In Vitro and In Vivo Antiplasmodial Activities of Risedronate and Its Interference with Protein Prenylation in Plasmodium falciparum
In Vitro and In Vivo Antiplasmodial Activities of Risedronate and Its Interference with Protein Prenylation in Plasmodium falciparum
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DOI：
10.1128/aac.01820-10
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发表时间：
2011-05-01
影响因子：
4.9
通讯作者：
Katzin, Alejandro Miguel
中科院分区：
文献类型：
--
作者：
Jordao, Fabiana Morandi;Saito, Alexandre Yukio;Katzin, Alejandro Miguel
疟疾寄生虫对几乎所有可用药物的耐药性不断增强，需要鉴定新化合物并检测新靶点。在此，我们确定了利塞膦酸盐（临床上用于治疗骨吸收疾病的最有效的双膦酸盐之一）针对恶性疟原虫血液阶段的抗疟活性（50% 抑制浓度 [IC(50)] 为 20.3 +/- 1.0 μM）。我们还提出了利塞膦酸盐对抗恶性疟原虫红细胞内阶段的作用机制，并表明蛋白质异戊二烯化似乎是由该药物直接调节的。利塞膦酸盐抑制法尼基焦磷酸基团向寄生虫蛋白的转移，而香叶基香叶基焦磷酸基团的转移未观察到这种效应。我们的体内实验进一步证明，利塞膦酸钠在治疗第七天对小鼠体内的啮齿类寄生虫伯氏疟原虫有 88.9% 的抑制作用；然而，利塞膦酸盐治疗并没有导致生存率普遍提高。
The increasing resistance of malarial parasites to almost all available drugs calls for the identification of new compounds and the detection of novel targets. Here, we establish the antimalarial activities of risedronate, one of the most potent bisphosphonates clinically used to treat bone resorption diseases, against blood stages of Plasmodium falciparum (50% inhibitory concentration [IC(50)] of 20.3 +/- 1.0 mu M). We also suggest a mechanism of action for risedronate against the intraerythrocytic stage of P. falciparum and show that protein prenylation seems to be modulated directly by this drug. Risedronate inhibits the transfer of the farnesyl pyrophosphate group to parasite proteins, an effect not observed for the transfer of geranylgeranyl pyrophosphate. Our in vivo experiments further demonstrate that risedronate leads to an 88.9% inhibition of the rodent parasite Plasmodium berghei in mice on the seventh day of treatment; however, risedronate treatment did not result in a general increase of survival rates.