Figure 3. Schematic representation of the effects of -MSH analogs that act as MC1R agonists on human melanocytes. Recently, we reported that the melanocortins -MSH and ACTH modulate the responses of human melanocytes to UVR by enhancing the repair of DNA photoproducts, reducing the generation of hydrogen peroxide, and promoting survival, in addition to their known stimulatory effects on melanogenesis. We have designed, based on these findings, tetrapeptide analogs of -MSH and compared their effects to those of the native hormone -MSH. We found that these analogs are MC1R agonists, and that 2 and 3 are more potent with prolonged effect on melanogenesis, and greater antiapoptotic effect than -MSH. These two agonists also mimic the effects of -MSH on nucleotide excision repair and generation of hydrogen peroxide. We expect these agonists to restore the genomic stability of UVR-exposed human melanocytes and increase photoprotection of the skin, and thus prevent their malignant transformation to melanoma.