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Identification of Plasmodium falciparum Mitochondrial Malate: Quinone Oxidoreductase Inhibitors from the Pathogen Box

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Title: Identification of Plasmodium falciparum Mitochondrial Malate: Quinone Oxidoreductase Inhibitors from the Pathogen Box
Authors: Wang, Xinying / Miyazaki, Yukiko / Inaoka, Daniel Ken / Hartuti, Endah Dwi / Watanabe, Yoh-Ichi / Shiba, Tomoo / Harada, Shigeharu / Saimoto, Hiroyuki / Burrows, Jeremy Nicholas / Benito, Francisco Javier Gamo / Nozaki, Tomoyoshi / Kita, Kiyoshi
Issue Date: 21-Jun-2019
Publisher: MDPI
Citation: Genes, 10(6), art.no.471; 2019
Abstract: Malaria is one of the three major global health threats. Drug development for malaria, especially for its most dangerous form caused by Plasmodium falciparum, remains an urgent task due to the emerging drug-resistant parasites. Exploration of novel antimalarial drug targets identified a trifunctional enzyme, malate quinone oxidoreductase (MQO), located in the mitochondrial inner membrane of P. falciparum (PfMQO). PfMQO is involved in the pathways of mitochondrial electron transport chain, tricarboxylic acid cycle, and fumarate cycle.Recent studies have shown that MQO is essential for P. falciparum survival in asexual stage and for the development of experiment cerebral malaria in the murine parasite P. berghei, providing genetic validation of MQO as a drug target. However, chemical validation of MQO, as a target, remains unexplored. In this study, we used active recombinant protein rPfMQO overexpressed in bacterial membrane fractions to screen a total of 400 compounds from the Pathogen Box, released by Medicines for Malaria Venture. The screening identified seven hit compounds targeting rPfMQO with an IC50 of under 5 µM. We tested the activity of hit compounds against the growth of 3D7 wildtype strain of P. falciparum,among which four compounds showed an IC50 from low to sub-micromolar concentrations, suggesting that PfMQO is indeed a potential antimalarial drug target.
Keywords: Drug target / Energy metabolism / Inhibitor screening / Membrane protein / Mitochondria / Plasmodium falciparum
URI: http://hdl.handle.net/10069/39377
DOI: 10.3390/genes10060471
Rights: © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/39377

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