Rosette-Disrupting Effect of an Anti-Plasmodial Compound for the Potential Treatment of Plasmodium falciparum Malaria Complications.
Rosette-Disrupting Effect of an Anti-Plasmodial Compound for the Potential Treatment of Plasmodium falciparum Malaria Complications.
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DOI：
10.1038/srep29317
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发表时间：
2016-07-11
影响因子：
4.6
通讯作者：
Wahlgren M
中科院分区：
文献类型：
--
作者：
Ch'ng JH;Moll K;Quintana Mdel P;Chan SC;Masters E;Moles E;Liu J;Eriksson AB;Wahlgren M
对青蒿素有抗药性的寄生虫的传播可能导致疟疾并发症患者的发病率上升。然而，目前还没有直接从微血管系统中清除隔离寄生虫的治疗方法。我们发现，四种常见的抗疟原虫药物不分散红细胞簇（疟疾寄生虫形成的红细胞簇），因此开发了一种基于细胞的高通量检测方法，以确定潜在的玫瑰花结破坏化合物。对2693种化合物进行的中试筛选将疟疾盒化合物MMV 006764鉴定为潜在候选物。尽管MMV006764使玫瑰花结减少了20%，但经验证，MMV006764对三种实验室寄生虫系的O型和A型血型寄生虫的有效性相似。再加上其抗疟原虫活性和药物相似性，MMV006764代表了第一个破坏玫瑰花结的小分子化合物，并可能在资源有限的环境中用于治疗因疟疾并发症而迅速恶化的患者。这种同时恢复微循环和减少寄生虫负荷的双重作用药物可以显着降低疟疾发病率和死亡率。
The spread of artemisinin-resistant parasites could lead to higher incidence of patients with malaria complications. However, there are no current treatments that directly dislodge sequestered parasites from the microvasculature. We show that four common antiplasmodial drugs do not disperse rosettes (erythrocyte clusters formed by malaria parasites) and therefore develop a cell-based high-throughput assay to identify potential rosette-disrupting compounds. A pilot screen of 2693 compounds identified Malaria Box compound MMV006764 as a potential candidate. Although it reduced rosetting by a modest 20%, MMV006764 was validated to be similarly effective against both blood group O and A rosettes of three laboratory parasite lines. Coupled with its antiplasmodial activity and drug-likeness, MMV006764 represents the first small-molecule compound that disrupts rosetting and could potentially be used in a resource-limited setting to treat patients deteriorating rapidly from malaria complications. Such dual-action drugs that simultaneously restore microcirculation and reduce parasite load could significantly reduce malaria morbidity and mortality.