LAUSR

The melanocortin system is critical for survival. The melanocortin 3 and 4 receptors (hMC3R, hMC4R) play an important role in energy homeostasis and metabolism. The melanocortin 1 receptor (hMC1R) is important for pigmentation and skin cancer prevention. However, developing selectivity between the melanocortin 1, 3 and 4 receptors is still challenging due to the high level of similarity between them. In this study, we have systematically investigated the Cterminus of α-MSH, i.e. -KPV influence on the conformation of melanotropins which lead to selectivity at the melanocortin receptors. We have observed -KPV increase binding affinity towards hMCRs. Also, it induced receptor selectivity in several hMCRs. In this study we discovered a promising hMC3R selective antagonist and agonist: peptide 5 ([CO(CH 2 ) 2 CO-DNal(2')-Arg-Trp-Lys]-Gly-Lys-Pro-Val-NH 2 ) and peptide 20 (H-DNal(2')-c[Asp-Pro-DPhe-Arg-Trp-Lys]-Ala-Gly-Pro-Val-NH 2 ) respectively. Furthermore, a series of selective hMC1R agonistic peptides 9-11 and peptides 13-18 were also discovered.