CLIPSing Melanotan-II to Discover Multiple Functionally Selective hMCR Agonists

The pleiotropic role played by melanocortin receptors (MCRs) in both physiological and pathological processes has stimulated medicinal chemists to develop synthetic agonists/antagonists with improved potency and selectivity. Here, by deploying the Chemical Linkage of Peptide onto Scaffolds strategy, we replaced the lactam cyclization of melanotan II (MT-II), a potent and unselective agonist of human MCRs (hMCRs), with different xylene-derived thioethers. The newly designed peptides displayed binding affinities toward MCRs ranging from the low nanomolar to the sub-micromolar range, highlighting a correlation between the explored linkers and the affinity toward hMCRs. In contrast to the parent peptide (MT-II), compound 5 displayed a remarkable functional selectivity toward the hMC1R. Enhanced sampling molecular dynamics simulations were found to be instrumental in outlining how the employed cyclization strategy affects the peptides' conformational behavior and, as a consequence, the detected hMC1R affinity. Additionally, a model of the peptide 5/hMC1R complex employing the very recently reported cryogenic electron microscopy receptor structure was provided.

Automated summary

Melanocortin receptors play a pleiotropic role in various physiological and pathological processes. Scientists have developed synthetic agonists/antagonists with improved potency and selectivity by replacing the lactam cyclization of melanotan II (MT-II) with different xylene-derived thioethers. The newly designed peptides showed affinity towards melanocortin receptors within a certain range, indicating a correlation with the explored linkers. Compound 5 exhibited remarkable functional selectivity towards one of the melanocortin receptors. Molecular dynamics simulations and cryogenic electron microscopy receptor structure provided insights into the conformational behavior and affinity of the peptides.