Urbaniak, Michael D. and Capes, Amy S. and Crossman, Arthur and O'Neill, Sandra and Thompson, Stephen and Gilbert, Ian H. and Ferguson, Michael A. J. (2014) Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase. Carbohydrate Research, 387. pp. 54-58. ISSN 0008-6215
Urbaniak_CRes_2014.pdf - Published Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.
Download (1MB)
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.