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

作者：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^*

来源：Science, 2017, 358(6362): 522-+.

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.

• 出版日期2017-10-27