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

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  • Michael D. Urbaniak
  • Amy S. Capes
  • Arthur Crossman
  • Sandra O'Neill
  • Stephen Thompson
  • Ian H. Gilbert
  • Michael A. J. Ferguson
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<mark>Journal publication date</mark>31/03/2014
<mark>Journal</mark>Carbohydrate Research
Volume387
Number of pages5
Pages (from-to)54-58
Publication StatusPublished
<mark>Original language</mark>English

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.

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Copyright © 2013 Elsevier Ltd. All rights reserved. This article is distributed under the terms of the Creative Commons Attribution-Noncommercial-No Derivative Works License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.