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

P Pino ; R Caldelari ; B Mukherjee ; J Vahokoski ; N Klages ; B Maco ; CR Collins ; MJ Blackman ; I Kursula ; V Heussler ; +2 more... M Brochet ; D Soldati-Favre ; (2017) A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Technical Report. American Association for the Advancement of Science. DOI: 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.<br/>


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