Weiner January, Kooij Taco W A
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Department of Medical Microbiology & Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Microb Cell. 2016 Aug 30;3(10):511-521. doi: 10.15698/mic2016.10.534.
In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date.
为了抗击持续的疟疾流行，发现新的药物靶点仍然至关重要。对疟原虫生存至关重要且具有特异性的蛋白质是关键候选对象。为了在宿主细胞内生存，疟原虫需要跨多个膜获取营养并处理废物。此外，与所有真核生物一样，它们必须在其各种内部膜结合区室之间重新分配离子和有机分子。膜转运蛋白介导所有这些过程，并且本身被认为是耐药性的重要介导者以及药物靶点。最近，我们使用先进的实验遗传学方法和简化的生命周期分析，生成了大量基因缺失突变体并确定了必需基因的功能，突出了预防、治疗和阻断传播的抗疟药物的潜在靶点。在此，我们展示了所有推定的膜转运蛋白的全面直系同源物分配，并详细概述了通过在人类和鼠类模型寄生虫中进行的实验遗传学研究获得的相关必需基因功能。此外，我们讨论了在我们的功能筛选中鉴定出的选定潜在药物靶点的系统发育。我们在使用迄今为止可用的基因靶向获得的功能分配的背景下广泛讨论了结果。
