Malaria is a devastating disease that resulted in an estimated 627,000 deaths in 2020. About 80% of those deaths were among children under the age of five. Our approach is to develop small molecule inhibitors against cytoskeletal targets that are vital components of parasite function, essential at multiple stages of parasite infection, can be targeted with high specificity, and are highly druggable. Here we describe KNX-115, which inhibits purified Plasmodium falciparum myosin A (PfMyoA) actin-activated ATPase with a potency in the 10s of nanomolar range and >50-fold selectivity against cardiac, skeletal, and smooth muscle myosins. KNX-115 inhibits the blood and liver stages of Plasmodium with an EC₅₀ of about 100 nanomolar, with negligible liver cell toxicity. In addition, KNX-115 inhibits sporozoite cell traversal and blocks the gametocyte to oocyst conversion in the mosquito. KNX-115 displays a similar killing profile to pyrimethamine and parasites are totally killed after 96 hours of treatment. In line with its novel mechanism of action, KNX-115 is equally effective at inhibiting a panel of Plasmodium strains resistant to experimental and marketed antimalarials. In vitro evolution data likely suggests a refractory potential of KNX-115 in developing parasite resistance.

中文翻译：

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一种小分子肌球蛋白抑制剂作为靶向多阶段抗疟药

疟疾是一种毁灭性疾病，2020 年估计有 627,000 人死亡。其中约 80% 的死亡病例发生在 5 岁以下的儿童中。我们的方法是开发针对细胞骨架靶点的小分子抑制剂，这些靶点是寄生虫功能的重要组成部分，在寄生虫感染的多个阶段必不可少，可以以高特异性靶向，并且具有高度的成药性。在这里，我们描述了 KNX-115，它抑制纯化的恶性疟原虫肌球蛋白 A (PfMyoA) 肌动蛋白激活的 ATP 酶，其效力在 10 纳摩尔范围内，对心脏、骨骼和平滑肌肌球蛋白的选择性超过 50 倍。KNX-115 通过EC ₅₀抑制疟原虫的血液和肝脏阶段约100纳摩尔，肝细胞毒性可忽略不计。此外，KNX-115 抑制子孢子细胞的穿越并阻止蚊子的配子体向卵囊的转化。KNX-115 显示出与乙胺嘧啶相似的杀灭特性，并且在处理 96 小时后寄生虫被完全杀死。根据其新的作用机制，KNX-115 在抑制一组对实验性和市售抗疟药耐药的疟原虫菌株方面同样有效。体外进化数据可能表明 KNX-115 在发展寄生虫抗性方面具有难治的潜力。