRP 31-37 1260. rat CGRP 32-37 1261. rat CGRP 33-37 1262. rat CGRP 31-37 1263. rat ({Cys(Acm).sup.2, 7}-CGRP elcatonin 1264. {Tyr.sup.0}-CGRP, human {Tyr.sup.0}- 1265. human {Tyr.sup.0}-CGRP 28-37 CGRP II 1266. rat {Tyr.sup.0}-CGRP 1267. {Tyr.sup.22}-CGRP 22-37, rat 1268. human CART 55-102 1269. human CART 1270. rat CART 55-102 1271. beta-casomorphin 1272. human beta-casomorphin 1-3 1273. beta-casomorphin 1-3, amide 1274. beta-casomorphin, bovine 1275. beta-casomorphin 1-4 1276. bovine beta-casomorphin 1-5 1277. bovine beta-casomorphin 1-5, amide 1278. bovine beta-casomorphin 1-6 1279. bovine {DAla.sup.2}-beta-casomorphin 1-3, amide 1280. bovine {DAla.sup.2, Hyp.sup.4, Tyr.sup.5}-beta- 1281. {DAla.sup.2, DPro.sup.4, Tyr.sup.5}-beta-casomorphin casomorphin 1-5 amide 1-5, amide 1282. {DAla.sup.2, Tyr.sup.5}-beta-casomorphin 1- 1283. bovine {DAla.sup.2, 4, Tyr.sup.5}-beta- 5, amide casomorphin 1-5, amide 1284. bovine {DAla.sup.2, (pCl)Phe.sup.3}-beta- 1285. bovine {DAla.sup.2}-beta-casomorphin 1-4, casomorphin, amide amide 1286. bovine {DAla.sup.2}-beta-casomorphin 1287. bovine {DAla.sup.2}-beta-casomorphin 1-5, 1-5 amide 1288. bovine {DAla.sup.2, Met.sup.5}-beta- 1289. bovine {DPro.sup.2}-beta-casomorphin 1-5, casomorphin 1-5 amide 1290. bovine {DAla.sup.2}-beta-casomorphin 1291. bovine {DPro.sup.2}-beta-casomorphin 1-4, 1-6 amide 1292. {Des-Tyr.sup.1}-beta-casomorphin 1293. bovine {DAla.sup.2, 4, Tyr.sup.5}-beta- casomorphin 1-5, amide 1294. bovine {DAla.sup.2, (pCl)Phe.sup.3}-beta- 1295. bovine {DAla.sup.2}-beta-casomorphin 1-4, casomorphin, amide amide 1296. bovine (DAla.sup.2}-beta-casomorphin 1297. bovine {DAla.sup.2}-beta-casomorphin 1-5, 1-5 amide 1298. bovine {DAla.sup.2, Met.sup.5}-beta- 1299. bovine {DPro.sup.2}-beta-casomorphin 1-5, casomorphin 1-5 amide 1300. bovine {DAla.sup.2}-beta-casomorphin 1301. bovine {DPro.sup.2}-beta-casomorphin 14, 1-6 amide 1302. {Des-Tyr.sup.1}-beta-casomorphin 1303. bovine {Val.sup.3}-beta-casomorphin 1-4, amide 1304. defensin 1 (human) 1305. HNP-1 (human neutrophil peptide-1) 1306. N-formyl-Met-Leu-Phe 1307. caerulein 1308. cholecystokinin 1309. cholecystokinin-pancreozymin CCK-33 1310. human cholecystokinin octapeptide 1311. cholecystokinin octapeptide 14 (non-sulfated) (CCK 26-29, unsulfated) (CCK 26-33) 1312. cholecystokinin octapeptide (non- 1313. cholecystokinin heptapeptide sulfated) (CCK 26-33, unsulfated) (CCK 27-33) 1314. cholecystokinin tetrapeptide (CCK 1315. porcine CR 1409 30-33) CCK-33 1316. cholecystokinin antagonist CCK 1317. N-acetyl cholecystokinin, flanking peptide (unsulfated) CCK 26-30 1318. sulfated N-acetyl cholecystokinin, 1319. sulfated N-acetyl cholecystokinin, CCK 26-31 CCK 26-31 1320. non-sulfated prepro CCK fragment 1321. proglumide V-9-M 1322. colony-stimulating factor (CSF) 1323. GMCSF 1324. MCSF 1325. G-CSF 1326. astressin alpha-helical CRF 12-41 1327. biotinyl-CRF 1328. ovine biotinyl-CRF 1329. porcine CRF 1330. human CRF 1331. rat CRF 1332. bovine CRF 1333. ovine CRF 1334. porcine {Cys.sup.21}-CRF 1335. CRF antagonist human (alpha-helical CRF 9-41) 1336. CRF antagonist rat (alpha-helical 1337. CRF 6-33 CRF 9-41) 1338. human {DPro.sup.5}-CRF 1339. rat {DPro.sup.5}-CRF 1340. human {D-Phe.sup.12, Nle.sup.21, 38}-CRF 12- 1341. rat {D-Phe.sup.12, Nle.sup.21, 38}-CRF 12-41 41 1342. human eosinophilotactic peptide 1343. rat eosinophilotactic peptide {Met(0).sup.21}- {Met(0).sup.21}-CRF CRF 1344. ovine {Nle.sup.21, Tyr.sup.32}-CRF 1345. ovine prepro CRF 125-151 1346. human sauvagine 1347. frog {Tyr.sup.0}-CRF 1348. human {Tyr.sup.0}-CRF 1349. rat {Tyr.sup.0}-CRF 1350. ovine {Tyr.sup.0}-CRF 34-41 1351. ovine {Tyr.sup.0}-urocortin urocortin amide 1352. human urocortin 1353. rat urotensin I (Catostomus commersoni) 1354. urotensin II 1355. urotensin II (Rana ridibunda 1356. cortistatin 29 1357. cortistatin 29 (1-13) 1358. {Tyr.sup.0}-cortistatin 29 1359. pro-cortistatin 28-47 1360. pro-cortistatin 51-81 1361. tumor necrosis factor 1362. TNF- 1363. dermorphin 1364. dermorphin analog 1-4 1365. big dynorphin (prodynorphin 209-240) 1366. porcine biotinyl-dynorphin A 1367. {DAla.sup.2, DArg.sup.6} dynorphin A 1-13 (biotinyl-prodynorphin 209-225) 1368. porcine {D-Ala.sup.2}-dynorphin A 1369. porcine {D-Ala.sup.2}-dynorphin A amide 1370. porcine {D-Ala.sup.2}-dynorphin A 1-13, 1371. porcine {D-Ala.sup.2}-dynorphin A 1-9 amide 1372. porcine {DArg.sup.6}-dynorphin A 1-13 1373. porcine {DArg.sup.8}-dynorphin A 1-13 1374. porcine {Des-Tyr.sup.1}-dynorphin 1375. {D-Pro.sup.10}-dynorphin A 1-11 A 1-8 1376. porcine dynorphin A amide 1377. porcine dynorphin A 1-6 1378. porcine dynorphin A 1-7 1379. porcine dynorphin A 1-8 1380. porcine dynorphin A 1-9 1381. porcine dynorphin A 1-10 1382. porcine dynorphin A 1-10 amide 1383. porcine dynorphin A 1-11 1384. porcine dynorphin A 1-12 1385. porcine dynorphin A 1-13 1386. porcine dynorphin A 1-13 amide 1387. porcine DAKLI (dynorphin A-analogue kappa ligand) 1388. DAKLI-biotin 1389. ({Arg.sup.11, 13}-dynorphin A (1-13)-Gly- NH(CH.sub.2).sub.5NH-biotin) dynorphin A 2-17 1390. porcine dynorphin 2-17, amide 1391. porcine dynorphin A 2-12 1392. porcine dynorphin A 3-17, amide 1393. porcine dynorphin A 3-8 1394. porcine dynorphin A 3-13 1395. porcine dynorphin A 3-17 1396. porcine dynorphin A 7-17 1397. porcine dynorphin A 8-17 1398. porcine dynorphin A 6-17 1399. porcine dynorphin A 13-17 1400. porcine dynorphin A (prodynorphin 1401. porcine dynorphin B 1-9 209-225) 1402. {MeTyr.sup.1, MeArg.sup.7, D-Leu.sup.8}- 1404. porcine {Phe.sup.7}-dynorphin A 1-7 dynorphin 1-8 ethyl amide {(nMe)Tyr.sup.1} dynorphin A 1-13, 1403. amide 1405. porcine {Phe.sup.7}-dynorphin A 1-7, 1406. prodynorphin 228-256 (dynorphin B 29) amide (leumorphin) 1407. human ACTH 1-10 1408. ACTH 1-13 1409. human ACTH 1-16 1410. human ACTH 1-17 1411. ACTH 1-24 1412. human ACTH 4-10 1413. ACTH 4-11 1414. ACTH 6-24 1415. ACTH 7-38 1416. human ACTH 18-39 1417. human ACTH 1418. rat ACTH 12-39 1419. rat beta-cell tropin (ACTH 22-39) 1420. biotinyl-ACTH 1-24 1421. human biotinyl-ACTH 7-38 1422. human corticostatin 1423. rabbit {Met(02).sup.4, DLys.sup.8, Phe.sup.9} 1424. human {Met(0).sup.4, DLys.sup.8, Phe.sup.9} ACTH 4- ACTH 4-9 9 1425. human N-acetyl, ACTH 1-17 1426. ebiratide 1427. adrenomedullin 1428. adrenomedullin 1-52 1429. human adrenomedullin 1-12 1430. human adrenomedullin 13-52 1431. human adrenomedullin 22-52 1432. human pro-adrenomedullin 45-92 1433. human pro-adrenomedullin 153-185 1434. human adrenomedullin 1-52 1435. porcine pro-adrenomedullin (N-20) 1436. porcine adrenomedullin 1-50 1437. rat adrenomedullin 11-50 1438. rat proAM-N20 (proadrenomedullin N- terminal 20 peptide 1439. allatostatin I 1440. allatostatin II 1441. allatostatin III 1442. allatostatin IV 1443. acetyl-amylin 8-37 1444. human acetylated amylin 8-37 1445. rat AC187 amylin antagonist AC253 1446. amylin antagonist AC625 1447. amylin antagonist amylin 8-37 1448. human amylin (IAPP) 1449. cat amylin (insulinoma or islet 1450. human amylin 1-13 (diabetes-associated amyloid polypeptide(IAPP)) amylin amide peptide 1-13) 1451. human amylin 20-29 (IAPP 20-29) 1452. human AC625 amylin antagonist 1453. amylin 8-37 1454. human amylin (IAPP) 1455. cat amylin 1456. rat amylin 8-37 1457. rat biotinyl-amylin 1458. rat biotinyl-amylin amide 1459. human biotinyl-amylin amide 1460. Alzheimer's disease beta-protein 12-28 (SP17) 1461. amyloid beta-protein 25-35 1462. amyloid beta/A4-protein precursor 328- 332 1463. amyloid beta/A4 protein precursor 1464. amyloid beta-protein 1-43 amyloid beta- (APP) 319-335 protein 1-42 1465. amyloid beta-protein 1-40 1466. amyloid beta-protein 10-20 1467. amyloid beta-protein 22-35 1468. Alzheimer's disease beta-protein (SP28) 1469. beta-amyloid peptide 1-42 1470. rat beta-amyloid peptide 1-40 1471. rat beta-amyloid 1-11 1472. beta-amyloid 31-35 1473. beta-amyloid 32-35 1474. beta-amyloid 35-25 1475. beta-amyloid/A4 protein precursor 1476. beta-amyloid precursor protein 657-676 96-110 1477. beta-amyloid 1-38 1478. {Gln.sup.11}-Alzheimer's disease beta- protein 1479. {Gln.sup.11}-beta-amyloid 1-40 1480. {Gln.sup.22}-beta-amyloid 6-40 1481. non-A beta component of 1482. Alzheimer's disease amyloid -peptide Alzheimer's disease amyloid (NAC) P3, (A beta 17-40) 1483. SAP (serum amyloid P component) 1484. A-779 Ala-Pro-Gly-angiotensin II 194-204 1485. {Ile.sup.3, Val.sup.5}-angiotensin II 1486. angiotensin III 1487. antipeptide angiogenin fragment 1488. angiogenin fragment 108-123 108-122 1489. angiotensin I converting enzyme 1490. human angiotensin I converting enzyme inhibitor angiotensin I substrate angiotensin I 1-7 1491. human angiopeptin angiotensin II 1492. human angiotensin II antipeptide angiotensin II 1-4 1493. human angiotensin II 3-8 1494. human angiotensin II 4-8 1495. human angiotensin II 5-8 1496. human angiotensin III ({Des-Asp.sup.1}- angiotensin II) 1497. human angiotensin III inhibitor 1498. angiotensin-converting enzyme inhibitor ({Ile.sup.7}-angiotensin III) (Neothunnus macropterus) 1499. {Asn.sup.1, Val.sup.5}-angiotensin I 1500. goosefish {Asn.sup.1, Val.sup.5, Asn.sup.9}- angiotensin I 1501. salmon {Asn.sup.1, Val.sup.5, Gly.sup.9}- 1502. eel {Asn.sup.1, Val.sup.5}-angiotensin I 1-7 angiotensin I 1503. eel {Asn.sup.1, Val.sup.5}-angiotensin II 1504. goosefish {Asn.sup.1, Val.sup.5}-angiotensin II 1505. salmon {Asn.sup.1, Val.sup.5}-angiotensin II 1506. biotinyl-angiotensin I 1507. human biotinyl-angiotensin II 1508. human biotinyl-Ala-Ala-Ala-angiotensin II 1509. {Des-Asp.sup.1}-angiotensin I 1510. human {p-aminophenylalanine.sup.6}- angiotensin II 1511. renin substrate 1512. human preangiotensinogen 1-14 (renin (angiotensinogen 1-13) substrate tetradecapeptide) 1513. human renin substrate 1514. porcine {Sar.sup.1}-angiotensin II tetradecapeptide (angiotensinogen 1-14) 1515. {Sar.sup.1}-angiotensin II 1-7 amide 1516. {Sar.sup.1, Ala.sup.8}-angiotensin II 1517. {Sar.sup.1, Ile.sup.8}-angiotensin II {Sar.sup.1, 1518. {Sar.sup.1, Tyr(Me).sup.4}-angiotensin II Thr.sup.8}-angiotensin II (Sarmesin) 1519. {Sar.sup.1, Val.sup.5, Ala.sup.8}-angiotensin II 1520. {Sar.sup.1, Ile.sup.7)-angiotensin III 1521. synthetic tetradecapeptide renin 1522. {Val.sup.4}-angiotensin III substrate (No. 2) 1523. {Val.sup.5}-angiotensin II 1524. {Val.sup.5}-angiotensin I 1525. human {Val.sup.5}-angiotensin I 1526. bullfrog {Val.sup.5, Asn.sup.9}-angiotensin I 1527. fowl {Val.sup.5, Ser.sup.9}-angiotensin I 1528. Ac-SQNY 1529. bovine bactenecin 1530. CAP 37 (20-44) 1531. carbormethoxycarbonyl-DPro- 1532. CD36 peptide P 139-155 DPhe-OBzl 1533. CD36 peptide P 93-110 1534. cecropin A-melittin hybrid peptide 1535. {CA(1-7)M(2-9)NH.sub.2} cecropin B, 1536. CYS(Bzl)84 CD fragment 81-92 free acid 1537. defensin (human) 1538. HNP-2 1539. dermaseptin immunostimulating 1540. human lactoferricin peptide 1541. bovine lactoferricin 1542. Hepatocyte Growth Factor (HGF) 1543. HGFR

TABLE-US-00034 Lengthy table referenced here US20240374689A1-20241114-T00001 Please refer to the end of the specification for access instructions.

[0821] For purposes of interpreting Table 4, please refer to the following legend: [0822] AcAcylation [0823] p-Cl-dF=para-Chlorine, D-Phenylalanine [0824] 4cl=Chlorinated Phenylalaine [0825] .sub.dF=para-Chlorine, D-Phenylalanine [0826] .sub.dR=D-Arginine [0827] .sub.dY=D-Tyrosine [0828] .sub.dA=D-Alanine [0829] .sub.hR=homoarginine [0830] pY=Phosphoroylated Tyrosine [0831] pS=Phosphoroylated Serine [0832] pE=Pyroglutamic acid [0833] PEG=Polyetheythlene Glycol [0834] PEG{number kD}=Polyetheythlene Glycol with a molecular weight near {number} in kilodaltons. [0835] Nle=Noraleucine [0836] N.sub.le=Noraleucine [0837] Y.sub.m=methoxy-tyrosine. [0838] Y.sub.M=methoxy-tyrosine. [0839] K.sub.m=methalyated-lysine. [0840] Aib=-aminoisobutyric acid [0841] Abu=ALPHA-AMINOBUTYRIC ACID [0842] Gab=-aminobutyric acid; [0843] Dip=,-diphenyl-L-alanine; [0844] *=indicates cyclization between residues (lactam ring) [0845] dHis=D-His [0846] w=D-Tryptophan [0847] Dnp=di-nitro-phenol [0848] Mca=methoxycoumarin 4 acetic acid [0849] Sar=sarcosine [0850] Sta=statine [0851] Ste=Stearyl [0852] Pyr=pyroglutamic acid [0853] Fam=carboxyfluoresceine [0854] LC=(NH.sub.2(CH.sub.2).sub.5CO) [0855] TAMRA=carboxytetramethylrhodamine [0856] T*=N-acetyl galactosamine labeled Thr [0857] NH.sub.2 amidation of carboxy terminus [0858] Orn=omithine [0859] K(W)=Trp residue which is coupled to the side chain of a Lys [0860] Y(OMe)=methylated Tyrosine [0861] Cit=citrulline [0862] C6=hexanoyl [0863] Nva=Norvaline
In some embodiments, analogs of the present invention (including any polypeptide sequence identified in Tables 1, 2, 3, or 4) are either be N-terminal acylated or an N-terminal free-amine. In some embodiments, analogs of the present invention are either a c-terminal amine or a c-terminal acid. These terminal groups do not preclude additional solubilization and/or stabilization attachments such a poly-ethylene glycol.

[0864] The following examples are provided to describe the invention in greater detail. They are intended to illustrate, not to limit, the invention. Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety.

EXAMPLES

Example 1: Chemical Scheme to Synthesize Helical Polypeptides

[0865] This example describes how the polypeptide analogs may be designed prior to manufacture. The sequence of human vasoactive intestinal peptide (VIP) is given below, using the standard one-letter code for proteinogenic amino acid residues. For purposes of interpretation position 1 of the sequence below is the N-terminal histidine. Each amino acid residue is numbered in sequence from the N-terminal end of the polypeptide to the C-terminal. Therefore, position 28 of the sequence below is the C-terminal asparagine.

TABLE-US-00035 (SEQIDNO:10) HSDAVFTDNYTRLRKQMAVKKYLNSILN

[0866] Design A. A family of the following VIP analogues were synthesized each containing at least two alpha to .sup.3 replacements per seven -amino acid residues of VIP:

TABLE-US-00036 (SEQIDNO:1342) HSDAVFTDNYTRLRKQLAVKKYLNAILN (SEQIDNO:1342) HSDAVFTDNYTRLRKQLAVKKYLNAILN (SEQIDNO:1342) HSDAVFTDNYTRLRKQLAVKKYLNAILN (SEQIDNO:1342) HSDAVFTDNYTRLRKQLAVKKYLNAILN (SEQIDNO:1343) HSDAVFTDNYTRLZKQLXVKKYLNXILN (SEQIDNO:1344) HSDAVFTDNYTRLZKQLXVKZYLNXILN (SEQIDNO:1345) HSDAVFTDNYXRLZKQLXVKKYLNXILN (SEQIDNO:1346) HSDAVFTDNYXRLZKQLXVKZYLNXILN (SEQIDNO:1347) HSDAVFTDNYTRLRZQLXVKKYLNXILN (SEQIDNO:1348) HSDAVFTDNYXRLRZQLXVKKYLNXILN (SEQIDNO:1349) HSDAVFTDNYTRLZKQLAVKZYLXAILN (SEQIDNO:1350) HSDAVFTDNYTRLZKQXAVKKYLXAILN (SEQIDNO:1351) HSDAVFTDNYTRLZKQXAVKZYLXAILN

[0867] In each of sequences above, at least one -3 residue has been replaced by a cyclic or heterocyclic residue. In some embodiments, based upon the above sequences, X=ACPC, Z=APC; uncharged side chains replaced by ACPC, basic side chains replaced by APC. Protected .sup.3-amino acids): the positions indicated with bold and underlined letters are those at which -to-3 replacement has occurred. Reagents for /-Peptide synthesis (Fmoc on the backbone nitrogen and appropriate protecting groups on side chains, when necessary) will be obtained from commercial suppliers or prepared via reported methods in Home et. al. PNAS, Sep. 1, 2009, vol. 106, no. 35, 14751-14756. Each 3-amino acid residue bore the side chain of the -amino acid found at that site in the VIP sequence. Thus, for example, analogues that contain a -residue at position 10 of the sequence had a 3-homotyrosine at this position, in place of the tyrosine at position 10 of VIP itself. The analogues shown above were synthesized manually by microwave-assisted Fmoc solid phase peptide synthesis on NovaSyn TGR resin. Coupling steps were carried out with a three-fold excess of the appropriate protected - or -amino acid, using HBTU and HOBt to mediate amide bond formation. Piperidine was used for Fmoc deprotection steps. Each peptide was cleaved from resin by treatment with 94:2.5:2.5 TFA/H2O/triisopropylsilane, precipitated by addition of cold ethyl ether, and purified by reverse phase HPLC on a prep-C18 column using gradients between 0.1% TFA in water and 0.1% TFA in acetonitrile. The identity and purity of the HSDAVFTDNYXRLZKQLXVKZYLNXILN (Compound 8) was determined by MALDI-TOF-MS and analytical HPLC, respectively. Data from the MALDI-TOF-MS analysis showing the expected mass values is shown in FIG. 1. The sample was examined by MALDI-TOF to determine molecular weight. A 50:50 mixture of acetonitrile/water was used to dissolve alpha cyano-cinnamic acid matrix together with a 5 uM aliquot of sample. The sample was dried on an appropriate sample plate and examined in positive, reflectron mode with a 25 KV voltage, 100 mV electronic gain and a laser frequency of 60 Hz. The resulting spectra demonstrated an observed mass (mass/charge, m/z) of 3351.4 which compares favorably with the expected mass of 3350.79. In addition, the observed doubly charged species, (Z=2) of 1675.684 was also observed and compares favorably to the expected +2 peak of 1675.395.

[0868] Design B (prophetic). A family of analogues will be prepared, each containing two alpha to .sup.3 replacements per seven -amino acid residues of VIP. Each .sup.3-amino acid residue will bear the side chain of the -amino acid found at that site in the VIP sequence. Thus, for example, analogues that contain a -residue at position 4 of the sequence will have .sup.3-homoalanine at this position, in place of the alanine at position 4 of VIP itself. The analogues to be prepared are shown below: the positions indicated with bold and underlined letters are those at which -to-.sup.3 replacement has occurred.

TABLE-US-00037 (SEQIDNO:10) HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQIDNO:10) HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQIDNO:10) HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQIDNO:10) HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQIDNO:10) HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQIDNO:10) HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQIDNO:10) HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQIDNO:1342) HSDAVFTDNYTRLRKQLAVKKYLNAILN (SEQIDNO:1342) HSDAVFTDNYTRLRKQLAVKKYLNAILN (SEQIDNO:1342) HSDAVFTDNYTRLRKQLAVKKYLNAILN (SEQIDNO:1344) HSDAVFTDNYTRLZKQLXVKZYLNXILN (SEQIDNO:1345) HSDAVFTDNYXRLZKQLXVKKYLNXILN (SEQIDNO:1346) HSDAVFTDNYXRLZKQLXVKZYLNXILN (SEQIDNO:1349) HSDAVFTDNYTRLZKQLAVKZYLXAILN (SEQIDNO:1350) HSDAVFTDNYTRLZKQXAVKKYLXAILN (SEQIDNO:1351) HSDAVFTDNYTRLZKQXAVKZYLXAILN (SEQIDNO:1367) HSDAVFTDNYXRLRKQLAVKKYLNAILN (SEQIDNO:1368) HSDAVFTDNYTRLZKQLAVKKYLNAILN (SEQIDNO:1369) HSDAVFTDNYTRLRKQLXVKKYLNAILN (SEQIDNO:1370) HSDAVFTDNYTRLRKQLAVKZYLNAILN (SEQIDNO:1371) HSDAVFTDNYTRLRKQLAVKKYLNXILN (SEQIDNO:1346) HSDAVFTDNYXRLZKQLXVKZYLNXILN (SEQIDNO:1372) HSDAVFTDNYTRLRRQLAARRYLNAIKK

[0869] In each of sequences above, at least one 0-3 residue has been replaced by a cyclic or heterocyclic residue. In some embodiments, based upon the above sequences, X=ACPC. Z=APC: uncharged side chains replaced by ACPC, basic side chains replaced by APC, Protected .sup.3-amino acids). /-Peptide synthesis (Fmoc on the backbone nitrogen and appropriate protecting groups on side chains, when necessary) will be obtained from commercial suppliers or prepared via reported methods. Each .sup.3-peptide will be prepared manually by microwave-assisted Fmoc solid phase peptide synthesis on NovaSyn TGR resin. Coupling steps will be carried out with a three-fold excess of the appropriate protected - or .sup.3-amino acid, using HBTU and HOBt to mediate amide bond formation. Piperidine will be used for Fmoc deprotection steps. Each peptide will be cleaved from resin by treatment with 94:2.5:2.5:1 TFA/H2O/ethanedithiol/triisopropylsilane, precipitated by addition of cold ethyl ether, and purified by reverse phase HPLC on a prep-C18 column using gradients between 0.1% TFA in water and 0.1% TFA in acetonitrile. The identity and purity of the final products will be determined by MALDI-TOF-MS and analytical HPLC respectively.

[0870] Design and Synthesis of VPAC1-selective VIP analogues. VPAC1-selective VIP analogues will be synthesized in accordance with the protocol outlined above. The predicted -helical portion of VIP polypeptide is from positions 10-28 which are depicted in FIG. 6. The amino acid residues will be substituted with non-natural amino acid residues. .sup.3-amino acid residue positions indicated in bold and underline, and, on the helical wheel diagrams shown in FIG. 7 (which correspond to the positions on the diagram depicted in FIG. 6), .sup.3-amino acid residue positions indicated as solid dots. In some species, the non-polar .sup.3-residues (e.g., .sup.3-hAla, .sup.3-hVal) will be replaced by (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), while basic .sup.3-residues (such as .sup.3-hLys or .sup.3-hArg) will be replaced by APC:

TABLE-US-00038 (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:435) HSDAVFTDNYARLRKQMAVKKALNSILA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA
/-Peptide analogues below will be synthesized:

TABLE-US-00039 (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA (SEQIDNO:434) HADAVFTAAYARLRKQMAAKKALAAIAA

Designs Targeted Toward the VPAC2 Receptor-Selective Analogues.

[0871] VPAC1-selective VIP analogues will be synthesized in accordance with the protocol outlined above. -helical portion of VIP polypeptide sequences will be substituted with non-natural amino acid residues where .sup.3-amino acid residue positions indicated in bold and underlined. In some species, the non-polar .sup.3-residues (e.g., .sup.3-hAla, .sup.3-hVal) will be replaced by (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), while basic .sup.3-homo residues (such as .sup.3-hLys or .sup.3-hArg) will be replaced by the pyrrolidine analogue of (S,S)-ACPC, which is designated APC (Note: Ac=acetyl: N.sup.le=norleucine: K*---D* indicates that the side chains of these two residues may be linked via an amide bond.)

[0872] a/b-Peptide analogues will be synthesized:

TABLE-US-00040 (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1373) Ac-HSDAVFTENYTKLRKQN.sup.leAVKK*YLND*LKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT (SEQIDNO:1374) Ac-HSDAVFTENYTKLRKRN.sup.leAAKN.sup.leYLNNLKKGGT
wherein Ac=acetyl; N.sup.le=norleucine; K*---D* indicates that the side chains of these two residues may be linked via an amide bond.

[0873] One purpose of this study will be to demonstrate that the analogs of the application may be designed to increase the half-life of the polypeptide as compared to the half-life of the naturally encoded protein by introducing non-natural amino acid analogs that are resistant to degradation and/or induce an equivalent or increased bioactivity as compared to the naturally encoded polypeptide sequence upon which the analog is based or derived through the possible incorporation of conformationally-constrained residues.

Example 2: Structural Analysis of Helical Polypeptides

Structural Analysis A

[0874] This example describes how a VIP analogue was characterized after chemical synthesis and purification.

[0875] Circular Dichroism Spectroscopy. Circular dichroism measurements were carried out on a Aviv 202SF Circular Dichroism Spectrophotometer (FIG. 2). Samples of each peptide were prepared with a determined UV absorbance in the range of 0.1-1.0 at 280 nm in a phosphate-buffered solution at a pH of 7.5 for a final concentration of about 14 M. The analogue was transferred a 0.1 cm path length cell for measurement. Wavelength scans were carried out with a 1 nm step and 8 sec averaging time, in quadruplicate at 23 C. All spectra were corrected against buffer measured in the same cell.

[0876] The data of FIG. 2 demonstrate the expected circular dichroism measurements of an alpha-beta hybrid polypeptide. The results are consistent with previously published data of an alpha-beta hybrid polypeptide that has similar backbone length and similar beta-amino acid percent and similar sample concentration.

Structural Analysis B (Prophetic)

[0877] This prophetic example describes how the polypeptide analogs of this invention may be characterized after manufacture through structural conformational assays such as circular dichrosim (CD) and Nuclear magnetic resonance (NMR).

[0878] Circular Dichroism Spectroscopy. Circular dichroism measurements will be carried out on an Aviv 202SF Circular Dichroism Spectrophotometer. Samples of each peptide will be prepared with a determined UV absorbance in the range of 0.1-1.0 at 280 nm in a pH buffered solution. Spectra will be recorded in a 1 mm cell with a step size of 1 nm and an averaging time of 5 sec. All spectra will be background corrected against buffer measured in the same cell. Thermal melts will be carried out in 1-degree increments with an equilibration time of 2 min between each temperature change. Thermal unfolding data will be fit to a simple two state folding model Shortle, D. Meeker, A. K. Freire, E. Biochemistry 1988, 27, 4761-4768) using GraphPad Prism.

[0879] Nuclear Magnetic Resonance: Structure elucidation of the proposed analogs can also be accomplished based on analyses of heteronuclear NMR experimental data. Global backbone structural information complementing the local structure information provided by backbone chemical-shift assignments can be obtained from nuclear Overhauser effect spectroscopy (NOESY) which yield atomic distance constraints together with residual dipolar coupling (RDC) experiments which provide orientation restraint information. Together, these techniques can be used to provide valuable structural information regarding the positioning and alignment of the amino acids within the polypeptide analog. Samples of each peptide or analog will be prepared with a determined UV absorbance in the range of 0.1-1.0 at 280 nm in an appropriate pH buffered solution. Each preparation will then be used to conduct NOESY and RDC experiments using standard NMR equipment (i.e. Bruker NMR) and data analysis software (i.e. Talos+). Further structural insight can be ascertained by comparing the results of NMR experiments in the presence and absence of the intended binding partner.

[0880] One purpose of this study is to evidence that the conformation of the analog is structurally constrained and that certain non-natural amino acids have been incorporated in the synthesized peptide in their predicted location along a longitudinal axis of the polypeptide.

Example 3: Stability Analysis of Helical Polypeptides in Solution (Prophetic)

[0881] This prophetic example describes how the solubility of the polypeptide analogs of this invention may be characterized after manufacture through assays such as a protease resistance assay.

[0882] In Vitro Stability Assay: Stock solutions of the both the naturally occurring peptides as well as peptide analogs will be prepared at a concentration of 25 M (based on UV absorbance) in appropriate buffer. A solution of proteinase K in addition to other common animal proteases (i.e. Cathepsins and Trypsins) will be prepared at an appropriate concentration of 50 g/mL (based on weight to volume) in appropriate buffer. For each proteolysis reaction, 40 L of peptide stock will be mixed with 10 L of protease stock. The reaction will be allowed to proceed at room temperature and quenched at the desired time point by addition of 100 L of 1% TFA in water. 125 L of the resulting quenched reaction will be injected onto an analytical reverse phase HPLC, and the amount of starting peptide present quantified by integration of the appropriate chromatogram peak via absorbance at either 220 or 280 nm. Duplicate reactions will be run for each time point. Half-lives will be determined by fitting time dependent peptide concentration to an exponential decay using GraphPad Prism. Samples for some time points will be analyzed by MALDI-MS, and the products observed will be used to identify amide bonds cleaved in the course of the reaction. The relative stability enhancement will be determined through the comparison of the various analogs with its naturally occurring peptide counterpart.

[0883] In Vivo Stability Assay: To investigate the in vivo stability of the analogs, both the naturally occurring peptide as well as the analogs will be administered to mice and/or rats by IV, IP, SC, PO and/or inhalation routes at concentrations ranging from 0.001 to 50 mg/kg and blood specimens withdrawn at 0 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hr, 4 hrs, 8 hrs, 12 hrs, 24 hrs and 48 hrs post-injection. Levels of intact compound in 25 L of fresh serum will then be injected onto an analytical reverse phase HPLC, and the amount of starting peptide present quantified by integration of the appropriate chromatogram peak via absorbance at either 220 or 280 nm or other means of measuring the presence or absence of fully intact analog as described herein. The expected molecular weights will be determined through either LC/MS or MALDI/TOF analysis. This analysis technique also allows the examination of the in-vivo metabolites by determination of fragment molecular weights. The relative stability enhancement will be determined through the comparison of the various analogs with its naturally occurring peptide counterpart.

[0884] Cassette Dosing and Serum Analysis for Determination of Bioavailability: The oral bioavailability will be screened by dosing rats with a cassette, i.e. mixture of 1-5 analogs per dosing solution. The cassette includes 1-5 test articles and a standard compound, for a total dose of 10 mg/kg. Each compound/test article will be converted to an appropriate salt form and dissolved in water at 2 mg/mL The cassette will be prepared by mixing equal volumes of each of the two-six solutions. The cassette dosing solution should be mixed well and then the pH should be adjusted to 7.5-9. The dosing solution should be prepared the day before the study and stirred overnight at room temperature.

[0885] Male Sprague Dawley (SD) rats, 6-8 weeks old, will be used in this screen. Rats will be quarantined for at least one day and have continuous access to food and water. On the night before the administration of the cassette, the rats will be fasted for approximately 16 h.

[0886] Four SD rats will be assigned in each cassette. A single dose of the dosing solution will be administered orally to each rat. The dosing volume (5 mL/kg) and time will then be recorded and rats will be fed 2 h after dosing.

[0887] Blood samples will be collected via cardiac puncture at the following time points: 4 h, 8 h and 12 h. Immediately prior to blood collection, rats will be anesthetized with CO.sub.2 gas within 10-20 seconds. After the 12-hour samples are collected, the rats will be euthanized via CO.sub.2 asphyxiation followed by cervical dislocation.

[0888] Blood samples will be kept in heparinized microtainer tubes under subambient temperature (4 C.) before they are processed. Blood samples will be centrifuged (10,000 rpm for 5 minutes) and plasma samples should be removed and stored in a 20 C. freezer until analyzed for analog levels. Analog levels in the plasma will be analyzed using the following protocol for direct plasma precipitation.

[0889] The in vivo plasma samples will be prepared in a 1.5 mL 96-well plate, by adding, in order, 100 L of the test plasma, 150 l of methanol, followed by vortexing for 10-20 seconds. 150 L of 0.05 ng/L of an Internal Standard in acetonitrile shall be added and vortexed for 30 seconds.

[0890] The standard curve samples were prepared in a 1.5 mL 96-well plate, by adding, in order, 100 L of control mouse plasma, followed by 150 L of methanol and vortexing for 10-20 seconds. 150 L of 0.05 ng/L of an Internal Standard in acetonitrile shall be added and vortexed for 30 seconds. The samples will then be spiked with 0-200 ng (10 concentrations) of the compound of interest in 50% methanol to obtain a standard curve range of 0.5 ng/mL to 2,000 ng/mL. Again, the sample is vortexed for 30 seconds.

[0891] The samples should then be centrifuged for 20-30 minutes at 3,000 rpm in an Eppendorf microfuge before 80-90% of supernatant is transferred into a clean 96-well plate. The organic solvent will then be evaporated until the samples are dry (under N.sub.2 at 40 C./30-60 min. (ZymarkTurbovap)).

[0892] The residue will then be dissolved in 200-600 L mobile phase (50% CH.sub.3OH/0.1% TFA). LC/MS/MS will then be run using a mass spectrometer with pump. Dataanalysis and quantification accomplished using PE-Sciex Analyst (v 1.1). A 5-50 l sample volume will be injected onto a reverse phase column (Keystone 2.020 mm, 5 m, PN: 8823025-701) using a mobile phase of 25% CH.sub.3OH, 0.1% TFA-100% CH.sub.30H, 0.1% TFA. The run time will be about 8 minutes at a flow rate of about 300 L/minutes. The Area Under the Curve (AUC) will be calculated using the linear trapezoidal rule from t=0 to the last plasma concentration sampling time tx (see Handbook of Basic Pharmacokinetics, Wolfgang A. Ritschel and Gregory L. Kearns, 5th ed, 1999). AUC.sup.0-tx=.SIGMA..sup.0-n((C.sub.n+C.sub.n+1)/2))(t.sub.n+1t.sub.n) {in (g/mL)h}

[0893] In the case of the cassette dosing paradigm, samples at 4, 8 and 12 h post extravascular dosing, the AUC will be calculated from t=0 to t=12 h. Each of the analogs above when tested in this assay should provide for an AUC of at least 5 gh/mL when normalized for administration at a 10 mg/kg dose.

[0894] One purpose of this study is to evidence that the analog is more resistant to peptidases as compared to the resistance of similarly-structured, naturally occurring polypeptides upon which the structure of the analog is based or derived. The results may show that, when treated with the same proteolytic enzymes, the analogs of the invention will resist degradation and have longer half-lives than similarly-structured, naturally occurring polypeptides upon which the structure of the analog is based or derived.

Example 4: Functional Analysis of Helical Polypeptides

[0895] This prophetic example describes the function of polypeptide analogs of this invention may be characterized after manufacture through assays that measure bioactivity of the analogs when exposed to tissue culture or when administered to an animal model of one of the following human disease states: COPD, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndromeCalcinosis; Raynaud's disease: loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, elevated blood pressure levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction.

[0896] In Vitro Binding Assay 1: A VIP analogue (Compound 8) in appropriate phosphate buffer was at pH of 7.5 was exposed to a functional assay in parallel with wild-type VIP proteins, cAMP Hunter cell lines expressing VIPR1 and VIPR2 were expanded from freezer stocks in T25 flasks according to standard procedures and maintained in selective growth media prior to assay. Once it was established that the cells were healthy and growing normally, cells were passaged from flasks using cell dissociation reagent buffer and seeded into white walled clear bottom 384-well microplates for compound profiling. For profiling, cells were seeded at a density of 10,000 cells per well in a total volume of 20 L and were allowed to adhere and recover overnight prior to compound addition, cAMP modulation was determined using the DiscoveRx HitHunter cAMP XS+ assay.

[0897] For profiling compound in agonist mode, the cells were incubated in the presence of compound at 37 C. for 30 minutes. Cells expressing both VIPR1 and VIPR2 were exposed to serial dilutions of wild-type VIP and separate samples of the same type of cells were exposed to serial dilutions of VIP analogue (Compound 8) to determine EC.sub.50 values of the analogue as compared to wild-type VIP (FIG. 3). After appropriate compound incubation, assay signal was generated through incubation with DiscoverX lysis cocktail according to the manufacturers standard protocol. Dose curves were plotted using GraphPad Prism or Activity Base. Percentage activity is calculated using the following formula:

% Activity=100%(mean RLU of test samplemean RLU of vehicle control)/(mean RLU of MAX controlmean RLU of vehicle control).

[0898] Data from FIG. 3 demonstrates that Compound 8 was able to fully activate VIPR1, but not activate VIPR2. The following EC.sub.50 values were measured (peptide concentration for 50% VIPR1 activation): [0899] VIP: 0.4 nM [0900] Compound 8: 28 nM
Compound 8 apparently does not interact substantially with VIPR2. Raw fluorescence data of measurements taken from the agonist binding experiments performed in triplicate appears below in Table 5.

TABLE-US-00041 TABLE 5 VIP Analogue Agonist EC.sub.50 determination. Compound ID VIP Compound ID 8 [Starting] 0.50 M Readout cAMP [Starting] 0.50 M Readout cAMP Cell Line VIPR1 Mode Agonist Cell Line VIPR1 Mode Agonist [Compound] (M) Mean % CV % Activity [Compound] (M) Mean % CV % Activity 5.00E07M 7.0% 100.0% 5.00E07M 1.5% E07M 11.3% 1.00E07M 3.6% E08M 2.0% 5.00E08M 1.7% E08M 5.2% 1.00E08M 3.9% E09M 0.4% 5.00E09M 1.2% E09M 1.3% 1.00E09M 1.4% E10M 4.4% 5.00E10M 2.2% E10M 1.00E10M 2.9% E11M 1.00E11M 1.5% E11M 0.0 0.0% 2.0% 1.00E12M 5.2% 1.7% 0.00E+00M 0.0% 0.00E+00M 3.3% 0.0% 11.4 4.5% Compound ID 8 [Starting] 0.50 M Readout cAMP Cell Line VIPR2 Mode Agonist [Compound] (M) Mean % CV % Activity 5.00E07M 1.9% 1.00E07M 17.1% 0.4% 5.00E08M 0.8% 1.00E08M 0.9% 1.2% 5.00E09M 15.4% 0.1% 1.00E09M 0.4% 5.00E10M 1.5% 1.00E10M 1.1% 1.00E11M 0.8% 1.00E12M 6.7% 0.4% 0.00E+00M 0.0% 1.2 7.7% indicates data missing or illegible when filed

[0901] In Vitro Competition Assay 1: Antagonist Dose curves were calculated by first providing a VIP analogue (Compound 8) in appropriate phosphate buffer at pH of 7.5. Cells expressing both VIPR1 and VIPR2 were exposed to serial dilutions of VIP analogue (Compound 8) in combination with wild-type VIP to determine the level of inhibition of VIPR1 and VIPR2 (FIG. 4). cAMP Hunter cell lines expressing VIPR1 and VIPR2 were expanded from freezer stocks in T25 flasks according to standard procedures and maintained in selective growth media prior to assay. For profiling, cells were seeded according to manufacturer protocol using a cAMP modulation assay with the DiscoveRx HitHunter cAMP XS+ assay.

[0902] Before treatment of the cells, media was aspirated from cells and replaced with DiscoverX antibody solution according to their standard protocol. Agonist dose curves were performed to determine the EC80 value for the following antagonist testing with compounds. For antagonist determination, cells were pre incubated with Compound 8 followed by VIP challenge at the EC80 concentration of 2.2 nM. 5 L of 4 Compound 8 was added to cells and incubated at 37 C. for 30 minutes. 5 L of 4EC80 VIP agonist was added to cells and incubated at 37 C. for 30 minutes.

[0903] After appropriate compound incubation, assay signal was generated through incubation with DiscoverX lysis cocktail according to the manufacturers standard protocol. Dose curves were plotted using GraphPad Prism or Activity Base. Dose curves were plotted using GraphPad Prism or Activity Base. FIG. 4, Panel A, shows a percent inhibition of VIPR1 by Compound 8. For antagonist mode assays, percentage inhibition is calculated using the following formula: % Inhibition=100%(1(mean RLU of test samplemean RLU of vehicle control)/(mean RLU of EC80 controlmean RLU of vehicle control)). Data shown in FIG. 4 was normalized to the maximal and minimal response observed in the presence of EC80 ligand and vehicle respectively. The decrease in inhibition observed in FIG. 4, Panel A, is related to agonist activity and receptor selectivity of VIPR1. FIG. 4, Panel B, shows a percent inhibition of VIPR2 by Compound 8. Raw fluorescence data from the binding experiments performed in duplicate appears below in Table 6.

TABLE-US-00042 TABLE 6 VIP Analogue Antagonist Activity [Compound] (M) Mean RLU SD % CV % Inhibition Compound ID Readout cAMP [Starting] 0.50 M Cell Line VPR1 Basal Activity 992 .0 848.5 8.5% 100.0% 5.00E07 M 1243 0.0 4497.2 3.5% 30.3% 1.00E07 M 12382 .0 198.0 0.2% 29.6% 5.00E08 M 1231 .0.sup. 22 6.2 1. % 29.1% 1.00E08 M 11712 .0 1527.4 1.3% 22.2% 5.00E09 M 10674 .0 2530.4 2.5% 10.4% 1.00E09 M 92540.0 2573.9 2. % 5.6% 5.00E10 M 8792 .0 0.0 0.0% 11.1% 1.00E10 M 901 .0.sup. 5317.4 5.9% 8.5% 1.00E11 M 6872 .0 3224.4 3.5% 10.2% 1.00E12 M 92720.0 44648.9 4.5% 5.5% 0.00E+00 M 97640.0 214 .5 2.2% 0.0% S/B 9. Av CV 3.1% Compound ID 8 Readout cAMP [Starting] 0.50 M Cell Line VPR2 Basal Activity 9300.0 198.0 2.1% 100.0% 5.00E07 M 5422 .0 12877.4 14.3% 0.4% 1.00E07 M 795 0.0 3705.2 4.7% 6.6% 5.00E08 M 79 4 .0.sup. 10534.9 13.3% 6.2% 1.00E08 M 774 .0.sup. 14566.4 18.5% 9.4% 5.00E09 M 76320.0 7071.1 9.3% 10.9% 1.00E09 M 79620.0 7495.3 9.4% 6.5% 5.00E10 M 749 .0.sup. 6081.1 8.1% 12.7% 1.00E10 M 8134 .0 6081.1 7.5% 4.2% 1.00E11 M 7800 .0 6618.5 8.5% 8.7% 1.00E12 M 81720.0 11144.0 13.6% 3.7% 0.00E+00 M 84520.0 7523.6 8.9% 0.0% S/B 9.1 Av CV 9.9% indicates data missing or illegible when filed

[0904] In Vitro Binding Assay 2: The analogs of the present invention will be serially diluted into aqueous solutions with appropriate buffer. The various concentrations of analogs will be administered to a plurality of cells in culture that expresses relevant naturally occurring receptor family for the naturally occurring polypeptide upon which the analog is derived. In one method of detection, VPAC.sub.1 CHO-K1 Division Arrested (DA) cells or VPAC.sub.1-CRE--lactamase CHO-K1 cells (10,000 cells/well) are plated in a 384-well format and incubated for 16-20 hours. Cells can then be stimulated with a dilution series of each Secretin analog in the presence of 0.5% DMOS for 5 hours. Cells can then be loaded with an engineered fluorescent substrate containing two fluoroprobes, coumarin and fluorescein (2 uM final concentration if CCF4AM and 1 mM solution D) for two hours. In the absence of -lactamase expression, the substrate molecule remains intact. In this state, excitation of the coumarin results in fluorescence resonance energy transfer to the fluorescein moiety and emission of green light (530 nm). However, in the presence of -lactamase expression, the substrate is cleaved, thereby separating the fluorophores, and disrupting energy transfer. Excitation of the coumarin in the presence of enzyme -lactamase activity results in a blue fluorescence signal (460 nm). Fluorescence emission values at 460 nm and 530 nm can be obtained using a standard fluorescence plate reader and plotted for each replicate against the concentration of analog present. The resulting blue:green ratio provides a normalized reporter response. The degree of -lactamase expression is directly correlated to the stimulation of the specific receptor being interrogated. The particular receptor construct is covalently linked to a -lactamase transcription factor, which is released upon receptor stimulation. Serially diluted analogs in the appropriate concentration of buffered solution (or medium alone as a control) will be added to individual wells together with cells expressing a specific receptor that is capable of -lactamase production. A polypeptide that engages in competitive binding to the analog receptor, or medium only as a background control, will also be added to each well. After sufficient time, the wells will be inspected by light spectrometry to determine the relative light units, which serve a readout for receptor activation. Another mechanism for determining binding values is through the monitoring of a second messenger readout. For the intended receptor class, the detection of cAMP can be a direct indicator for receptor activation. Through the detection of cAMP (using known protocols) across a range of analog concentrations, the specific degree of receptor binding for each analog and concentration can be determined. The binding of the analog to receptor will be monitored by calculating the IC.sub.50 values in media. The signal of test wells will be normalized to that of control wells without inhibitor after background subtraction from both. The percent inhibition of activity will be expressed as a function of the log 10 concentration of any competitive inhibitor added to the system. A four-parameter sigmoid function will be fitted to the data in Prism. The R.sup.2 values for the fits will be determined. Finally, the meansS.E.M. of the IC.sub.50 values from the individual fits of the three repeat experiments will be calculated.

[0905] In Vitro Binding Assay 3: The analogs of the present invention will be serially diluted into aqueous solutions with appropriate buffer. The various concentrations of analogs will be administered to a plurality of cells in culture that expresses relevant naturally occurring receptor family for the naturally occurring polypeptide upon which the analog is derived. The analogs will be adminstered to the cAMP Hunter eXpress CHO-K1 VIPR2 (DisocveRx) cells according to the manufacturers suggested protocol. cAMP Hunter Detection Reagents will be used to detect the concentration of analog bound on the surface of the cells as a function of signal strength in the absence and presence of wild-type VIP provided as a control. Various EC.sub.50 values for the VIP analogs will be calculated per the manufacturer's recommended instructions.

[0906] In Vitro Selectivity Binding Assay: Binding assays: Membranes prepared from a stable VPAC2 cell line (such as a CHOS cell line stably expressing human VPAC2 receptor or from cells transiently transfected with human VPAC1 or PAC1) are used. A filter binding assay is performed using .sup.125I-labeled VIP for VPAC1 and VPAC2 and .sup.125I-labeled PACAP-27 for PAC as the tracers. For this assay, the solutions and equipment include: [0907] Presoak solution: 0.5% Polyethyleneamine in Aqua dest [0908] Buffer for flushing filter plates: 25 mM HEPES pH 7.4 [0909] Blocking buffer: 25 mM HEPES pH 7.4; 0.2% protease free BSA [0910] Assay buffer: 25 mM HEPES pH 7.4; 0.5% protease free BSA [0911] Dilution and assay plate: PS-Microplate, U form [0912] Filtration Plate Multiscreen FB Opaque Plate; 1.0 mM Type B Glasfiber filter
In order to prepare the filter plates, the presoak solution will be aspirated by vacuum filtration. The plates will be flushed twice with 200 L flush buffer. 200 L blocking buffer will be added to the filter plate. The filter plate will then be incubated with 200 L presoak solution for 1 hour at room temperature. The assay plate will be filled with 25 L assay buffer, 25 L membranes (2.5 g) suspended in assay buffer, 25 L agonist in assay buffer, and 25 L tracer (about 40000 cpm) in assay buffer. The filled plate will be incubated for 1 hour with shaking. The transfer from assay plate to filter plate will be conducted. The blocking buffer will be aspirated by vacuum filtration and washed two times with flush buffer. 90 L will be transferred from the assay plate to the filter plate. The 90 L transferred from assay plate will be aspirated and washed three times with 200 L flush buffer. The plastic support is removed. It is dried for 1 hour at 60 C. 30 L Microscint will be added. The count will be performed based upon analog affinity to VPAC1, VPAC2, or PAC1 receptors. IC.sub.50 and EC.sub.50 calculations will be performed based upon affinity scoring.

[0913] In Vivo Efficacy in Animal Models: To determine the activity of analogs of the invention in vivo as compared to the naturally occurring polypeptides upon which the analogs are derived, the analogs will be administered alone (IP, IV, SC, PO, by inhalation or nasal routes) or in combination with known active agent to monitor the above-mentioned disease states. Secretin family analogs alone or in combination with sub-optimal doses of relevant active agents for specific indications or disease states will be, for example, administered to an appropriate animal model mice (8-10 days after injection/day 1 of experiment) by tail vein or IP routes at doses ranging from 0.0001 mg/kg to 50 mg/kg for 1 to 21 days. Optionally, the mice will be assayed throughout the experiment with a selection marker relevant to the particular studies disease state every other day and survival monitored daily for the duration of the experiment. Expired mice will be optionally subjected to necropsy at the end of the experiment. These in vivo tests optionally generate preliminary pharmacokinetic, pharmacodynamic and toxicology data.

[0914] Adjuvant-induced Arthritis in Rats: Adjuvant induced arthritis (AIA) is an animal model useful in the study of rheumatoid arthritis (RA), which is induced by injecting M. tuberculosis in the base of the tail of Lewis rats. Between 10 and 15 days following injection, animals develop a severe, progressive arthritis.

[0915] Generally, analogs will be tested for their ability to alter hind paw swelling and bone damage resulting from adjuvant induced edema in rats. To quantitate the inhibition of hind paw swelling resulting from AIA, two phases of inflammation have been defined: (1) the primary and secondary injected hind paw, and (2) the secondary uninjected hind paw, which generally begins developing about eleven days from the induction of inflammation in the injected paw. Reduction of the latter type of inflammation is an indication of immunosuppressive activity. Cf. Chang, Arth. Rheum., 20, 1135-1141 (1977).

[0916] Using an animal model of RA, such as AIA, enables one to study the cellular events involved in the early stages of the disease. CD44 expression on macrophages and lymphocytes is up regulated during the early development of adjuvant arthritis, whereas LFA 1 expression is up regulated later in the development of the disease. Understanding the interactions between adhesion molecules and endothelium at the earliest stages of adjuvant arthritis could lead to significant advances in the methods used in the treatment of RA.

[0917] Collagen Induced Arthritis in Rats: To determine the efficacy of a representative analog of this invention administered by po bid dosing (Days (1)-20) for inhibition of the inflammation, cartilage destruction and bone resorption that occurs in developing type 11 collagen arthritis in rats.

[0918] Animals: Female Lewis rats (Harlan), weighing 125-150 g on arrival. (inject subtotal of rats with collagen to get responders on days 10, 11, 12 for 6 groups of 10). The animals (a group for arthritis, a group for normal control), housed 4-5/cage, will be acclimated for 4-8 days. The animals will be dosed from about po1 mg/kg bid to po100 mg/kg bid.

[0919] Materials: Peptides or analogs in vehicle, Type II collagen, Freund's incomplete adjuvant, methotrexate (Sigma)

[0920] General Study Design: Dosing initiated on day minus 1. The acclimated animals will be anesthetized with isoflurane and given collagen injections (D0). On day 6 they will be anesthetized again for the second collagen injection. Collagen is prepared by making a 4 mg/mL solution in 0.01 N acetic acid. Equal volumes of collagen and Freund's incomplete adjuvant, will be emulsified by hand mixing until a bead of this material held its form when placed in water. Each animal will receive 300 L of the mixture each time spread over 3 sites on back. Calipering of normal (pre-disease) right and left ankle joints are to be done approximately one ay prior to the expected days on onset of disease.

[0921] Rats will be weighed on days () 1, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of the study and caliper measurements of ankles taken every day beginning on day 9. Final body weights will be taken on day 20. After final body weight measurement, animals are to be anesthetized for terminal plasma collection and then euthanization. Both hind paws and knees will be removed. Hind paws will be weighed, placed (with knees) in formalin and then processed for microscopy.

[0922] Processing of Joints: Following 1-2 days in fixative and then 4-5 days in decalcifier, the ankle joints will be cut in half longitudinally, knees will be cut in half in the frontal plane, processed, embedded, sectioned and stained with toluidine blue.

[0923] Induction of Colitis in HLA-B27 Rats: The efficacy of the analogs of the present invention in reversing colitis can be determined in HLA-B27 transgenic rats. HLA-B27 transgenic rats have been utilized as an animal model of Inflammatory Bowel Disease which mimics Crohn's Disease in humans. The rats overexpress the human MHC class I HLA-B27 heavy chain and beta-2 microglobulin proteins, which induces a variety of autoimmune diseases that include inflammation of the colon.

[0924] The therapeutic effect of the analogs described in this invention in terms of resolving colitis can be evaluated in HLA-B27 transgenic rats. Diseased rats will be dosed subcutaneously with 0.001-100 mg/kg of a single analog of this invention once or twice a day for 16 days or once per week for two weeks.

[0925] Disease Activity Index (DAI) scores will be used to determine the efficacy of each analog as compared to rats dosed with vehicle. In addition, fecal consistency and FOB scores for both rats dosed with analogs will be statistically compared to the vehicle group.

[0926] Induction of Colitis: 1-20 HLA-B27 (6-9 weeks old) transgenic rats will be acclimated in animal facility for 10 weeks. Animal bedding will be mixed from different cages once a week to control for a dirty environmental flora.

[0927] Treatments: Rats are to be enrolled and randomized into four groups (n=5) based on weight and DAI scores (FC.gtoreq.3, FOB.gtoreq.2). The experimental groups will be dosed subcutaneously with an analog 0.001-100 mg/kg once or twice a day for 16 days or once per week for two weeks and terminated at trough. The control groups include a vehicle-treated group and a GG5/3 (mouse anti-rat alpha-4 integrin antibody) positive control group dosed subcutaneously at 10 mg/kg (5 mUkg) on d0, d3, and d6 and terminated at trough on d8. Fresh analog and vehicle treatments are to be formulated in advance of treatment.

[0928] Endpoint Read-outs: Disease Activity Index scores, Fecal Consistency test and Fecal Occult Blood test, are to be taken 4 times a week to generate in-life clinical scores. The primary read-out for the study is a histopathological analysis of cecum, proximal colon, mid-colon, and distal colon. An IBD scoring system was applied (Table H2). TABLE H2 IBD Scoring System Multiple Endpoints A Destruction of epithelium and glands B Dilatation of glandular crypts C Depletion and loss of goblet cells D Inflammatory cell infiltrates E Edema F Vascular congestion G Crypt Abscesses H Atrophia

[0929] Primary Arterial Hypertension animal model: 36 adult male Sprague-Dawley rats (300-350 g in body weight were randomized for treatment 22 days after a s.c. injection of saline or 60 mg/kg MCT (Sigma-Aldrich) to induce pulmonary hypertension. In addition to a group of untreated rats, the experimental groups included rats that received either daily, weekly or monthly delivery of a secretin analog at an appropriate dose of (0.001-50 mg/kg or the delivery vehicle alone. On Day 22 a carotid/femoral artery will be accessed for arterial blood gases (systemic blood pressure can be monitored as well). Thoracotomy performed and right ventricle catheterized with a Millar catheter (or other appropriate catheter) which will be advanced to the pulmonary artery. Animals will have anesthesia induced and maintained on isoflurane through out the experiment. Rats will be intubated prior to surgical procedures. Hemodynamic measurements such as Pulmonary arterial pressure, systemic blood pressure (SAP, DAP, MAP) and heart rate are to be collected continuously via a Gould-Ponemah physiograph. Statistical analysis will be performed on all hemodynamic data. Arterial blood samples collected at protocol specified time points (up to 8 time points) for analysis of drug concentration and/or arterial blood gases. Animals euthanized after 30 minutes and lungs collected and snap frozen for shipment to the Sponsor. Lungs analyzed for levels of drug. Animals are to be clinically observed once daily with body weight measured weekly. While some embodiments of the invention have been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.

[0930] Small Cell Lung Cancer Model: Female athymic BALByc nude mice, 4-5 weeks old, will be housed in filter-top cages in a pathogenfree, temperature-controlled, laminar-flow, filtered-air, isolated room and will be exposed to light from 7:00 am. to 7:00 p.m. NCI-H69 cells will be injected subcutaneously into the right flank of each mouse. There were four experimental groups, of four mice each, three of which will receive VIP and/or an analog of VIP (1.0, 5.0, or 10 mg/day) in PBS; as a control, the fourth will receive only PBS. All solutions will be infused for 8 weeks, beginning 1 week after injection of the cells, and delivered by i.v., i.p., subc., i.m. injection or osmotic pumps placed aseptically under the skin of the back of the mice. The pump will release its contents at a rate of 0.5 ml/h for a duration of 2 weeks. The spent pumps will be removed every 2 weeks, and new pumps, containing fresh solutions, will be implanted with known techniques; this procedure will be repeated three times. After treatment, The tumors will be measured with calipers, and the mice will be weighed weekly for 8 weeks. Tumor volume will be calculated for an ellipsoid as (maximal length)(maximal height)(maximal width)(n/6). On the last day of the experiment, blood will be sampled from the retroorbital plexus into chilled heparin-containing tubes rinsed with 0.05% NaEDTA and containing three protease inhibitors. 10 mg/ml soybean trypsin inhibitor, 100 TIU/ml aprotinin, and 10 mg/ml phosphamidon), as well as 0.1 mM IBMX for measurement of plasma VIP and cAMP levels. The mice will then euthanized. The tumors will be excised, weighed, and frozen in liquid nitrogen for subsequent extraction (in methanol) and for measurement of protein content by known techniques; a portion of the tumor will be fixed in 10% neutral buffered formalin for morphologic examination.

[0931] One purpose of these studies is to evidence that the analogs are capable of producing the desired biological, biochemical, diagnostic, medicinal and/or therapeutic outcome in a living animal.

Example 5

DPPIV Protease Assay (Prophetic)

[0932] Digest buffer {100 mM Tris-HCl (pH 8)} containing 15 M peptide and 1 g porcine kidney DPPIV (Sigma-Aldrich) will be incubated at 37 C. The reaction will be terminated at the specified time point by adding 10 l 10% TFA, followed by reverse-phase HPLC on a Gemini C18 column (Phenomenex, Macclesfield, UK). The column will be eluted with a linear gradient of 27-31% AcN over 50 min at 1 ml/min. Peptides and their degradation products will be monitored by their absorbance at 214 nm. Percent degradation will be quantified by integration of peak areas related to undigested peptide peaks and corrected for degradation in the absence of enzyme.

Example 6

Method for Measuring Triglyceride Levels

[0933] hApoA1 mice (obtained from Jackson Laboratories, Bar Harbor, Me.) are bled (by either eye or tail vein) and grouped according to equivalent mean serum triglyceride levels. They are dosed orally (by gavage in a pharmaceutically acceptable vehicle) with the test polypeptide once daily for 8 days. The animals are then bled again by eye or tail vein, and serum triglyceride levels are determined. In each case, triglyceride levels are measured using a Technicon Axon Autoanalyzer (Bayer Corporation, Tarrytown, N.Y.).

Method for Measuring HDL-Cholesterol Levels

[0934] To determine plasma HDL-cholesterol levels, hApoA1 mice are bled and grouped with equivalent mean plasma HDL-cholesterol levels. The mice are orally dosed once daily with vehicle or test polypeptide for 7 days, and then bled again on day 8. Plasma is analyzed for HDL-cholesterol using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, Calif.).

[0935] Method for Measuring Total Cholesterol, HDL-Cholesterol, Triglycerides, and Glucose Levels. In another in vivo assay, obese monkeys are bled, then orally dosed once daily with vehicle or test polypeptide for 4 weeks, and then bled again. Serum is analyzed for total cholesterol, HDL-cholesterol, triglycerides, and glucose using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, Calif.). Lipoprotein subclass analysis is performed by NMR spectroscopy as described by Oliver, et al., (Proc. Natl. Aced. Sci. USA 98:5306-5311, 2001).

[0936] The following journal articles, which are herein incorporated by reference, disclose secretin family analogs contemplated to be a polypeptide backbone for the secretin family analogs of the invention. The journal articles also disclose a series of methods of administering secretin family analogs as part of pharmaceutical compositions: [0937] 1. Gozes, et. al., Current Pharmaceutical Design, 2003, Vol. 9, No. 6 [0938] 2. Delgado, et. al., Brain Behav Immun. 2008 November; 22(8): 1146-1151. doi:10.1016/j.bbi.2008.06.001. [0939] 3. L. Dickson, K. Finlayson/Pharmacology & Therapeutics 121 (2009) 294-316. [0940] 4. Gonzales-Rey, et. al., TRENDS in Pharmacological Sciences Vol. 28 No. 9. [0941] 5. Varela, et. al., Expert Opin. Biol. Ther. (2007) 7(4):461-478 [0942] 6. Brenneman, Peptides 28 (2007) 1720-1726: [0943] 7. Onoue, et. al., Naunyn-Schmiedeberg's Arch Pharmacol (2008) 377:579-590

[0944] Any journal article, patent application, issued patent or other publication referenced in this application is herein incorporated by reference. The embodiments listed herein are not meant to be restrictive, but rather illustrative of the invention.

TABLE-US-LTS-00001 LENGTHY TABLES The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).