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

Carbohydr Res. 2014 Mar 31;387(100):54-8. doi: 10.1016/j.carres.2013.12.016. Epub 2013 Dec 30.

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.

Keywords: GPI; Hydroxamic acid; Inhibitor; N-Deacetylase; Trypanosoma brucei.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism*
  • Humans
  • Hydroxamic Acids / chemistry*
  • Protein Binding
  • Salicylates / chemistry*
  • Small Molecule Libraries
  • Structure-Activity Relationship
  • Substrate Specificity
  • Trypanosoma brucei brucei / enzymology*
  • Trypanosomiasis, African / enzymology
  • Trypanosomiasis, African / parasitology*
  • Zinc / chemistry
  • Zinc / metabolism

Substances

  • Hydroxamic Acids
  • Salicylates
  • Small Molecule Libraries
  • Amidohydrolases
  • N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase
  • Zinc