title: Peptoid inhibition of trypanothione reductase as a potential antitrypanosomal and antileishmanial drug lead.
abstract: One route to the design of lead compounds for rational drug design approaches to developing drugs against trypanosomiasis, Chagas' disease and leishmaniasis is to develop novel inhibitors of the parasite-specific enzyme trypanothione reductase. A lead inhibitor based on a peptoid structure was designed in the present study based on the known strong competitive inhibition of trypanothione reductase by N-benzoyl-Leu-Arg-Arg-beta-naphthylamide and N-benzyloxycarbonyl-Ala-Arg-Arg-4-methoxy- beta-naphthylamide. In the target peptoid the arginyl residues were replaced by alkylimidazolium units and the benzyloxycarbonyl group by the benzylaminocarbonyl function. The peptoid was synthesised using t-butoxycarbonyl protection chemistry and couplings were activated by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. The resulting peptoid was shown to be a competitive inhibitor of recombinant trypanothione reductase from Trypanosoma cruzi with a K(i) value of 179 microM and with only weak inhibition of human erythrocyte glutathione reductase (the inhibition of glutathione reductase was at least 291-fold weaker than of trypanothione reductase).
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
authors.forename: C
authors.initials: C
authors.lastname: Chan
authors.forename: H
authors.initials: H
authors.lastname: Yin
authors.forename: J H
authors.initials: JH
authors.lastname: McKie
authors.forename: A H
authors.initials: AH
authors.lastname: Fairlamb
authors.forename: K T
authors.initials: KT
authors.lastname: Douglas
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D034444:Peptoids / Q000138:chemical synthesis / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents; D034444:Peptoids; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005980:Glutathione Reductase