nNOS inhibition, antimicrobial and anticancer activity of the amphibian skin peptide, citropin 1.1 and synthetic modifications. The solution structure of a modified citropin 1.1.
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 alpha-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 alpha-helix.
Doyle
Jason
J
Australian Institute for Marine Science, Townsville MC, Queensland, Australia.
Brinkworth
Craig S
CS
Wegener
Kate L
KL
Carver
John A
JA
Llewellyn
Lyndon E
LE
Olver
Ian N
IN
Bowie
John H
JH
Wabnitz
Paul A
PA
Tyler
Michael J
MJ
D029845:Amphibian Proteins; D000663:Amphibians; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D008826:Microbial Sensitivity Tests; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation
D029845:Amphibian Proteins; D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D010455:Peptides; C121829:citropin 1.1 protein, Litoria; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I