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Science. 2017 Oct 27;358(6362):522-528. doi: 10.1126/science.aaf8675.

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

Author information

1
Department of Microbiology and Molecular Medicine, Faculty of Medicine-University of Geneva, Centre Médical Universitaire (CMU), 1211 Geneva, Switzerland. paco.pino@unige.ch dominique.soldati-favre@unige.ch.
2
Institute of Cell Biology, University of Bern, 3012 Bern, Switzerland.
3
Department of Microbiology and Molecular Medicine, Faculty of Medicine-University of Geneva, Centre Médical Universitaire (CMU), 1211 Geneva, Switzerland.
4
Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
5
Malaria Biochemistry Laboratory, The Francis Crick Institute, Mill Hill, London NW1 1AT, UK.
6
Department of Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK.
7
Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Aapistie 7, 90220 Oulu, Finland.

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.

PMID:
29074775
PMCID:
PMC5730047
DOI:
10.1126/science.aaf8675
[Indexed for MEDLINE]
Free PMC Article

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