MELANOCORTIN ANALOGS HAVING ENHANCED ACTIVITY AND TRANSPORT

1 . A non-naturally occurring melanocortin analog comprising the sequence according to Formula I: X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 Y 1 Y 2 Y 3 , wherein:

X 1 , X 2 , and X 3 represent optional stabilizing N-terminal residues or an amino acid residue mimetic;

R 1 to R 7 represent residues of the melanocortin analog; and

Y 1 , Y 2 , and Y 3 represent degradation-resistant C-terminal residues or an amino acid residue mimetic.

2 . The non-naturally occurring melanocortin analog of claim 1 , wherein:

R 1 is absent or is selected from the group consisting of cysteine, norleucine, acetylated norleucine, acetylated cysteine, D -phenylalanine, methylated D -phenylalanine, succinic acid, o-phtalic acid, tyrosine, aspartic acid, glutaric acid, CO-cis-CH═CH—CO, an n-pentanoyl group, and an n-hexanoyl group;

R 2 is absent or is selected from the group consisting of proline, aspartic acid, glutamic acid, glycine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, an n-pentanoyl group, and an n-hexanoyl group;

R 3 is selected from the group consisting of histidine, histidine methylated at positions 1 or 3 , D -proline, L -proline, D -Nal(2′), L -Nal(2′), succinic acid, tButGly, Hyp(Bzl), Mamb, Oic, norleucine, Aba, β-alanine, and Tic;

R 4 is selected from the group consisting of histidine, D -phenylalanine, L -phenylalanine, D -Nal(2′), pCl- D -Phe, and (o-Phe)Phe;

R 5 is selected from the group consisting of arginine, homoarginine, ornithine, alanine, proline, Pip, Nip, Tic, Phg, Sar, and Azt;

R 6 is selected from D -tryptophan, L -tryptophan, D -Nal(2′), L -Nal(2′), Tic, and Bip;

R 7 is absent or is selected from the group consisting of glycine, glutamic acid, cysteine, lysine, and 2,3-diamino-propionic acid;

wherein if R 3 is Aba, then R 4 is selected from the group consisting of D -Phe, D -Nal(2′), and pCl- D -Phe; and

wherein if R 2 is an n-pentanoyl group or an n-hexanoyl group, then R 1 , Y 1 , Y 2 , and Y 3 are absent.

3 . The non-naturally occurring melanocortin analog of claim 1 , wherein the melanocortin analog is cyclized.

4 . The non-naturally occurring melanocortin analog of claim 1 , wherein:

X 1 is selected from the group consisting of D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, β-alanine, D -valine, L -valine, 3-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, and a piperazin-2-one ring;

X 2 is absent or is selected from the group consisting of D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, β-alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, and a piperazin-2-one ring; and

X 3 is absent or is selected from the group consisting of D -cysteine, L -cysteine, D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, and a piperazin-2-one ring.

5 . The non-naturally occurring melanocortin analog of claim 4 , wherein the N-terminus is modified by acylation.

6 . The non-naturally occurring melanocortin analog of claim 1 , wherein:

Y 1 is absent or is D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, or a piperazin-2-one ring;

Y 2 is absent or is D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, or a piperazin-2-one ring; and

Y 3 is absent or is D -cysteine, L -cysteine, D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, or a piperazin-2-one ring.

7 . The non-naturally occurring melanocortin analog of claim 6 , wherein the C-terminus is modified by amidation.

8 . A non-naturally occurring melanocortin analog comprising the sequence according to Formula II: X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 Y 1 Y 2 Y 3 , wherein:

X 1 , X 2 , and X 3 represent optional stabilizing N-terminal residues or an amino acid residue mimetic;

R 1 to R 9 represent residues of the melanocortin analog; and

Y 1 , Y 2 , and Y 3 represent degradation-resistant C-terminal residues or an amino acid residue mimetic.

9 . The non-naturally occurring melanocortin analog of claim 8 , wherein:

R 1 is L -tyrosine;

R 2 is L -valine;

R 3 is L -methionine, norleucine, L -cysteine, or L -penicillamine;

R 4 is glycine, D -cysteine, L -cysteine, L -aspartic acid, or norleucine;

R 5 is L -histidine, norleucine, L -proline, or Aib;

R 6 is L -phenylalanine, D -Nal(2′), or L -Nal(2′);

R 7 is L -arginine;

R 8 is L -tryptophan or D -Nal(2′); and

R 9 is absent or is L -aspartic acid, L -cysteine, L -penicillamine, or L -lysine.

10 . The non-naturally occurring melanocortin analog of claim 9 , wherein the melanocortin analog is cyclized.

11 . The non-naturally occurring melanocortin analog of claim 8 , wherein:

X 1 is selected from the group consisting of D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, β-alanine, D -valine, L -valine, 3-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, and a piperazin-2-one ring;

X 2 is absent or is selected from the group consisting of D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, β-alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, and a piperazin-2-one ring; and

X 3 is absent or is selected from the group consisting of D -cysteine, L -cysteine, D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, and a piperazin-2-one ring.

12 . The non-naturally occurring melanocortin analog of claim 11 , wherein the N-terminus is modified by acylation.

13 . The non-naturally occurring melanocortin analog of claim 8 , wherein:

Y 1 is absent or is D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, or a piperazin-2-one ring;

Y 2 is absent or is D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, or a piperazin-2-one ring; and

Y 3 is absent or is D -Cystine, L -Cysteine, of D -threonine, L -threonine, D -proline, L -proline, β-homo proline, D -alanine, L -alanine, D -valine, L -valine, β-valine, 3-methyl-β-valine, D -leucine, L -leucine, β-leucine, D -isoleucine, L -isoleucine, β-isoleucine, or a piperazin-2-one ring.

14 . The non-naturally occurring melanocortin analog of claim 13 , wherein the C-terminus is modified by amidation.

15 . The non-naturally occurring melanocortin analogs comprising SEQ ID NOs: 15-201.

16 . The non-naturally occurring melanocortin analog of claim 15 , wherein the melanocortin analog can traverse the epithelium, the blood-brain barrier, or both.

17 . The non-naturally occurring melanocortin analog of claim 15 , wherein the half-life is 10-fold, 100-fold, 1,000-fold, 10,000-fold, or >10,000-fold greater than a natural melanocortin peptide.

18 . The non-naturally occurring melanocortin analog of claim 15 , wherein the side effects are suppressed or eliminated compared to a natural melanocortin peptide.

19 . The non-naturally occurring melanocortin analog of claim 15 , wherein the melanocortin analog is effective in modulating one or more of cachexia, lethargy, appetite, sleep, arousal, libido, locomotion, cardiovascular anomalies, vasodilatation, hypertension, hypotension, sodium regulation, pain, pain perception, increasing endogenous opioid activity, or decreasing opioid tolerance.

20 . A pharmaceutical composition comprising the non-naturally occurring melanocortin analog of claim 15

21 . The pharmaceutical composition of claim 20 , further comprising a pharmaceutical salt.

22 . The pharmaceutical composition of claim 20 , wherein the side effects are reduced compared to a natural melanocortin.

23 . A method of treating a disorder in a subject in need thereof comprising administering a non-naturally occurring melanocortin analog of any one of claims 15 - 201 .

24 . The method of claim 23 , wherein the administration route is intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, or orally.

25 . The method of claim 24 , wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier.

26 . The method of any one of claims 20 - 25 , wherein the side effects are reduced compared to a natural melanocortin.

27 . A means for treating cachexia comprising administering the non-naturally occurring melanocortin analog of any one of SEQ ID NOs: 15-201.

28 . The means of claim 27 , wherein the side effects are reduced compared to a natural melanocortin.

29 . A kit for treating for treating cachexia in a subject in need thereof, comprising individual containers containing the pharmaceutical composition of claim 20 , a device for administering the pharmaceutical composition, a reagent for diluting the pharmaceutical composition, and instructions for use.

30 . A non-naturally occurring melanocortin analog as substantially described herein with reference to and as illustrated by the accompanying text and drawings.