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Inhibitors incorporating zinc-binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness

Abdelwahab, Nuha Z. and Crossman, Arthur T. and Sullivan, Lauren and Ferguson, Michael A J and Urbaniak, Mick (2012) Inhibitors incorporating zinc-binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness. Chemical Biology and Drug Design, 79 (3). pp. 270-278. ISSN 1747-0277

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    Abstract

    Disruption of glycosylphosphatidylinositol biosynthesis is genetically and chemically validated as a drug target against the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. The N-acetylglucosamine-phosphatidylinositol de-N-acetylase (deNAc) is a zinc metalloenzyme responsible for the second step of glycosylphosphatidylinositol biosynthesis. We recently reported the synthesis of eight deoxy-2-C-branched monosaccharides containing carboxylic acid, hydroxamic acid, or N-hydroxyurea substituents at the C2 position that may act as zinc-binding groups. Here, we describe the synthesis of a glucocyclitol-phospholipid incorporating a hydroxamic acid moiety and report the biochemical evaluation of the monosaccharides and the glucocyclitol-phospholipid as inhibitors of the trypanosome deNAc in the cell-free system and against recombinant enzyme. Monosaccharides with carboxylic acid or hydroxamic acid substituents were found to be the inhibitors of the trypanosome deNAc with IC50 values 0.1–1.5 mM, and the glucocyclitol-phospholipid was found to be a dual inhibitor of the deNAc and the α1-4-mannose transferase with an apparent IC50 = 19 ± 0.5 μM.

    Item Type: Article
    Journal or Publication Title: Chemical Biology and Drug Design
    Additional Information: Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms
    Uncontrolled Keywords: carbohydrates ; glycosylphosphatidylinositol ; lipid ; mechanism-based drug design ; metalloenzymes ; Trypanosoma brucei
    Subjects:
    Departments: Faculty of Health and Medicine > Biomedical & Life Sciences
    ID Code: 66387
    Deposited By: ep_importer_pure
    Deposited On: 17 Sep 2013 09:07
    Refereed?: Yes
    Published?: Published
    Last Modified: 21 Sep 2017 05:47
    Identification Number:
    URI: http://eprints.lancs.ac.uk/id/eprint/66387

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