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A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress

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journal contribution
posted on 15.10.2020, 16:33 by Paco Pino, Reto Caldelari, Budhaditya Mukherjee, Juha Vahokoski, Natacha Klages, Bohumil Maco, Christine R Collins, Michael J Blackman, Inari Kursula, Volker Heussler, Mathieu Brochet, Dominique Soldati-Favre
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.