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

Paco Pino | Zendy; Reto Caldelari | Zendy; Budhaditya Mukherjee | Zendy; Juha Vahokoski | Zendy; Natacha Klages | Zendy; Bohumil Maco | Zendy; Christine R. Collins | Zendy; Michael J. Blackman | Zendy; Inari Kursula | Zendy; Volker T. Heussler | Zendy; Mathieu Brochet | Zendy; Dominique SoldatiFavre | Zendy

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

Author(s) -

Paco Pino,

Reto Caldelari,

Budhaditya Mukherjee,

Juha Vahokoski,

Natacha Klages,

Bohumil Maco,

Christine R. Collins,

Michael J. Blackman,

Inari Kursula,

Volker T. Heussler,

Mathieu Brochet,

Dominique SoldatiFavre

Publication year - 2017

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aaf8675

Subject(s) - microneme , proteases , exocytosis , microbiology and biotechnology , rhoptry , biology , effector , organelle , biochemistry , secretion , apicomplexa , plasmodium falciparum , malaria , immunology , enzyme

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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