Peptoid inhibition of trypanothione reductase as a potential antitrypanosomal and antileishmanial drug lead.
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).
Chan
C
C
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
Yin
H
H
McKie
J H
JH
Fairlamb
A H
AH
Douglas
K T
KT
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
D000981:Antiprotozoal Agents; D034444:Peptoids; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005980:Glutathione Reductase