title: Structure-function relationships and conformational properties of alpha-MSH(6-13) analogues with candidacidal activity.
abstract: Alpha-melanocyte-stimulating hormone (alpha-MSH) is an endogenous linear tridecapeptide with potent anti-inflammatory effects. We firstly 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. Successively, in an attempt to improve the candidacidal activity of alpha-MSH and to better understand the peptide structure-antifungal activity relations, we have recently designed and synthesized novel peptide analogues. We focused on the sequence alpha-MSH(6-13), which contains the invariant melanocortin core sequence His-Phe-Arg-Trp (6-9) and also contains the sequence Lys-Pro-Val (11-13) important for antimicrobial activity. In that structure-activity study, we discovered several compounds that have greater candidacidal activity than alpha-MSH, among which the peptide [d-Nal-7,Phe-12]-alpha-MSH(6-13) was the most potent. Here, we report a detailed conformational analysis by spectroscopic and computational methods of three peptides, alpha-MSH(6-13) (1), [d-Nal-7,Phe-12]-alpha-MSH(6-13) (2) and [d-Nal-7,Asp-12]-alpha-MSH(6-13) (3). Peptides were chosen on the basis of their candidacidal activities and were studied in membrane mimetic environment (SDS micelles). Different turn structures were observed for the three peptides and a conformation-activity model was developed based on these results. This study offers a structural basis for the design of novel peptide and non-peptide analogues to be used as new antimicrobial agents.
authors.affiliation: Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, Via D. Montesano 49, I-80131 Naples, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Saviello
authors.forename: Luigia
authors.initials: L
authors.lastname: Auriemma
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.forename: Anna
authors.initials: A
authors.lastname: Catania
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002176:Candida albicans / Q000187:drug effects*; D019295:Computational Biology; D009074:Melanocyte-Stimulating Hormones / Q000737:chemistry / Q000494:pharmacology; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D013057:Spectrum Analysis; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D010446:Peptide Fragments; C053656:ACTH (6-9); D000521:alpha-MSH; C043156:MSH (11-13); D000324:Adrenocorticotropic Hormone; D009074:Melanocyte-Stimulating Hormones