Mitosis has been validated by numerous anti-cancer drugs as being a druggable process, and selective inhibition of parasite proliferation provides an obvious opportunity for therapeutic intervention against malaria. Mitosis is controlled through the interplay between several protein kinases and phosphatases. We show here that inhibitors of human mitotic kinases belonging to the Aurora family inhibit P. falciparum proliferation in vitro with various potencies, and that a genetic selection for mutant parasites resistant to one of the drugs, Hesperadin, identifies a resistance mechanism mediated by a member of a different kinase family, PfNek1 (PF3D7_1228300). Intriguingly, loss of PfNek1 catalytic activity provides protection against drug action. This points to an undescribed functional interaction between Ark and Nek kinases and shows that existing inhibitors can be used to validate additional essential and druggable kinase functions in the parasite.

有丝分裂已被许多抗癌药物证实是可药物化的过程，对寄生虫增殖的选择性抑制为治疗疟疾提供了明显的机会。有丝分裂是通过几种蛋白激酶和磷酸酶之间的相互作用来控制的。我们在这里显示属于Aurora家族的人类有丝分裂激酶的抑制剂抑制恶性疟原虫体外增殖具有各种潜能，并且对一种药物Hesperadin产生抗药性的突变寄生虫的遗传选择确定了由另一种激酶家族PfNek1（PF3D7_1228300）介导的抗药性机制。有趣的是，PfNek1催化活性的丧失为药物作用提供了保护。这表明了Ark和Nek激酶之间未描述的功能相互作用，表明现有的抑制剂可用于验证该寄生虫中其他必需的和可药用的激酶功能。