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

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 (2017). A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science, 358(6362), pp. 522-528. American Association for the Advancement of Science 10.1126/science.aaf8675

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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.

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