TOXICITY OF MYRISTIC ACID ANALOGS TOWARD AFRICAN TRYPANOSOMES

New drugs are needed for treatment of diseases caused by African trypa nosomes. One possible target for chemotherapy is the biosynthesis of t he glycosyl phosphatidylinositol (GPI) of this parasite's variant surf ace glycoprotein (VSG). Unlike mammalian GPIs, the diacylglycerol moie ty of the VSG anchor contains only myristate (tetradecanoate), added i n unique remodeling reactions. We previously found that 11-oxatetradec anoic acid [i.e., 10-(propoxy)decanoic acid] is selectively toxic to t rypanosomes. We have now assayed 244 different fatty acid analogs, mos t with chain lengths comparable to that of myristate, for trypanocidal effects. In these assays we surveyed the effects on toxicity of syste matic alterations in the analogs' steric, conformational, and hydropho bic properties. We also used three H-3-labeled oxatetradecanoic acids to explore the mechanism of analog action. Their incorporation into VS G correlated roughly with toxicity, although they also were incorporat ed into phospholipids and other proteins. Myristate analogs are useful for studying the mechanism of GPI myristoylation, and they are candid ates for antitrypanosomal chemotherapy.