Rational design of peptide-based inhibitors of trypanothione reductase as potential antitrypanosomal drugs

J. Garforth, J. H. McKie, R. Jaouhari, T. J. Benson, A. H. Fairlamb, K. T. Douglas

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    26 Citations (Scopus)

    Abstract

    The rational design of ligands for the substrate-binding site of a homology-modelled trypanothione reductase (TR) was performed. Peptides were designed to be selective for TR over human glutathione reductase (GR). The design process capitalized on the proposed differences between the activesites of TR and human GR, subsequently confirmed by the TR crystal structure. Enzyme kinetics confirmed that for T. cruzi TR benzoyl-Leu-Arg-Arg-ß-naphthylamide was an inhibitor (Ki 13.8 μM) linearly competitive with the native substrate, trypanothione disulphide, and did not inhibit glutathione reductase.

    Original languageEnglish
    Pages (from-to)295-299
    Number of pages5
    JournalAmino Acids
    Volume6
    Issue number3
    DOIs
    Publication statusPublished - Oct 1994

    Keywords

    • Amino acids
    • Drug design
    • Glutathione reductase
    • Homology model
    • Leishmaniasis
    • Trypanosomiasis
    • Trypanothione reductase

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