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

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 sal...

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Autores principales: Urbaniak, Michael D., Capes, Amy S., Crossman, Arthur, O’Neill, Sandra, Thompson, Stephen, Gilbert, Ian H., Ferguson, Michael A.J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2014
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991331/
https://www.ncbi.nlm.nih.gov/pubmed/24589444
http://dx.doi.org/10.1016/j.carres.2013.12.016
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author Urbaniak, Michael D.
Capes, Amy S.
Crossman, Arthur
O’Neill, Sandra
Thompson, Stephen
Gilbert, Ian H.
Ferguson, Michael A.J.
author_facet Urbaniak, Michael D.
Capes, Amy S.
Crossman, Arthur
O’Neill, Sandra
Thompson, Stephen
Gilbert, Ian H.
Ferguson, Michael A.J.
author_sort Urbaniak, Michael D.
collection PubMed
description 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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spelling pubmed-39913312014-04-18 Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase Urbaniak, Michael D. Capes, Amy S. Crossman, Arthur O’Neill, Sandra Thompson, Stephen Gilbert, Ian H. Ferguson, Michael A.J. Carbohydr Res Article 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. Elsevier 2014-03-31 /pmc/articles/PMC3991331/ /pubmed/24589444 http://dx.doi.org/10.1016/j.carres.2013.12.016 Text en © 2013 Elsevier Ltd. http://creativecommons.org/licenses/by/3.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Urbaniak, Michael D.
Capes, Amy S.
Crossman, Arthur
O’Neill, Sandra
Thompson, Stephen
Gilbert, Ian H.
Ferguson, Michael A.J.
Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase
title Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase
title_full Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase
title_fullStr Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase
title_full_unstemmed Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase
title_short Fragment screening reveals salicylic hydroxamic acid as an inhibitor of Trypanosoma brucei GPI GlcNAc-PI de-N-acetylase
title_sort fragment screening reveals salicylic hydroxamic acid as an inhibitor of trypanosoma brucei gpi glcnac-pi de-n-acetylase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991331/
https://www.ncbi.nlm.nih.gov/pubmed/24589444
http://dx.doi.org/10.1016/j.carres.2013.12.016
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