Design, Synthesis, and Biological Evaluation of Novel Chimeric and Cyclic Peptide Ligands Targeting the Human Melanocortin-3 Receptor

摘要

In an effort to develop potent and selective agonists and antagonists for the human melanocortin-3 receptor, several new peptide design approaches were employed. This includes peptides featuring a chimeric fusion of the alpha-MSH and AgRP critical pharmacophores, as well as a variety of cyclic ligands which incorporated a variety of amino acid substitutions and dicarboxylic acid linkers for the construction of lactam bridges. Not only were potent and selective hMC3R superagonists obtained through this study (SRJ-(17-18)S), but several hMC1R (SRJ-(20-31)S) and hMC5R (SRJ-(02-03)L) selective peptides were also found. The active peptides identified in this study not only provide a basis for the rational design of melanocortin receptor ligands in the future, but show promise in therapeutic applications.