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
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.
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。
