Toxicity of Myristic Acid Analogs Toward African Trypanosomes

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 a...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1994-10, Vol.91 (21), p.9735-9739
Main Authors: Doering, Tamara L., Lu, Tianbao, Werbovetz, Karl A., Gokel, George W., Hart, Gerald W., Gordon, Jeffrey I., Englund, Paul T.
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Biological Transport
Ethanol
Fatty acids
Glycolipids
Lipids
Molecular Structure
Myristates
Myristic Acids - chemistry
Myristic Acids - metabolism
Myristic Acids - toxicity
Nonesterified fatty acids
Phospholipids
Proteins
Structure-Activity Relationship
Tritium
Trypanocidal Agents - chemistry
Trypanocidal Agents - toxicity
Trypanosoma brucei
Trypanosoma brucei brucei - drug effects
Trypanosoma brucei brucei - growth & development
Trypanosoma brucei brucei - metabolism
Trypanosome
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Summary: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 three3H-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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.91.21.9735