α-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes

Zalfa A. Abdel-Malek, Andrew Ruwe, Renny Kavanagh-Starner, Ana Luisa Kadekaro, Viki Swope, Carrie Haskell-Luevano, Leonid Koikov, James J. Knittel

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

One skin cancer prevention strategy that we are developing is based on synthesizing and testing melanocortin analogs that reduce and repair DNA damage resulting from exposure to solar ultraviolet (UV) radiation, in addition to stimulating pigmentation. Previously, we reported the effects of tetrapeptide analogs of α-melanocortin (α-MSH) that were more potent and stable than the physiological α-MSH, and mimicked its photoprotective effects against UV-induced DNA damage in human melanocytes. Here, we report on a panel of tripeptide analogs consisting of a modified α-MSH core His 6-d-Phe7-Arg8, which contained different N-capping groups, C-terminal modifications, or arginine mimics. The most potent tripeptides in activating cAMP formation and tyrosinase of human melanocytes were three analogs with C-terminal modifications. The most effective C-terminal tripeptide mimicked α-MSH in reducing hydrogen peroxide generation and enhancing nucleotide excision repair following UV irradiation. The effects of these three analogs required functional MC1R, as they were absent in human melanocytes that expressed non-functional receptor. These results demonstrate activation of the MC1R by tripeptide melanocortin analogs. Designing small analogs for topical delivery should prove practical and efficacious for skin cancer prevention.

Original languageEnglish (US)
Pages (from-to)635-644
Number of pages10
JournalPigment Cell and Melanoma Research
Volume22
Issue number5
DOIs
StatePublished - Oct 2009

Keywords

  • DNA damage
  • DNA repair
  • Melanocortin 1 receptor
  • Melanoma
  • Skin cancer
  • α-MSH analogs

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