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

    Fingerprint

    N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase
    Hydroxamic Acids
    Salicylic acid
    Trypanosoma brucei brucei
    Salicylic Acid
    Zinc
    Screening
    African Trypanosomiasis
    Trypanosomiasis
    Biosynthesis
    Structure-Activity Relationship
    Anchors
    Substitution reactions
    Ligands
    Molecules

    Cite this

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    title = "Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase",
    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.",
    author = "Urbaniak, {Michael D.} and Capes, {Amy S.} and Arthur Crossman and Sandra O'Neill and Stephen Thompson and Gilbert, {Ian H.} and Ferguson, {Michael A. J.}",
    note = "Copyright {\circledC} 2013 Elsevier Ltd. All rights reserved.",
    year = "2014",
    month = "3",
    day = "31",
    doi = "10.1016/j.carres.2013.12.016",
    language = "English",
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    journal = "Carbohydrate Research",
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    TY - JOUR

    T1 - Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase

    AU - Urbaniak, Michael D.

    AU - Capes, Amy S.

    AU - Crossman, Arthur

    AU - O'Neill, Sandra

    AU - Thompson, Stephen

    AU - Gilbert, Ian H.

    AU - Ferguson, Michael A. J.

    N1 - Copyright © 2013 Elsevier Ltd. All rights reserved.

    PY - 2014/3/31

    Y1 - 2014/3/31

    N2 - 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.

    AB - 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.

    U2 - 10.1016/j.carres.2013.12.016

    DO - 10.1016/j.carres.2013.12.016

    M3 - Article

    C2 - 24589444

    VL - 387

    SP - 54

    EP - 58

    JO - Carbohydrate Research

    JF - Carbohydrate Research

    SN - 0008-6215

    ER -