Stabilized melanocortin ligands

A non-naturally occurring melanocortin ligand comprising a melanocortin analog coupled to a degradation-resistant C-terminal extension and an N-terminal extension, the non-naturally occurring melanocortin ligand comprising Formula I:

• Y1-Y2-Y3-R1-R2-R3-R4-R5-R6-R7-X1-X2-X3 (Formula I)
• wherein the melanocortin analog comprises R1 to R7, wherein:
• R1 is absent or is selected from the group consisting of cysteine, norleucine, acetylated norleucine, acetylated cysteine, acetylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, aspartic acid, glutaric acid, CO-cis-CH═CH—CO, an n-pentanoyl group, and an n-hexanoyl group;
• R2 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;
• R3 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;
• R4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2′), pCl-D-Phe, and (o-Phe)Phe;
• R5 is selected from the group consisting of arginine, homoarginine, ornithine, alanine, proline, Pip, Nip, Tic, Phg, Sar, and Azt;
• R6 is selected from D-tryptophan, L-tryptophan, D-Nal(2′), L-Nal(2′), Tic, and Bip;
• R7 is absent or is selected from the group consisting of glycine, glutamic acid, cysteine, lysine, and 2,3-diamino-propionic acid;
• wherein if R3 is Aba, then R4 is selected from the group consisting of D-Phe, D-Nal(2′), and pCl-D-Phe;
• and
• wherein if R2 is an n-pentanoyl group or an n-hexanoyl group, then R1, Y1, Y2, and Y3 are absent;
• wherein the degradation-resistant C-terminal extension comprises X1 to X3:
• X1 is selected from the group consisting of cysteine, D-threonine, D-proline, and L-proline and a piperazin-2-one ring;
• X2 is absent or is selected from the group consisting D-threonine, D-proline, L-proline, and a piperazin-2-one ring;
• X3 is absent or is selected from the group consisting of D-threonine, and a piperazin-2-one ring;
• and
• wherein when X1 is cysteine, X2 is not absent;
• wherein the N-terminal extension comprises Y1 to Y3:
• Y1 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, and L-proline;
• Y2 is absent or is selected from the group consisting of D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring;
• Y3 is absent or is selected from the group consisting of cysteine, D-threonine, L-threonine, D-proline, L-proline, and a piperazin-2-one ring;
• and
• wherein the melanocortin ligand is cyclized through a moiety selected from the group consisting of:
• a disulfide bond between R1 or R2 and R7 or X1 when R1 or R2 is cysteine and R7 or X1 is cysteine;
• a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid;
• a side-chain lactam bridge between R2 and R7 when R2 is glutamic acid or aspartic acid and R7 is lysine;
• a lactam closure between R1 and R7 when R1 is succinic acid or o-phthalic acid and R7 is lysine;
• and
• a lactam closure between R2 or R3 and R7 when R2 or R3 is succinic acid and R7 is 2,3-diamino-propionic acid.