Rodrigues Goulart Herbert, Kimura Emília A, Peres Valnice J, Couto Alicia S, Aquino Duarte Fulgencio A, Katzin Alejandro M
Universidade de São Paulo, Av. Professor Lineu Prestes, 1374, CEP 05508-900 São Paulo, Brazil.
Antimicrob Agents Chemother. 2004 Jul;48(7):2502-9. doi: 10.1128/AAC.48.7.2502-2509.2004.
Development of new drugs is one of the strategies for malaria control. The biosynthesis of several isoprenoids in Plasmodium falciparum was recently described. Interestingly, some intermediates and final products biosynthesized by this pathway in mammals differ from those biosynthesized in P. falciparum. These facts prompted us to evaluate various terpenes, molecules with a similar chemical structure to the intermediates of the isoprenoids pathway, as potential antimalarial drugs. Different terpenes and S-farnesylthiosalicylic acid were tested on cultures of the intraerythrocytic stages of P. falciparum, and the 50% inhibitory concentrations for each one were found: farnesol, 64 microM; nerolidol, 760 nM; limonene, 1.22 mM; linalool, 0.28 mM; and S-farnesylthiosalicylic acid, 14 microM. All the terpenes tested inhibited dolichol biosynthesis in the trophozoite and schizont stages when [1-(n)-(3)H]farnesyl pyrophosphate triammonium salt ([(3)H]FPP) was used as precursor. Farnesol, nerolidol, and linalool showed stronger inhibitory activity on the biosynthesis of the isoprenic side chain of the benzoquinone ring of ubiquinones in the schizont stage. Treatment of schizont stages with S-farnesylthiosalicylic acid led to a decrease in intensity of the band corresponding a p21(ras) protein. The inhibitory effect of terpenes and S-farnesylthiosalicylic acid on the biosynthesis of both dolichol and the isoprenic side chain of ubiquinones and the isoprenylation of proteins in the intraerythrocytic stages of P. falciparum appears to be specific, because overall protein biosynthesis was not affected. Combinations of some terpenes or S-farnesylthiosalicylic acid tested in this work with other antimalarial drugs, like fosmidomycin, could be a new strategy for the treatment of malaria.
开发新药是疟疾控制策略之一。最近描述了恶性疟原虫中几种类异戊二烯的生物合成。有趣的是，该途径在哺乳动物中生物合成的一些中间体和终产物与在恶性疟原虫中生物合成的不同。这些事实促使我们评估各种萜类化合物，即与类异戊二烯途径中间体具有相似化学结构的分子，作为潜在的抗疟药物。对恶性疟原虫红细胞内期培养物测试了不同的萜类化合物和S - 法呢基硫代水杨酸，并确定了每种化合物的50%抑制浓度：法呢醇，64微摩尔；橙花叔醇，760纳摩尔；柠檬烯，1.22毫摩尔；芳樟醇，0.28毫摩尔；以及S - 法呢基硫代水杨酸，14微摩尔。当使用[1 - (n)-(3)H]法呢基焦磷酸三铵盐([(3)H]FPP)作为前体时，所有测试的萜类化合物在滋养体和裂殖体阶段均抑制了多萜醇的生物合成。法呢醇、橙花叔醇和芳樟醇在裂殖体阶段对泛醌苯醌环的异戊二烯侧链生物合成表现出更强的抑制活性。用S - 法呢基硫代水杨酸处理裂殖体阶段导致对应p21(ras)蛋白的条带强度降低。萜类化合物和S - 法呢基硫代水杨酸对恶性疟原虫红细胞内期多萜醇和泛醌异戊二烯侧链生物合成以及蛋白质异戊烯化的抑制作用似乎具有特异性，因为总体蛋白质生物合成未受影响。在这项工作中测试的一些萜类化合物或S - 法呢基硫代水杨酸与其他抗疟药物（如磷霉素）的联合使用可能是治疗疟疾的新策略。
