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.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Urbaniak
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Capes
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Crossman
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: O'Neill
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Thompson
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK. Electronic address: i.h.gilbert@dundee.ac.uk.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK. Electronic address: m.a.j.ferguson@dundee.ac.uk.
authors.forename: Michael A J
authors.initials: MA
authors.lastname: Ferguson
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D011485:Protein Binding; D012459:Salicylates / Q000737:chemistry*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000201:enzymology / Q000469:parasitology*; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D006877:Hydroxamic Acids; D012459:Salicylates; D054852:Small Molecule Libraries; D000581:Amidohydrolases; C087696:N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase; D015032:Zinc
keywords: GPI; Hydroxamic acid; Inhibitor; N-Deacetylase; Trypanosoma brucei