Toxicity of myristic acid analogs toward African trypanosomes

Tamara L. Doering, Tianbao Lu, Karl A. Werbovetz, George W. Gokel, Gerald W. Hart, Jeffrey I. Gordon, Paul T. Englund

Research output: Contribution to journalArticlepeer-review

Abstract

New drugs are needed for treatment of diseases caused by African trypanosomes. One possible target for chemotherapy is the biosynthesis of the glycosyl phosphatidylinositol (GPI) of this parasite's variant surface glycoprotein (VSG). Unlike mammalian GPIs, the diacylglycerol moiety of the VSG anchor contains only myristate (tetradecanoate), added in unique remodeling reactions. We previously found that 11-oxatetradecanoic acid [i.e., 10-(propoxy)decanoic acid] is selectively toxic to trypanosomes. We have now assayed 244 different fatty acid analogs, most with chain lengths comparable to that of myristate, for trypanocidal effects. In these assays we surveyed the effects on toxicity of systematic alterations in the analogs' steric, conformational, and hydrophobic properties. We also used three 3H- labeled oxatetradecanoic acids to explore the mechanism of analog action. Their incorporation into VSG correlated roughly with toxicity, although they also were incorporated into phospholipids and other proteins. Myristate analogs are useful for studying the mechanism of GPI myristoylation, and they are candidates for antitrypanosomal chemotherapy.

Original languageEnglish (US)
Pages (from-to)9735-9739
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number21
DOIs
StatePublished - Oct 11 1994

ASJC Scopus subject areas

  • General

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