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

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 (2017). A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science, 358(6362), pp. 522-528. American Association for the Advancement of Science 10.1126/science.aaf8675

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Biology > Institute of Cell Biology > Malaria
08 Faculty of Science > Department of Biology > Institute of Cell Biology

UniBE Contributor:

Caldelari, Reto and Heussler, Volker

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0036-8075

Publisher:

American Association for the Advancement of Science

Funders:

[42] Schweizerischer Nationalfonds
[UNSPECIFIED] SystemsX

Language:

English

Submitter:

Volker Heussler

Date Deposited:

01 Dec 2017 13:50

Last Modified:

27 Oct 2019 05:16

Publisher DOI:

10.1126/science.aaf8675

PubMed ID:

29074775

BORIS DOI:

10.7892/boris.107198

URI:

https://boris.unibe.ch/id/eprint/107198

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