Doering T L, Lu T, Werbovetz K A, Gokel G W, Hart G W, Gordon J I, Englund P T
Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205.
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9735-9. doi: 10.1073/pnas.91.21.9735.
New drugs are needed for treatment of diseases caused by African trypanosomes. One possible target for chemotherapy is the biosynthesis of the glycosyl phosphatidyl-inositol (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 myristolyation, and they are candidates for antitrypanosomal chemotherapy.
治疗由非洲锥虫引起的疾病需要新型药物。化疗的一个可能靶点是这种寄生虫可变表面糖蛋白（VSG）的糖基磷脂酰肌醇（GPI）生物合成。与哺乳动物的GPI不同，VSG锚定物的二酰基甘油部分仅含有肉豆蔻酸（十四烷酸），这是在独特的重塑反应中添加的。我们之前发现11 - 氧代十四烷酸[即10 - （丙氧基）癸酸]对锥虫具有选择性毒性。我们现在检测了244种不同的脂肪酸类似物，其中大多数的链长与肉豆蔻酸相当，以评估它们的杀锥虫效果。在这些检测中，我们研究了类似物体积、构象和疏水性质的系统性改变对毒性的影响。我们还使用了三种3H标记的氧代十四烷酸来探究类似物的作用机制。它们掺入VSG的情况大致与毒性相关，尽管它们也会掺入磷脂和其他蛋白质中。肉豆蔻酸类似物可用于研究GPI肉豆蔻酰化的机制，并且它们是抗锥虫化疗的候选药物。
