Synthesis, conformational analysis and biological properties of a dicarba derivative of the antimicrobial peptide, brevinin-1BYa

• Published in: Biophysics of structure and mechanism 2011-04, Vol.40 (4), p.555-564
• Main Authors: Hossain, Mohammed Akhter, Guilhaudis, Laure, Sonnevend, Agnes, Attoub, Samir, van Lierop, Bianca J., Robinson, Andrea J., Wade, John D., Conlon, J. Michael
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii; Amino Acid Sequence; Amino Acids - chemistry; Amino Acids - pharmacology; Amphibian Proteins - chemistry; Amphibian Proteins - pharmacology; Animals; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Antimicrobial agents; Antimicrobial Cationic Peptides - chemical synthesis; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Bacteria - drug effects; Biochemistry; Biological and Medical Physics; Biological properties; Biomedical and Life Sciences; Biophysics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Candida albicans; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell Line; Chemical Sciences; Circular Dichroism; Cytotoxicity; Drug Resistance, Microbial; Drug Resistance, Neoplasm; E coli; Erythrocytes - metabolism; Erythrocytes - pathology; Escherichia coli; Frogs; Humans; Irradiation; Life Sciences; Membrane Biology; Microbial Sensitivity Tests; Molecular Conformation; Molecular Sequence Data; Nanotechnology; Neurobiology; Organic chemistry; Original Paper; Peptides; Protein synthesis; Rana boylii; Staphylococcus aureus
• ISSN: 0175-7571; 0340-1057; 1432-1017
• DOI: 10.1007/s00249-011-0679-2

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).