TY - JOUR
T1 - Synthesis, conformational analysis and biological properties of a dicarba derivative of the antimicrobial peptide, brevinin-1BYa
AU - Hossain, Mohammed Akhter
AU - Guilhaudis, Laure
AU - Sonnevend, Agnes
AU - Attoub, Samir
AU - Van Lierop, Bianca J.
AU - Robinson, Andrea J.
AU - Wade, John D.
AU - Conlon, J. Michael
PY - 2011/4
Y1 - 2011/4
N2 - 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,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 [Ser 18,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).
AB - 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,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 [Ser 18,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).
KW - Antibacterial and antifungal peptide
KW - Brevinin-1
KW - Cytotoxicity
KW - Dicarba bond
KW - Ring-closing metathesis
UR - http://www.scopus.com/inward/record.url?scp=79956018809&partnerID=8YFLogxK
U2 - 10.1007/s00249-011-0679-2
DO - 10.1007/s00249-011-0679-2
M3 - Article
C2 - 21312033
AN - SCOPUS:79956018809
SN - 0175-7571
VL - 40
SP - 555
EP - 564
JO - European Biophysics Journal
JF - European Biophysics Journal
IS - 4
ER -