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Science. 2017 Oct 27;358(6362):518-522. doi: 10.1126/science.aan1478.

Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion.

Author information

1
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
2
Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
3
Section on Integrative Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
4
Faculty of Biology, Medicine and Health, Division of Infection Immunity and Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester, UK.
5
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
6
Center for World Health and Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA.
7
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
8
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA. dgoldberg@wustl.edu.

Abstract

Proteases of the malaria parasite Plasmodium falciparum have long been investigated as drug targets. The P. falciparum genome encodes 10 aspartic proteases called plasmepsins, which are involved in diverse cellular processes. Most have been studied extensively but the functions of plasmepsins IX and X (PMIX and PMX) were unknown. Here we show that PMIX is essential for erythrocyte invasion, acting on rhoptry secretory organelle biogenesis. In contrast, PMX is essential for both egress and invasion, controlling maturation of the subtilisin-like serine protease SUB1 in exoneme secretory vesicles. We have identified compounds with potent antimalarial activity targeting PMX, including a compound known to have oral efficacy in a mouse model of malaria.

PMID:
29074774
PMCID:
PMC5928414
DOI:
10.1126/science.aan1478
[Indexed for MEDLINE]
Free PMC Article

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