Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase

Michael D. Urbaniak, Amy S. Capes, Arthur Crossman, Sandra O'Neill, Stephen Thompson, Ian H. Gilbert (Lead / Corresponding author), Michael A. J. Ferguson (Lead / Corresponding author)

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    Abstract

    The zinc-metalloenzyme GlcNAc-PI de-N-acetylase is essential for the biosynthesis of mature GPI anchors and has been genetically validated in the bloodstream form of Trypanosoma brucei, which causes African sleeping sickness. We screened a focused library of zinc-binding fragments and identified salicylic hydroxamic acid as a GlcNAc-PI de-N-acetylase inhibitor with high ligand efficiency. This is the first small molecule inhibitor reported for the trypanosome GPI pathway. Investigating the structure activity relationship revealed that hydroxamic acid and 2-OH are essential for potency, and that substitution is tolerated at the 4- and 5-positions.
    Original languageEnglish
    Pages (from-to)54-58
    Number of pages5
    JournalCarbohydrate Research
    Volume387
    DOIs
    Publication statusPublished - 31 Mar 2014

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