alpha-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes.
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 alpha-melanocortin (alpha-MSH) that were more potent and stable than the physiological alpha-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 alpha-MSH core His(6)-d-Phe(7)-Arg(8), 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 alpha-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.
Abdel-Malek
Zalfa A
ZA
Department of Dermatology, University of Cincinnati, Cincinnati, OH, USA. abdelmza@uc.edu
Ruwe
Andrew
A
Kavanagh-Starner
Renny
R
Kadekaro
Ana Luisa
AL
Swope
Viki
V
Haskell-Luevano
Carrie
C
Koikov
Leonid
L
Knittel
James J
JJ
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000378:metabolism*; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism*
D010455:Peptides; D044102:Receptor, Melanocortin, Type 1; D000521:alpha-MSH; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase