title: Synthesis, conformational analysis and biological properties of a dicarba derivative of the antimicrobial peptide, brevinin-1BYa.
abstract: Brevinin-1BYa (FLPILASLAAKFGPKLFCLVTKKC), first isolated from skin secretions of the frog Rana boylii, displays broad-spectrum antimicrobial activity and potent haemolytic activity. This study investigates the effects on conformation and biological activity of replacement of the intramolecular disulphide bridge in the peptide by a non-reducible dicarba bond. Dicarba-brevinin-1BYa was prepared by microwave irradiation of [Agl(18),Agl(24)]-brevinin-1BYa (Agl = allylglycine) in the presence of a second generation Grubbs' catalyst. Circular dichroism spectroscopy in 50% trifluoroethanol-water indicated that the degree of α-helicity of the dicarba derivative (22%) was less than that of brevinin-1BYa (27%) but comparable to that of the acyclic derivative [Ser(18),Ser(24)]-brevinin-1BYa (23%). Dicarba-brevinin-1BYa showed a two-fold increase in potency against reference strains of Escherichia coli, Staphylococcus aureus, and Candida albicans compared with the native peptide and displayed potent bactericidal activity against clinical isolates of methicillin-resistant S. aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MIC in the range 1-8 μM). Compared with brevinin-1BYa and [Ser(18),Ser(24)]-brevinin-1BYa, the dicarba derivative was associated with increased cytotoxicity against human erythrocytes (2.5-fold), MDA-MB-231 breast carcinoma cells (1.3-fold) and HepG2 hepatoma-derived cells (1.5-fold).
authors.affiliation: Florey Neuroscience Institutes and School of Chemistry, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Mohammed Akhter
authors.initials: MA
authors.lastname: Hossain
authors.forename: Laure
authors.initials: L
authors.lastname: Guilhaudis
authors.forename: Agnes
authors.initials: A
authors.lastname: Sonnevend
authors.forename: Samir
authors.initials: S
authors.lastname: Attoub
authors.forename: Bianca J
authors.initials: BJ
authors.lastname: van Lierop
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Robinson
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.forename: J Michael
authors.initials: JM
authors.lastname: Conlon
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology; D029845:Amphibian Proteins / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002942:Circular Dichroism; D004352:Drug Resistance, Microbial; D019008:Drug Resistance, Neoplasm; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D008969:Molecular Sequence Data
chemical_list: D000596:Amino Acids; D029845:Amphibian Proteins; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; C078413:brevinin-1 protein, Rana