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

ABSTRACT: 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.

SUBMITTER: Pino P

PROVIDER: S-EPMC5730047 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Pino Paco P Caldelari Reto R Mukherjee Budhaditya B Vahokoski Juha J Klages Natacha N Maco Bohumil B Collins Christine R CR Blackman Michael J MJ Kursula Inari I Heussler Volker V Brochet Mathieu M Soldati-Favre Dominique D

Science (New York, N.Y.) 20171001 6362

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 targ ...[more]

PMID: 29074775

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