Gilson Paul R, Chisholm Scott A, Crabb Brendan S, de Koning-Ward Tania F
Burnet Institute, Melbourne, Victoria, Australia; Monash University, Melbourne, Victoria, Australia.
Deakin University, Waurn Ponds, Victoria, Australia.
Int J Parasitol. 2017 Feb;47(2-3):119-127. doi: 10.1016/j.ijpara.2016.06.001. Epub 2016 Jun 29.
When in their human hosts, malaria parasites spend most of their time housed within vacuoles inside erythrocytes and hepatocytes. The parasites extensively modify their host cells to obtain nutrients, prevent host cell breakdown and avoid the immune system. To perform these modifications, malaria parasites export hundreds of effector proteins into their host cells and this process is best understood in the most lethal species to infect humans, Plasmodium falciparum. The effector proteins are synthesized within the parasite and following a proteolytic cleavage event in the endoplasmic reticulum and sorting of mature proteins into the correct vesicular trafficking pathway, they are transported to the parasite surface and released into the vacuole. The effector proteins are then unfolded before extrusion across the vacuole membrane by a unique translocon complex called Plasmodium translocon of exported proteins. After gaining access to the erythrocyte cytoplasm many effector proteins continue their journey to the erythrocyte surface by utilising various membranous structures established by the parasite. This complex trafficking pathway and a large number of the effector proteins are unique to Plasmodium parasites. This pathway could, therefore, be developed as new drug targets given that protein export and the functional role of these proteins are essential for parasite survival. This review explores known and potential drug targetable steps in the protein export pathway and strategies for discovering novel drug targets.
疟原虫在人类宿主体内时，大部分时间都寄生于红细胞和肝细胞内的液泡中。疟原虫会对其宿主细胞进行广泛修饰，以获取营养、防止宿主细胞分解并躲避免疫系统。为了进行这些修饰，疟原虫会向宿主细胞输出数百种效应蛋白，而在最致命的人类感染疟原虫物种——恶性疟原虫中，对这一过程的了解最为深入。效应蛋白在疟原虫内合成，在内质网中经历蛋白水解切割事件并将成熟蛋白分选到正确的囊泡运输途径后，它们被运输到疟原虫表面并释放到液泡中。然后，效应蛋白在通过一种名为疟原虫输出蛋白转运体的独特转运体复合物穿过液泡膜之前会发生解折叠。进入红细胞细胞质后，许多效应蛋白会利用疟原虫建立的各种膜结构继续前往红细胞表面。这种复杂的运输途径以及大量效应蛋白是疟原虫所特有的。鉴于蛋白输出以及这些蛋白的功能作用对疟原虫的生存至关重要，因此这一途径可被开发为新的药物靶点。本综述探讨了蛋白输出途径中已知的和潜在的可药物靶向步骤以及发现新型药物靶点的策略。
