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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

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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.; Crossman, Arthur T.; Sullivan, Lauren; Ferguson, Michael A J; Urbaniak, Mick.

In: Chemical Biology and Drug Design, Vol. 79, No. 3, 03.2012, p. 270-278.

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Abdelwahab, Nuha Z. ; Crossman, Arthur T. ; Sullivan, Lauren ; Ferguson, Michael A J ; Urbaniak, Mick. / Inhibitors incorporating zinc-binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness. In: Chemical Biology and Drug Design. 2012 ; Vol. 79, No. 3. pp. 270-278.

Bibtex

@article{a5fb59646ba0496da5d99e9d8fa34555,
title = "Inhibitors incorporating zinc-binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness",
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.",
keywords = "carbohydrates, glycosylphosphatidylinositol, lipid, mechanism-based drug design, metalloenzymes, Trypanosoma brucei",
author = "Abdelwahab, {Nuha Z.} and Crossman, {Arthur T.} and Lauren Sullivan and Ferguson, {Michael A J} and Mick Urbaniak",
note = "Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms",
year = "2012",
month = mar,
doi = "10.1111/j.1747-0285.2011.01300.x",
language = "English",
volume = "79",
pages = "270--278",
journal = "Chemical Biology and Drug Design",
issn = "1747-0277",
publisher = "Blackwell",
number = "3",

}

RIS

TY - JOUR

T1 - Inhibitors incorporating zinc-binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness

AU - Abdelwahab, Nuha Z.

AU - Crossman, Arthur T.

AU - Sullivan, Lauren

AU - Ferguson, Michael A J

AU - Urbaniak, Mick

N1 - Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms

PY - 2012/3

Y1 - 2012/3

N2 - 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.

AB - 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.

KW - carbohydrates

KW - glycosylphosphatidylinositol

KW - lipid

KW - mechanism-based drug design

KW - metalloenzymes

KW - Trypanosoma brucei

U2 - 10.1111/j.1747-0285.2011.01300.x

DO - 10.1111/j.1747-0285.2011.01300.x

M3 - Journal article

VL - 79

SP - 270

EP - 278

JO - Chemical Biology and Drug Design

JF - Chemical Biology and Drug Design

SN - 1747-0277

IS - 3

ER -