First small molecular inhibitors of T. brucei dolicholphosphate mannose synthase (DPMS), a validated drug target in African sleeping sickness.

Abstract

Drug-like molecules with activity against Trypanosoma brucei are urgently required as potential therapeutics for the treatment of African sleeping sickness. Starting from known inhibitors of other glycosyltransferases, we have developed the first small molecular inhibitors of dolicholphosphate mannose synthase (DPMS), a mannosyltransferase critically involved in glycoconjugate biosynthesis in T. brucei. We show that these DPMS inhibitors prevent the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, and possess trypanocidal activity against live trypanosomes.

• Authors: Terry K Smith, Benjamin L Young, Helen Denton, David L Hughes, Gerd K Wagner
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 6 Pg. 1749-52 (Mar 15 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19217283 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ethanol
• Mannosyltransferases
• dolichyl-phosphate beta-D-mannosyltransferase

Topics

• Animals
• Chemistry, Pharmaceutical (methods)
• Crystallography, X-Ray (methods)
• Drug Design
• Drug Evaluation, Preclinical
• Ethanol (chemistry)
• Humans
• Mannosyltransferases (antagonists & inhibitors, chemistry)
• Models, Chemical
• Molecular Conformation
• Molecular Structure
• Trypanosoma brucei brucei (enzymology)
• Trypanosomiasis, African (drug therapy)