| Inhibitors incorporating zinc binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness. | |
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MedLine Citation:
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PMID: 22222041 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Disruption of glycosylphosphatidylinositol (GPI) 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 GPI 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 inhibitors of the trypanosome deNAc with IC(50) 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 IC(50) = 19 ± 0.5 μM. © 2011 John Wiley & Sons A/S. |
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Authors:
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Nuha Z Abdelwahab; Arthur T Crossman; Lauren Sullivan; Michael A J Ferguson; Michael D Urbaniak |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-12-16 |
Journal Detail:
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Title: Chemical biology & drug design Volume: - ISSN: 1747-0285 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2012-1-6 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101262549 Medline TA: Chem Biol Drug Des Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2011 John Wiley & Sons A/S. |
Affiliation:
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Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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