Peptide ligands for peptide GPCRs have exciting potential as therapeutics exemplified by the incredible success of setmelanotide for treatment of diabetes and obesity. The melanocortin receptors, MC1R-MC5R are targets for an array of therapeutic indications and peptide-based, sub-type selective agonists and antagonists are keenly sought. The MC4R antagonist, setmelanotide, is a disulfide linked peptide with high potency (and moderate selectivity) for MC4R and has been approved for a range of obesity-related genetic conditions.
Our group is looking at a range of cyclic peptide architectures with the aim of identifying structure-selectivity features that might drive improved selectivity for specific sub-types. Here we have looked at HS024, a reported cyclic disulfide peptide, Cys-Nle-Arg-His-D-Nal(2)-Arg-Trp-Gly-Cys-CONH2, a non-selective MC4R antagonist that was also reported to have melanocortin 5 receptor (MC5R) antagonist activity. It thus represented a potential lead for development of a selective MC5R antagonist, and we have re-examined this scaffold with that view in mind.
In contrast to the literature report, we found that HS024 is in fact a potent agonist of MC5R with an EC50 of 100 pM in an assay of MC5R-induced cAMP-synthesis in transfected HEK293 cells. In many respects it mirrored other well known MC4R antagonists SHU9119 and PG-901. We have pursued a preliminary additional SAR study and found this analogy to hold quite well, with the larger 26-membered disulfide-bridged ring system of HS024 not impacting much upon selectivity compared to the 23-membered lactam-bridged ring of the SHU9119 and PG-901.
This work contributes to the understanding of structural features governing MC5R selectivity and highlights the importance of accurate functional characterisation in melanocortin ligand development.
Ref; Kask, A et al; Endocrinology, 1998, 139, 5006-5014