(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium
(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium
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DOI：
10.1073/pnas.1414221111
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发表时间：
2014-12-16
影响因子：
11.1
通讯作者：
Guy, R. Kiplin
中科院分区：
文献类型：
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作者：
Belen Jimenez-Diaz, Maria;Ebert, Daniel;Guy, R. Kiplin
在过去的5年里，通过表型筛选发现了许多新的先导化合物，从而改变了疟疾药物的发现。开发这些化合物作为药物先导并研究它们诱导的细胞反应的过程揭示了调节引起疟疾的疟原虫寄生虫关键过程的新靶点。我们在本文中公开了临床候选物（+）-SJ 733作用于这些靶标之一ATP 4。ATP 4被认为是负责维持寄生虫细胞内低Na+水平的阳离子转运ATP酶。在体外用（+）-SJ 733处理寄生的红细胞引起寄生虫中Na+稳态的快速扰动。这种扰动之后，感染细胞发生了深刻的物理变化，包括膜刚性增加和磷脂酰丝氨酸的外化，与红细胞凋亡（红细胞自杀）或衰老一致。提出这些变化是为了支持体内观察到的（+）-SJ 733诱导的寄生虫快速清除。恶性疟原虫ATP酶4（pfatp 4）突变赋予对（+）-SJ 733的抗性，其携带高适应性成本。（+）-SJ 733杀死寄生虫的速度以及与赋予耐药性的突变相关的高适应度成本似乎会减缓并抑制体内高度耐药突变体的选择。总之，我们的数据表明，PfATP 4抑制剂具有非常有吸引力的功能，可用于全球根除运动的速效抗疟药。
Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na+ levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na+ homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.