Title: Development of hMC1R Selective Small Agonists for Sunless Tanning and Prevention of Genotoxicity of UV in Melanocytes.
Authors: Koikov, Leonid; Starner, Renny J; Swope, Viki B; Upadhyay, Parth; Hashimoto, Yuki; Freeman, Katie T; Knittel, James J; Haskell-Luevano, Carrie; Abdel-Malek, Zalfa A
Published In J Invest Dermatol, (2021 07)
Abstract: Activation of the human melanocortin 1 receptor (hMC1R) expressed on melanocytes by α-melanocortin plays a central role in regulating human pigmentation and reducing the genotoxicity of UV by activating DNA repair and antioxidant defenses. For the 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 of the existing analogs of the physiological tridecapeptide α-melanocortin because of 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, enhanced repair of UV-induced DNA photoproducts, and reduced apoptosis. One of the tripeptides, designated as LK-514 (5), with a molecular weight of 660 Da, has unprecedented (>100,000) hMC1R selectivity when compared with the other melanocortin receptors hMC3R, hMC4R, and hMC5R, and increases pigmentation (sunless tanning) in a cultured, three-dimensional skin model. These new analogs should be efficacious in preventing skin cancer, including melanoma, and treatment of skin disorders, such as vitiligo and polymorphic light eruptions.
PubMed ID: 33609553
MeSH Terms: Cells, Cultured; DNA Damage/drug effects*; DNA Damage/radiation effects; Dermatologic Agents/pharmacology*; Dermatologic Agents/therapeutic use; Humans; Melanocytes/drug effects; Melanocytes/metabolism; Melanocytes/radiation effects; Melanoma/etiology; Melanoma/prevention & control; Photosensitivity Disorders/drug therapy; Photosensitivity Disorders/genetics; Primary Cell Culture; Receptor, Melanocortin, Type 1/agonists*; Receptor, Melanocortin, Type 1/metabolism; Skin Diseases, Genetic/drug therapy; Skin Diseases, Genetic/genetics; Skin Neoplasms/etiology; Skin Neoplasms/prevention & control; Skin Pigmentation/drug effects*; Skin Pigmentation/radiation effects; Skin/drug effects; Skin/radiation effects; Ultraviolet Rays/adverse effects*; Vitiligo/drug therapy; Vitiligo/genetics; alpha-MSH/metabolism