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.