Peptoid inhibition of trypanothione reductase as a potential antitrypanosomal and antileishmanial drug lead

C. Chan, H. Yin, J. H. McKie, A. H. Fairlamb, K. T. Douglas

    Research output: Contribution to journalArticlepeer-review

    17 Citations (Scopus)

    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-β-naphthylamide and N-benzyloxycarbonyl-Ala-Arg-Arg-4-methoxy-β-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 Ki value of 179μM 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).

    Original languageEnglish
    Pages (from-to)297-308
    Number of pages12
    JournalAmino Acids
    Volume22
    Issue number4
    DOIs
    Publication statusPublished - Jun 2002

    Keywords

    • Antiparasitics
    • Drug leads
    • Enzyme inhibitors
    • Glutathione
    • Rational drug design

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