Open AccessnNOS inhibition, antimicrobial and anticancer activity of the amphibian skin peptide, citropin 1.1 and synthetic modifications
Author(s) -
Doyle Jason,
Brinkworth Craig S.,
Wegener Kate L.,
Carver John A.,
Llewellyn Lyndon E.,
Olver Ian N.,
Bowie John H.,
Wabnitz Paul A.,
Tyler Michael J.
Publication year - 2003
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1033.2003.03462.x
Subject(s) - amphiphile , peptide , antimicrobial , chemistry , nitric oxide , biological activity , nitric oxide synthase , structure–activity relationship , biochemistry , mechanism of action , stereochemistry , in vitro , enzyme , organic chemistry , copolymer , polymer
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 1.1, 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 1.1 has been shown previously to form an amphipathic α‐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 1.1) was determined in aqueous trifluoroethanol, showing that this peptide also forms an amphipathic α‐helix.