Design of MC1R Selective γ‑MSH Analogues with Canonical Amino Acids Leads to Potency and Pigmentation

Melanoma is a lethal
form of skin cancer. Skin pigmentation, which
is regulated by the melanocortin 1 receptor (MC1R), is an effective
protection against melanoma. However, the endogenous MC1R agonists
lack selectivity for the MC1R and thus can have side effects. The
use of noncanonical amino acids in previous MC1R ligand development
raises safety concerns. Here we report the development of the first
potent and selective hMC1R agonist with only canonical amino acids.
Using γ-MSH as a template, we developed a peptide, [Leu3, Leu7, Phe8]-γ-MSH-NH2 (compound 5), which is 16-fold selective for the hMC1R
(EC50 = 4.5 nM) versus other melanocortin receptors. Conformational
studies revealed a constrained conformation for this linear peptide.
Molecular docking demonstrated a hydrophobic binding pocket for the
melanocortin 1 receptor. In vivo pigmentation study shows high potency
and short duration. [Leu3, Leu7, Phe8]-γ-MSH-NH2 is ideal for inducing short-term skin
pigmentation without sun for melanoma prevention.