We report the discovery of MED6-189, an analog of the kalihinol family of isocyanoterpene natural products that is effective against drug-sensitive and drug-resistant Plasmodium falciparum strains, blocking both asexual replication and sexual differentiation. In vivo studies using a humanized mouse model of malaria confirm strong efficacy of the compound in animals with no apparent hemolytic activity or toxicity. Complementary chemical, molecular, and genomics analyses revealed that MED6-189 targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses revealed that a mutation in PfSec13 , which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. Its high potency, excellent therapeutic profile, and distinctive mode of action make MED6-189 an excellent addition to the antimalarial drug pipeline.

中文翻译：

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kalihinol 类似物破坏恶性疟原虫疟疾的顶质体功能和囊泡运输


我们报告了 MED6-189 的发现，它是异氰酸酯天然产物 kalihinol 家族的类似物，可有效对抗药物敏感和耐药的恶性疟原虫菌株，阻断无性复制和性分化。使用疟疾人源化小鼠模型进行的体内研究证实，该化合物在动物体内具有强大的功效，且没有明显的溶血活性或毒性。补充化学、分子和基因组学分析表明，MED6-189 以寄生虫顶端质体为目标，并通过抑制脂质生物发生和细胞运输发挥作用。遗传分析显示，编码寄生虫分泌机制成分的 PfSec13 的突变降低了对该药物的敏感性。其高效力、卓越的治疗特性和独特的作用模式使 MED6-189 成为抗疟药物管道的绝佳补充。