Novel alpha-melanocyte stimulating hormone peptide analogues with high candidacidal activity.
alpha-Melanocyte stimulating hormone (alpha-MSH) is an endogenous linear tridecapeptide with potent antiinflammatory effects. We recently demonstrated that alpha-MSH and its C-terminal sequence Lys-Pro-Val (alpha-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 alpha-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 alpha-MSH were receptor-mediated, we chose to focus on the sequence alpha-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 alpha-MSH. The peptide [d-Nal-7,Phe-12]-alpha-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.
Grieco
Paolo
P
Department of Pharmaceutical Chemistry and Toxicology, University of Naples, 80131 Naples, Italy.
Rossi
Claudia
C
Colombo
Gualtiero
G
Gatti
Stefano
S
Novellino
Ettore
E
Lipton
James M
JM
Catania
Anna
A
D000409:Alanine / Q000737:chemistry; D019943:Amino Acid Substitution; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000302:isolation & purification; D009074:Melanocyte-Stimulating Hormones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000737:chemistry; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000935:Antifungal Agents; D010446:Peptide Fragments; C472570:alpha-melanocyte stimulating hormone (6-13), Nal(7)-Phe(12)-; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones; D011392:Proline; D000409:Alanine