title: Specific peptide inhibitors of trypanothione reductase with backbone structures unrelated to that of substrate: potential rational drug design lead frameworks.
abstract: By introducing cationic charge sites novel peptide lead inhibitor structures for trypanothione reductase have been designed using molecular modelling methods. The inhibitors showed reversible, linear competitive inhibition and the strongest peptide inhibitor to date was found to be N-benzyloxycarbonyl-Ala-Arg-Arg-4-methoxy-beta-naphthylamide with a Ki value of 2.4 microM and a selectivity for parasitic enzyme (trypanothione reductase) over the host enzyme (human glutathione reductase) of over 3 orders of magnitude.
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, University of Manchester, United Kingdom.
authors.forename: J H
authors.initials: JH
authors.lastname: McKie
authors.forename: J
authors.initials: J
authors.lastname: Garforth
authors.forename: R
authors.initials: R
authors.lastname: Jaouhari
authors.forename: C
authors.initials: C
authors.lastname: Chan
authors.forename: H
authors.initials: H
authors.lastname: Yin
authors.forename: T
authors.initials: T
authors.lastname: Besheya
authors.forename: A H
authors.initials: AH
authors.lastname: Fairlamb
authors.forename: K T
authors.initials: KT
authors.lastname: Douglas
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000737:chemistry; D005980:Glutathione Reductase / Q000187:drug effects / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D009842:Oligopeptides; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D013095:Spermidine / Q000031:analogs & derivatives / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010455:Peptides; C070514:N-benzyloxycarbonyl-alanyl-arginyl-arginine 4-methoxy-2-naphthylamide; C044809:trypanothione; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005980:Glutathione Reductase; D005978:Glutathione; D013095:Spermidine