Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor‑1

Ultrastable cyclic peptide frameworks
offer great potential for
drug design due to their improved bioavailability compared to their
linear analogues. Using the sunflower trypsin inhibitor-1 (SFTI-1)
peptide scaffold in combination with systematic N-methylation of the grafted pharmacophore led to the identification
of novel subtype selective melanocortin receptor (MCR) agonists. Multiple
bicyclic peptides were synthesized and tested toward their activity
at MC1R and MC3–5R. Double N-methylated compound 18 showed a pKi of 8.73 ±
0.08 (Ki = 1.92 ± 0.34 nM) and a
pEC50 of 9.13 ± 0.04 (EC50 = 0.75 ±
0.08 nM) at the human MC1R and was over 100 times more selective for
MC1R. Nuclear magnetic resonance structural analysis of 18 emphasized the role of peptide bond N-methylation
in shaping the conformation of the grafted pharmacophore. More broadly,
this study highlights the potential of cyclic peptide scaffolds for
epitope grafting in combination with N-methylation
to introduce receptor subtype selectivity in the context of peptide-based
drug discovery.