Australian Army Malaria Institute, Gallipoli Barracks, Enoggera, QLD.
Curr Top Med Chem. 2012;12(5):456-72. doi: 10.2174/156802612799362922.
Millions of deaths each year are attributed to malaria worldwide. Transmitted through the bite of an Anopheles mosquito, infection and subsequent death from the Plasmodium species, most notably P. falciparum, can readily spread through a susceptible population. A malaria vaccine does not exist and resistance to virtually every antimalarial drug predicts that mortality and morbidity associated with this disease will increase. With only a few antimalarial drugs currently in the pipeline, new therapeutic options and novel chemotypes are desperately needed. Hit-to-Lead diversity may successfully provide novel inhibitory scaffolds when essential enzymes are targeted, for example, the plasmodial protein kinases. Throughout the entire life cycle of the malaria parasite, protein kinases are essential for growth and development. Ongoing efforts continue to characterize these kinases, while simultaneously pursuing them as antimalarial drug targets. A collection of structural data, inhibitory profiles and target validation has set the foundation and support for targeting the malarial kinome. Pursuing protein kinases as cancer drug targets has generated a wealth of information on the inhibitory strategies that can be useful for antimalarial drug discovery. In this review, progress on selected protein kinases is described. As the search for novel antimalarials continues, an understanding of the phosphor-regulatory pathways will not only validate protein kinase targets, but also will identify novel chemotypes to thwart malaria drug resistance.
每年有数百万人因疟疾而死亡。疟疾通过疟蚊叮咬传播，由疟原虫属引起，特别是恶性疟原虫，感染后很容易在易感人群中传播。目前还没有疟疾疫苗，而且几乎所有抗疟药物都产生了耐药性，这预示着与这种疾病相关的死亡率和发病率将会增加。由于目前只有几种抗疟药物在研发中，因此迫切需要新的治疗方法和新型化学结构。当针对关键酶（例如疟原虫蛋白激酶）时，命中至先导物的多样性可能会成功提供新颖的抑制支架。在疟原虫整个生命周期中，蛋白激酶对于生长和发育都是必不可少的。目前仍在继续努力对这些激酶进行表征，同时将它们作为抗疟药物靶点进行研究。一系列结构数据、抑制谱和靶标验证为靶向疟原虫激酶组奠定了基础并提供了支持。将蛋白激酶作为癌症药物靶点进行研究，为抗疟药物发现提供了大量关于抑制策略的信息。在这篇综述中，描述了选定蛋白激酶的研究进展。随着对新型抗疟药物的研究不断深入，对磷酸化调节途径的了解不仅将验证蛋白激酶靶标，还将确定新型化学结构来阻止疟疾药物耐药性。
