Department of Biochemistry & Molecular Biology, School of Biomedical Sciences, Monash University, Wellington Road, Clayton VIC, 3800, Australia.
Future Med Chem. 2012 Dec;4(18):2295-310. doi: 10.4155/fmc.12.183.
There is an urgent need for the development of new antimalarial drugs with novel modes of actions. The malarial parasite, Plasmodium falciparum, has a relatively small kinome of <100 kinases, with many members exhibiting a high degree of structural divergence from their host counterparts. A number of Plasmodium kinases have recently been shown by reverse genetics to be essential for various parts of the complex parasitic life cycle, and are thus genetically validated as potential targets. Implementation of mass spectrometry-based phosphoproteomics approaches has informed on key phospho-signalling pathways in the parasite. In addition, global phenotypic screens have revealed a large number of putative protein kinase inhibitors with antimalarial potency. Taken together, these investigations point to the Plasmodium kinome as a rich source of potential new targets. In this review, we highlight recent progress made towards this goal.
迫切需要开发具有新型作用模式的新抗疟药物。疟原虫，恶性疟原虫，激酶组相对较小，<100 个激酶，许多成员的结构与宿主对应物高度分化。最近的反向遗传学研究表明，许多疟原虫激酶对于复杂的寄生虫生命周期的各个部分都是必不可少的，因此在遗传上被验证为潜在的靶点。基于质谱的磷酸化蛋白质组学方法的实施为寄生虫中的关键磷酸信号通路提供了信息。此外，全局表型筛选揭示了大量具有抗疟潜力的假定蛋白激酶抑制剂。总之，这些研究表明恶性疟原虫激酶组是潜在新靶标的丰富来源。在这篇综述中，我们强调了在这一目标方面取得的最新进展。
