'Subversive' substrates for the enzyme trypanothione disulfide reductase: Alternative approach to chemotherapy of Chagas disease

G. B. Henderson, P. Ulrich, A. H. Fairlamb, I. Rosenberg, M. Pereira, M. Sela, A. Cerami

    Research output: Contribution to journalArticlepeer-review

    186 Citations (Scopus)

    Abstract

    The trypanosomatid flavoprotein disulfide reductase, trypanothione reductase, is shown to catalyze one-electron reduction of suitably substituted naphthoquinone and nitrofuran derivatives. A number of such compounds have been chemically synthesized, and a structure-activity relationship has been established; the enzyme is most active with compounds that contain basic functional groups in side-chain residues. The reduced products are readily reoxidized by molecular oxygen and thus undergo classical enzyme-catalyzed redox cycling. In addition to their ability to act as substrates for trypanothione reductase, the compounds are also shown to effectively inhibit enzymatic reduction of the enzyme's physiological substrate, trypanothione disulfide. Under aerobic conditions, trypanothione reductase is not inactivated by these redox-cycling substrates, whereas under anaerobic conditions the nitrofuran compounds cause irreversible inactivation of the enzyme. When tested for biological activity against Trypanosoma cruzi trypomastigotes, many of the compounds were trypanocidal, and this activity correlated with their relative ability to act as substrates for trypanothione reductase. The activity of the enzyme with these redox-cycling derivatives constitutes a subversion of its normal antioxidant role within the cell. For this reason these compounds may be termed 'subversive' substrates for trypanothione reductase.

    Original languageEnglish
    Pages (from-to)5374-5378
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume85
    Issue number15
    DOIs
    Publication statusPublished - 1 Aug 1988

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