Original Paper

European Biophysics Journal

, Volume 40, Issue 4, pp 555-564

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

  • Mohammed Akhter HossainAffiliated withFlorey Neuroscience Institutes and School of Chemistry, University of Melbourne
  • , Laure GuilhaudisAffiliated withLaboratoire de Chimie Organique Biologique et Structurale, CNRS UMR 6014, COBRA, European Institute for Peptide Research, Université de Rouen
  • , Agnes SonnevendAffiliated withDepartment of Medical Microbiology, Faculty of Medicine and Health Sciences, United Arab Emirates University
  • , Samir AttoubAffiliated withDepartment of Pharmacology, Faculty of Medicine and Health Sciences, United Arab Emirates University
  • , Bianca J. van LieropAffiliated withSchool of Chemistry, Monash University
  • , Andrea J. RobinsonAffiliated withSchool of Chemistry, Monash University
  • , John D. WadeAffiliated withFlorey Neuroscience Institutes and School of Chemistry, University of Melbourne
  • , J. Michael ConlonAffiliated withDepartment of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University Email author 

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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 [Agl18,Agl24]-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 [Ser18,Ser24]-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 [Ser18,Ser24]-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).

Keywords

Antibacterial and antifungal peptide Brevinin-1 Dicarba bond Cytotoxicity Ring-closing metathesis