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Article

  • The EMBO Journal (2004) 23, 4701 - 4708
  • doi:10.1038/sj.emboj.7600456

Published online: 4 November 2004

Chemical validation of GPI biosynthesis as a drug target against African sleeping sickness

Terry K Smith, Arthur Crossman, John S Brimacombe and Michael A J Ferguson

  1. Division of Biological Chemistry and Molecular Microbiology, The Wellcome Trust Biocentre, School of Life Sciences, University of Dundee, Dundee, Scotland, UK

Correspondence to:

Michael A J Ferguson, Department of Biochemistry, Medical Sciences Institute, University of Dundee, Dundee DD1 5EH, Scotland, UK. Tel.: +44 1382 344 219; Fax: +44 1382 345764; E-mail: m.a.j.ferguson@dundee.ac.uk

Received 16 August 2004; Accepted 1 October 2004

It has been suggested that compounds affecting glycosylphosphatidylinositol (GPI) biosynthesis in bloodstream form Trypanosoma brucei should be trypanocidal. We describe cell-permeable analogues of a GPI intermediate that are toxic to this parasite but not to human cells. These analogues are metabolized by the T. brucei GPI pathway, but not by the human pathway. Closely related nonmetabolizable analogues have no trypanocidal activity. This represents the first direct chemical validation of the GPI biosynthetic pathway as a drug target against African human sleeping sickness. The results should stimulate further inhibitor design and synthesis and encourage the search for inhibitors in natural product and synthetic compound libraries.

  • Keywords:

    • de-N-acetylase,
    • glycosylphosphatidylinositol,
    • inositol acyltransferase,
    • mannosyltransferase,
    • Trypanosoma