Novel α-Melanocyte Stimulating Hormone Peptide Analogues with High Candidacidal Activity

α-Melanocyte stimulating hormone (α-MSH) is an endogenous linear tridecapeptide with potent antiinflammatory effects. We recently demonstrated that α-MSH and its C-terminal sequence Lys-Pro-Val (a-MSH (11-13)) have antimicrobial effects against two major and representative pathogens: Staphylococcus aureus and Candida albicans. In an attempt to improve the candidacidal activity of α-MSH and to better understand the peptide structure-antifungal activity relations, we designed and synthesized novel peptide analogues. Because previous data suggested that antimicrobial effects of α-MSH were receptor-mediated, we chose to focus on the sequence α-MSH (6-13), which contains the invariant core sequence His-Phe-Arg-Trp (6-9) that is important for binding to the known melanocortin receptors and also contains the sequence Lys-Pro-Val (11-13) that is known to be important for antimicrobial activity. In this structure-activity study, we discovered several compounds that have greater candidacidal activity than α-MSH. The peptide [D-Nal-7,Phe-12]-α-MSH (6-13) was the most potent of the analogues tested. The present results are very encouraging because they show the great potential of these peptides as a truly novel class of candidacidal compounds.