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.