Trypanothione is the primary target for arsenical drugs against African trypanosomes

A. H. Fairlamb, G. B. Henderson, A. Cerami

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    164 Citations (Scopus)

    Abstract

    The trypanosomatid metabolite N1,N8-bis-(glutathionyl)spermidine (trypanothione) has been demonstrated to form a stable adduct with the aromatic arsenical drug melarsen oxide [p-(4,6-diamino-s-triazinyl-2-yl)aminophenyl arsenoxide]. The stability constant of the melarsen-trypanothione adduct (Mel T) has been determined to be 1.05 x 107 M-1. When bloodstream Trypanosoma brucei are incubated with either melarsen oxide or the 2,3-dimercaptopropanol adduct of melarsen oxide (melarsoprol), Mel T is the only arsenical derivative detectable in acid-soluble extracts of the cells. Trypanothione may therefore be regarded as a primary target for aromatic arsenical derivatives against African trypanosomes. The selective toxic action of these compounds might arise through sequestration of intracellular trypanothione in the form of Mel T, or Mel T itself may be toxic within the cell. The latter possibility is illustrated by the finding that Mel T is an inhibitor of trypanothione reductase from T. bruci (K(i) = 9.0 μM) - an enzyme that is central to the regulation of the thiol/disulfide redox balance in the parasite and absent from the host.

    Original languageEnglish
    Pages (from-to)2607-2611
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume86
    Issue number8
    DOIs
    Publication statusPublished - 1 Apr 1989

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