Development of hMC1R Selective Small Agonists for Sunless Tanning and Prevention of Genotoxicity of UV in Melanocytes.

Abstract

Activation of the human melanocortin 1 receptor (hMC1R) expressed on melanocytes by α-melanocortin (α-MSH) plays a central role in regulating human pigmentation, and reducing the genotoxicity of ultraviolet radiation (UV) by activating DNA repair and antioxidant defenses. Towards development of a hMC1R-targeted photoprotection strategy we designed tetra- and tripeptide agonists with modifications that provide the necessary lipophilicity and hMC1R selectivity to be effective drugs. These peptides proved to be superior to most existing analogs of the tridecapeptide α-MSH due to their small size and high hMC1R selectivity. Testing on primary cultures of human melanocytes showed that these peptides are highly potent with prolonged stimulation of melanogenesis, enhance repair of UV-induced DNA photoproducts and reduce apoptosis of human melanocytes. One of the tripeptides, designated as LK-514 (5), with molecular weight 660, has unprecedented (>100,000) hMC1R selectivity, versus other melanocortin receptors, hMC3R, hMC4R, and hMC5R, and increases pigmentation (sunless tanning) in a cultured 3D skin model. These analogs should be efficacious for preventing skin cancer, including melanoma, and treatment of skin disorders, such as vitiligo and polymorphic light eruptions.