Identification of a New Chemical Class of Antimalarials
Identification of a New Chemical Class of Antimalarials
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DOI：
10.1093/infdis/jis418
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发表时间：
2012-09-01
影响因子：
6.4
通讯作者：
Binkert, Christoph
中科院分区：
文献类型：
--
作者：
Brunner, Ralf;Aissaoui, Hamed;Binkert, Christoph
耐药疟疾菌株的日益蔓延强调了开发具有新型作用模式的新型抗疟药的必要性。在这里，我们描述了一种新型抗疟药的代表化合物。该分子ACT-213615能有效抑制所有恶性疟原虫菌株的体外红细胞生长，无论其耐药特性如何，其半数最大抑制浓度（IC50）值在低个位数纳摩尔范围内。与临床上使用的青蒿素一样，该化合物对无性红细胞寄生虫的所有3个阶段均有同等且非常迅速的影响。相反，微阵列研究表明，ACT-213615的MOA不同于青蒿素和其他已知抗疟药物。ACT-213615在小鼠体内是口服生物利用的，在小鼠伯氏疟原虫模型中显示出活性，在最近建立的恶性疟原虫SCID小鼠模型中显示出与对照药物氯喹相当的功效。ACT-213615是一类新的强效抗疟药，其临床潜力值得进一步研究。
The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (IC50) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials.ACT-213615 is orally bioavailable in mice, exhibits activity in the murine Plasmodium berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model.ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential.