NOVEL MODULATORS OF MELANOCORTIN RECEPTORS
Modulators of melanocortin receptors (MCR) are provided herein. An MC5R peptide ligand is represented by to Formula 1: R 1 -Nle 4 - c [Xaa 5 -Yaa 6 -(NMe)D-Nal(2′) 7 -Arg 8 -Trp 9 -(NMe)Zaa 10 ]-R 2 . R 1 can be an acetyl, a glycosylated amino acid, —CO—(CH 2 ) n —CH 3 , or −CO—(CH 2 ) n CF 3 with n ranging from 1 to 6. R 2 can be an —CONH 2 , —COOH, or —CH 2 OH. Xaa, Yaa, and Zaa can each be a natural amino acid or an unnatural amino acid.
1 . A melanocortin 5 receptor (MC5R) peptide ligand according to Formula 1:
R 1 -Nle 4 - c [Xaa 5 -Yaa 6 -(NMe)D-Nal(2′) 7 -Arg 8 -Trp 9 -(NMe)Zaa 10 ]-R 2
wherein R 1 is an acetyl, a glycosylated amino acid, or —CO—(CH 2 ) n CH 3 , wherein n ranges from 1 to 6,
wherein R 2 is an —CONH 2 , —COOH, or —CH 2 OH, and
wherein Xaa, Yaa, and Zaa are each a natural amino acid or an unnatural amino acid.
2 . The MC5R peptide ligand of claim 1 , wherein the glycosylated amino acid comprises a saccharide O-linked to a natural amino acid, wherein the natural amino acid is Ser, Thr, or Tyr, wherein the saccharide is a monosaccharide, a disaccharide, or an oligosaccharide.
3 . The MC5R peptide ligand of claim 1 , wherein the glycosylated amino acid comprises a saccharide N-linked to a natural amino acid, wherein the natural amino acid is Asn or Lys, wherein the saccharide is a monosaccharide, a disaccharide, or an oligosaccharide.
4 . The MC5R peptide ligand of claim 1 , wherein Xaa is a natural amino acid, wherein Xaa is Asp or Glu.
5 . The MC5R peptide ligand of claim 1 , wherein Xaa is an unnatural amino acid, wherein Xaa is Abu.
6 . The MC5R peptide ligand of claim 1 , wherein Yaa is a natural amino acid, wherein Yaa is His or Pro.
7 . The MC5R peptide ligand of claim 1 , wherein Yaa is an unnatural amino acid, wherein Yaa is selected from a group consisting of Oic, Ioc, Tic, Cpe, Che, Aic, and Acpc.
8 . The MC5R peptide ligand of claim 1 , wherein Zaa is a natural amino acid, wherein Zaa is Lys.
9 . The MC5R peptide ligand of claim 1 , wherein Zaa is an unnatural amino acid, wherein Zaa is Orn or Dab.
10 . The MC5R peptide ligand of claim 1 , wherein Xaa is linked to Zaa via a carba, lactam, disulfide, thioether, or succinic linker.
11 . The MC5R peptide ligand of claim 1 , wherein the MC5R peptide ligand is a 23 to 27-membered ring.
12 . A melanocortin 5 receptor (MC5R) peptide ligand according to Formula 2:
Ac-Nle 4 - c [Asp 5 -His 6 -(NMe)D-Nal(2′) 7 -Arg 8 -Trp 9 -(NMe)Lys 10 ]-NH 2 (PEPTIDE 9)
13 . A melanocortin 5 receptor (MC5R) peptide ligand according to Formula 3:
R 1 -Nle 4 - c [Asp 5 -His 6 -(NMe)D-Nal(2′) 7 -Arg 8 -Trp 9 -(NMe)Lys 10 ]-R 2 ,
wherein R 1 is an acetyl, a glycosylated amino acid, or —CO—(CH 2 ) n CH 3 , wherein n ranges from 1 to 6, and
wherein R 2 is an —CONH 2 , —COOH, or —CH 2 OH.
14 . The MC5R peptide ligand of claim 13 , wherein the glycosylated amino acid comprises a saccharide O-linked to a natural amino acid, wherein the natural amino acid is Ser, Thr, or Tyr, wherein the saccharide is a monosaccharide, a disaccharide, or an oligosaccharide.
15 . The MC5R peptide ligand of claim 13 , wherein the glycosylated amino acid comprises a saccharide N-linked to a natural amino acid, wherein the natural amino acid is Asn or Lys, wherein the saccharide is a monosaccharide, a disaccharide, or an oligosaccharide.