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Disruption of glycosylphosphatidylinositol biosynthesis is genetically and chemically validated as a drug target against the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. The N-acetylglucosamine-phosphatidylinositol de-N-acetylase (deNAc) is a zinc metalloenzyme responsible for the second step of glycosylphosphatidylinositol biosynthesis. We recently reported the synthesis of eight deoxy-2-C-branched monosaccharides containing carboxylic acid, hydroxamic acid, or N-hydroxyurea substituents at the C2 position that may act as zinc-binding groups. Here, we describe the synthesis of a glucocyclitol-phospholipid incorporating a hydroxamic acid moiety and report the biochemical evaluation of the monosaccharides and the glucocyclitol-phospholipid as inhibitors of the trypanosome deNAc in the cell-free system and against recombinant enzyme. Monosaccharides with carboxylic acid or hydroxamic acid substituents were found to be the inhibitors of the trypanosome deNAc with IC50 values 0.11.5 mm, and the glucocyclitol-phospholipid was found to be a dual inhibitor of the deNAc and the a1-4-mannose transferase with an apparent IC50 = 19 +/- 0.5 mu m.
- mechanism-based drug design
- Trypanosoma brucei
- GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHETIC-PATHWAY
- MEMBRANE ANCHOR BIOSYNTHESIS
- GPI BIOSYNTHESIS
FingerprintDive into the research topics of 'Inhibitors incorporating zinc-binding groups target the GlcNAc-PI de-N-acetylase in Trypanosoma brucei, the causative agent of African sleeping sickness'. Together they form a unique fingerprint.
- 1 Finished
Aref#d: 20731. The Biosynthesis of Glycoproteins in Trypanosoma Brucei: Basic and Translational Research
1/10/08 → 31/05/14