一种多阶段抗疟药靶向对疟原虫入侵和逸出至关重要的疟原虫天冬氨酸蛋白酶IX和X。
A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress.
作者信息
Pino Paco, Caldelari Reto, Mukherjee Budhaditya, Vahokoski Juha, Klages Natacha, Maco Bohumil, Collins Christine R, Blackman Michael J, Kursula Inari, Heussler Volker, Brochet Mathieu, Soldati-Favre Dominique
机构信息
Department of Microbiology and Molecular Medicine, Faculty of Medicine-University of Geneva, Centre Médical Universitaire (CMU), 1211 Geneva, Switzerland.
Institute of Cell Biology, University of Bern, 3012 Bern, Switzerland.
出版信息
Science. 2017 Oct 27;358(6362):522-528. doi: 10.1126/science.aaf8675.
Regulated exocytosis by secretory organelles is important for malaria parasite invasion and egress. Many parasite effector proteins, including perforins, adhesins, and proteases, are extensively proteolytically processed both pre- and postexocytosis. Here we report the multistage antiplasmodial activity of the aspartic protease inhibitor hydroxyl-ethyl-amine-based scaffold compound 49c. This scaffold inhibits the preexocytosis processing of several secreted rhoptry and microneme proteins by targeting the corresponding maturases plasmepsins IX (PMIX) and X (PMX), respectively. Conditional excision of PMIX revealed its crucial role in invasion, and recombinantly active PMIX and PMX cleave egress and invasion factors in a 49c-sensitive manner.
分泌细胞器调控的胞吐作用对疟原虫的入侵和逸出很重要。许多寄生虫效应蛋白，包括穿孔素、黏附素和蛋白酶，在胞吐作用前后都经过广泛的蛋白水解加工。在此，我们报告了基于天冬氨酸蛋白酶抑制剂羟乙胺的支架化合物49c的多阶段抗疟原虫活性。该支架分别通过靶向相应的成熟酶——疟原虫天冬氨酸蛋白酶IX（PMIX）和X（PMX），抑制几种分泌的棒状体和微线体蛋白的胞吐前加工。PMIX的条件性切除揭示了其在入侵中的关键作用，并且重组活性的PMIX和PMX以49c敏感的方式切割逸出和入侵因子。
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