Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle
Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle
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DOI：
10.1016/j.chom.2020.02.005
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发表时间：
2020-04-08
影响因子：
30.3
通讯作者：
Cowman, Alan F.
中科院分区：
文献类型：
--
作者：
Favuzza, Paola;Ruiz, Manuel de Lera;Cowman, Alan F.
青蒿素联合疗法（ACT）是治疗疟疾的主要选择，疟疾是由细胞内寄生虫疟原虫引起的。然而，ACT耐药性的增加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）被鉴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，它可以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，寄生虫的发展和出口所需的蛋白质的直接成熟的主调制器。口服WM 382治愈伯氏疟原虫小鼠，并防止肝脏血液感染。此外，WM 382在人源化小鼠中对恶性疟原虫无性感染有效，并防止传播给蚊子。体外筛选抗恶性疟原虫是不可能的。总之，这些表明PMIX和PMX双重抑制剂是疟疾治疗和预防的有希望的候选者。
Artemisin combination therapy (ACT) is themain 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.