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

Leonid Koikov, Renny J. Starner, Viki B. Swope, Parth Upadhyay, Yuki Hashimoto, Katie T. Freeman, James J. Knittel, Carrie Haskell-Luevano, Zalfa A. Abdel-Malek

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1819-1829
Number of pages11
JournalJournal of Investigative Dermatology
Volume141
Issue number7
DOIs
StatePublished - Jul 1 2021

Bibliographical note

Funding Information:
Supported in part by VA Merit Award BX 003668, R21 CA191761, R01 CA114-95, Melanoma Research Foundation (Unit ed States), Career Development Award, NIEHS p30 ES006096 (United States), University of Cincinnati Cancer Center Pilot Project, University of Cincinnati Pre-Accelerator Program, and donations from Melanoma Know More (United States) for ZAAM, and by NIH R01DK091906 (United States) for CHL . The authors thank Diya Mutasim and the Dermatopathology laboratory staff for providing their free services. We also thank previous students and fellows who contributed to this project: Chelesa Fearce, Kendall Schick, Bayan Abul-Haija, Ahmad Taftaf, and Megan Turner. The hMC1R agonists are protected by the following patents: Skin care compositions and methods comprising selective agonists of melanocortin 1 receptor. #: US 9,434,764 B2. Pharmaceutical compositions and therapeutic methods of use comprising selective agonists of melanocortin 1 receptor. #:US 9,834,580 B2. Methods of using pharmaceutical compositions comprising selective peptide-based agonists of melanocortin receptor. #: US 10,301,355 B2.

Funding Information:
Supported in part by VA Merit Award BX 003668, R21 CA191761, R01 CA114-95, Melanoma Research Foundation (United States), Career Development Award, NIEHS p30 ES006096 (United States), University of Cincinnati Cancer Center Pilot Project, University of Cincinnati Pre-Accelerator Program, and donations from Melanoma Know More (United States) for ZAAM, and by NIH R01DK091906 (United States) for CHL. The authors thank Diya Mutasim and the Dermatopathology laboratory staff for providing their free services. We also thank previous students and fellows who contributed to this project: Chelesa Fearce, Kendall Schick, Bayan Abul-Haija, Ahmad Taftaf, and Megan Turner. The hMC1R agonists are protected by the following patents: Skin care compositions and methods comprising selective agonists of melanocortin 1 receptor. #: US 9,434,764 B2. Pharmaceutical compositions and therapeutic methods of use comprising selective agonists of melanocortin 1 receptor. #:US 9,834,580 B2. Methods of using pharmaceutical compositions comprising selective peptide-based agonists of melanocortin receptor. #: US 10,301,355 B2. Conceptualization: LK, JJK, ZAAM; Data Curation: LK, RJS, VBS, ZAAM; Formal Analysis: LK, RJS, VBS, PU, KTF, CHL; Funding Acquisition: ZAAM, CHL; Investigation: LK, RJS, VBS, PU, UH, KTF, ZAAM; Methodology: LK, RJS, VBS, KTF, CHL, JJK, ZAAM; Project Administration: ZAAM; Resources: LK, ZAAM; Supervision: ZAAM, JJK, CHL; Writing - Original Draft Preparation: LK, ZAAM; Writing - Review and Editing: LK, JJK, CHL, VBS, ZAAM

Publisher Copyright:
© 2021 The Authors

PubMed: MeSH publication types

  • Journal Article

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