A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress
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Paco Pino Reto Caldelari Budhaditya Mukherjee Juha Vahokoski Natacha Klages Bohumil Maco Christine R Collins Michael Blackman Inari Kursula Volker Heussler Mathieu Brochet Dominique Soldati-FavreAbstract
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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Journal Science
Volume 358
Issue number 6362
Pages 522-528
Available online
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Publisher website (DOI) 10.1126/science.aaf8675
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Europe PubMed Central 29074775
Pubmed 29074775
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