Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins
Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins
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DOI：
10.1073/pnas.1306097110
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发表时间：
2013-07-23
影响因子：
11.1
通讯作者：
Mota, Maria M.
中科院分区：
文献类型：
--
作者：
Hanson, Kirsten K.;Ressurreicao, Ana S.;Mota, Maria M.
在定制的液泡中居住是各种细胞内微生物使用的一种非常成功的策略。寄生虫液泡膜(PVM)是疟原虫与其可能具有敌意但最终维持的宿主细胞环境之间的关键界面。我们发现，作为雷帕霉素(MTOR)激酶抑制剂的ATP竞争性哺乳动物靶标的Torins，是一种快速作用的抗疟原虫化合物，出人意料地直接靶向寄生虫，阻止疟原虫蛋白输出蛋白1(EXP1)的动态运输，并在子孢子4(UIS4)中上调到肝期PVM，导致肝细胞有效地清除寄生虫。在体外，Torin2在肝脏和血液感染阶段都具有个位数或更低的纳摩尔效力，在体内对这两个阶段都同样有效，单次口服剂量足以清除肝脏阶段感染。驱除寄生虫和扰动转运肝期PVM驻留蛋白都是Torin介导的肝期抑制疟原虫的特异性方面，表明Torins与目前使用的抗疟疾药物相比具有不同的作用模式。
Residence within a customized vacuole is a highly successful strategy used by diverse intracellular microorganisms. The parasitophorous vacuole membrane (PVM) is the critical interface between Plasmodium parasites and their possibly hostile, yet ultimately sustaining, host cell environment. We show that torins, developed as ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitors, are fast-acting antiplasmodial compounds that unexpectedly target the parasite directly, blocking the dynamic trafficking of the Plasmodium proteins exported protein 1 (EXP1) and upregulated in sporozoites 4 (UIS4) to the liver stage PVM and leading to efficient parasite elimination by the hepatocyte. Torin2 has single-digit, or lower, nanomolar potency in both liver and blood stages of infection in vitro and is likewise effective against both stages in vivo, with a single oral dose sufficient to clear liver stage infection. Parasite elimination and perturbed trafficking of liver stage PVM-resident proteins are both specific aspects of torin-mediated Plasmodium liver stage inhibition, indicating that torins have a distinct mode of action compared with currently used antimalarials.