Structure-Based Design of Melanocortin 4 Receptor Ligands Based on the SHU-9119-hMC4R Cocrystal Structure†

The melanocortin receptors (MC1R-MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist SHU-9119 (Ac-Nle⁴-c[Asp⁵-His⁶-DNal(2')⁷-Arg⁸-Trp⁹-Lys¹⁰]-NH₂). These analogues were pharmacologically characterized in vitro, giving key insights into exploiting binding site subpockets to deliver more selective ligands. More specifically, the side chains of the Nle⁴, DNal(2')⁷, and Trp⁹ residues in SHU-9119, as well as the amide linkage between the Asp⁵ and Lys¹⁰ side chains, were found to represent structural features engaging a hMC4R/hMC3R selectivity switch.