Chemical validation of GPI biosynthesis as a drug target against African sleeping sickness

Terry K. Smith, Arthur Crossman, John S. Brimacombe, Michael A. J. Ferguson

    Research output: Contribution to journalArticle

    54 Citations (Scopus)

    Abstract

    It has been suggested that compounds affecting glycosylphosphatidylinositol (GPI) biosynthesis in bloodstream form Trypanosoma brucei should be trypanocidal. We describe cell-permeable analogues of a GPI intermediate that are toxic to this parasite but not to human cells. These analogues are metabolized by the T. brucei GPI pathway, but not by the human pathway. Closely related nonmetabolizable analogues have no trypanocidal activity. This represents the first direct chemical validation of the GPI biosynthetic pathway as a drug target against African human sleeping sickness. The results should stimulate further inhibitor design and synthesis and encourage the search for inhibitors in natural product and synthetic compound libraries.
    Original languageEnglish
    Pages (from-to)4701-4708
    Number of pages8
    JournalThe EMBO Journal
    Volume23
    Issue number23
    DOIs
    Publication statusPublished - Nov 2004

    Fingerprint

    African Trypanosomiasis
    Glycosylphosphatidylinositols
    Biosynthesis
    Trypanosoma brucei brucei
    Pharmaceutical Preparations
    Poisons
    Biosynthetic Pathways
    Biological Products
    Libraries
    Parasites
    Cells

    Keywords

    • De-N-acetylase
    • Glycosylphosphatidylinositols
    • Inositol acyltransferase
    • Mannosyltransferase
    • Trypanosoma

    Cite this

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    title = "Chemical validation of GPI biosynthesis as a drug target against African sleeping sickness",
    abstract = "It has been suggested that compounds affecting glycosylphosphatidylinositol (GPI) biosynthesis in bloodstream form Trypanosoma brucei should be trypanocidal. We describe cell-permeable analogues of a GPI intermediate that are toxic to this parasite but not to human cells. These analogues are metabolized by the T. brucei GPI pathway, but not by the human pathway. Closely related nonmetabolizable analogues have no trypanocidal activity. This represents the first direct chemical validation of the GPI biosynthetic pathway as a drug target against African human sleeping sickness. The results should stimulate further inhibitor design and synthesis and encourage the search for inhibitors in natural product and synthetic compound libraries.",
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    Chemical validation of GPI biosynthesis as a drug target against African sleeping sickness. / Smith, Terry K.; Crossman, Arthur; Brimacombe, John S.; Ferguson, Michael A. J.

    In: The EMBO Journal, Vol. 23, No. 23, 11.2004, p. 4701-4708.

    Research output: Contribution to journalArticle

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    AU - Crossman, Arthur

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    AU - Ferguson, Michael A. J.

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