Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets. In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addition, WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.

中文翻译：

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靶向血浆蛋白酶的抗疟疾药物可破坏疟原虫生命周期的多个阶段。

青蒿素联合疗法（ACT）是疟疾的主要治疗选择，它是由细胞内寄生虫疟原虫引起的。但是，对ACT的耐药性增强凸显了寻找新药的重要性。最近，天冬氨酸蛋白酶Plasmepsin IX和X（PMIX和PMX）被确定为有前途的药物靶标。在这项研究中，我们描述了PMIX和PMX的双重抑制剂，包括WM382，它们可阻断疟原虫生命周期的多个阶段。我们证明，PMX是裂殖子入侵和入侵，寄生虫发展和出口所需的蛋白质的直接成熟的主要调节剂。口服WM382可治愈伯氏疟原虫的小鼠，并预防了肝脏的血液感染。此外，WM382对人源化小鼠中的恶性疟原虫无性感染有效，并阻止了其传播给蚊子。无法在体外选择抗药性恶性疟原虫。这些共同表明，PMIX和PMX双重抑制剂有望成为疟疾治疗和预防的候选者。