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

Terence Kenneth Smith, A Crossman, JS Brimacombe, MAJ Ferguson

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4701-4708
Number of pages8
JournalEMBO Journal
Volume23
Issue number23
DOIs
Publication statusPublished - 24 Nov 2004

Keywords

  • de-N-acetylase
  • glycosylphosphatidylinositol
  • inositol acyltransferase
  • mannosyltransferase
  • Trypanosoma
  • DE-N-ACETYLASE
  • GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHOR BIOSYNTHESIS
  • PHOSPHATIDYLINOSITOL MEMBRANE ANCHORS
  • VARIANT SURFACE GLYCOPROTEIN
  • TRYPANOSOMA-BRUCEI
  • SUBSTRATE-ANALOGS
  • INOSITOL-ACYLATION
  • MYRISTIC ACID
  • PATHWAY
  • PARASITE

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