CLIPSing Melanotan-II to Discover Multiple Functionally Selective hMCR Agonists

Abstract

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.

Late-Stage Functionalization with Cysteine Staples Generates Potent and Selective Melanocortin Receptor-1 Agonists

“…41 However, another MT-II investigation yielded selective MC1R agonists using a xylene stapling strategy. 42 These studies underline the potential role of aromatic functionalities at MC1R to tune both selectivity and functional activity, and it is probable that the aromatic staples implemented in our work contribute to a favorable hydrophobic binding interaction at this receptor.…”

“…Several investigations have also explored the used of aromatic cyclization linkers implemented in the MT-II framework, − with one investigation showing that phthalic acid linkages induce MC1R selectivity as well as a functional activity switch toward antagonism . However, another MT-II investigation yielded selective MC1R agonists using a xylene stapling strategy . These studies underline the potential role of aromatic functionalities at MC1R to tune both selectivity and functional activity, and it is probable that the aromatic staples implemented in our work contribute to a favorable hydrophobic binding interaction at this receptor.…”

“…Docking studies have shown that the MC1R has a preference for agonist ligands bearing hydrophobic aromatic residues that can form π–π stacking interactions within the binding pocket . Several investigations have also explored the used of aromatic cyclization linkers implemented in the MT-II framework, − with one investigation showing that phthalic acid linkages induce MC1R selectivity as well as a functional activity switch toward antagonism . However, another MT-II investigation yielded selective MC1R agonists using a xylene stapling strategy .…”