tailieunhanh - Báo cáo khoa học: nNOS inhibition, antimicrobial and anticancer activity of the amphibian skin peptide, citropin 1.1 and synthetic modifications

A large number of bioactive peptides have been isolated from amphibian skin secretions. These peptides have a variety of actions including antibiotic and anticancer acti-vities and the inhibition of neuronal nitric oxide synthase. We have investigated the structure–activity relationship of citropin , a broad-spectrum antibiotic and anticancer agent that also causes inhibition of neuronal nitric oxide synthase, by making a number of synthetically modified analogues. | Eur. J. Biochem. 270 1141-1153 2003 FEBS 2003 doi nNOS inhibition antimicrobial and anticancer activity of the amphibian skin peptide citropin and synthetic modifications The solution structure of a modified citropin Jason Doyle1 Craig S. Brinkworth2 Kate L. Wegener2 John A. Carver3 Lyndon E. Llewellyn1 Ian N. Olver4 John H. Bowie2 Paul A. Wabnitz2 and Michael J. Tyler5 1 Australian Institute for Marine Science Townsville MC Queensland Australia department of Chemistry The University of Adelaide Australia 3Department of Chemistry University of Wollongong Wollongong Australia 4Oncology Department Royal Adelaide Hospital and Department of Medicine The University of Adelaide South Australia Australia 5Department of Environmental Biology The University of Adelaide South Australia Australia A large number of bioactive peptides have been isolated from amphibian skin secretions. These peptides have a variety of actions including antibiotic and anticancer activities and the inhibition of neuronal nitric oxide synthase. We have investigated the structure-activity relationship of citropin a broad-spectrum antibiotic and anticancer agent that also causes inhibition of neuronal nitric oxide synthase by making a number of synthetically modified analogues. Citropin has been shown previously to form an amphipathic a-helix in aqueous trifluoroethanol. The results of the structure-activity studies indicate the terminal residues are important for bacterial activity and increasing the overall positive charge while maintaining an amphipathic distribution of residues increases activity against Gram-negative organisms. Anticancer activity generally mirrors antibiotic activity suggesting a common mechanism of action. The N-terminal residues are important for inhibition of neuronal nitric oxide synthase as is an overall positive charge greater than three. The structure of one of the more active synthetic modifications A4K14-citropin was