Dual plasmepsin-targeting antimalarial agents disrupt multiple stages of the malaria parasite life cycle
Details
Publication Year 2020-02-27, Volume 27, Issue #4, Page 642-58 e12
Journal Title
Cell Host & Microbe
Publication Type
Journal Article
Abstract
Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets. In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addition, WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.
Publisher
Cell Press
WEHI Research Division(s)
Infectious Diseases And Immune Defence; Advanced Technology And Biology; Bioinformatics; Ubiquitin Signalling; Chemical Biology
PubMed ID
32109369
Open Access at Publisher's Site
https://doi.org/10.1016/j.chom.2020.02.005
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2020-03-24 01:39:40
Last Modified: 2020-07-02 01:52:34
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