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; Michael A. J. Ferguson

doi:10.1016/j.carres.2013.12.016

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 language	English
Pages (from-to)	54-58
Number of pages	5
Journal	Carbohydrate Research
Volume	387
DOIs	https://doi.org/10.1016/j.carres.2013.12.016
Publication status	Published - 31 Mar 2014

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10.1016/j.carres.2013.12.016

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Protein Glycosylation in Trypanosomes: Defining and Exploiting a Biological System (Senior Investigator Award)
Ferguson, M. (Investigator)
1/10/13 → 30/06/23
Project: Research
Aref#d: 20731. The Biosynthesis of Glycoproteins in Trypanosoma Brucei: Basic and Translational Research
Ferguson, M. (Investigator) & Gilbert, I. (Investigator)
1/10/08 → 31/05/14
Project: Research

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.}",

year = "2014",

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day = "31",

doi = "10.1016/j.carres.2013.12.016",

language = "English",

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journal = "Carbohydrate Research",

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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.

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

SN - 0008-6215

VL - 387

SP - 54

EP - 58

JO - Carbohydrate Research

JF - Carbohydrate Research

ER -

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

Abstract

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Projects

Protein Glycosylation in Trypanosomes: Defining and Exploiting a Biological System (Senior Investigator Award)

Aref#d: 20731. The Biosynthesis of Glycoproteins in Trypanosoma Brucei: Basic and Translational Research

Cite this