. 2019 Jun 21;10(6):471.

doi: 10.3390/genes10060471.

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

Xinying Wang^{1

2}, Yukiko Miyazaki³, Daniel Ken Inaoka^{4

5

6}, Endah Dwi Hartuti⁷, Yoh-Ichi Watanabe⁸, Tomoo Shiba⁹, Shigeharu Harada¹⁰, Hiroyuki Saimoto¹¹, Jeremy Nicholas Burrows¹², Francisco Javier Gamo Benito¹³, Tomoyoshi Nozaki¹⁴, Kiyoshi Kita^{15

16

17}

Affiliations

¹ Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. xinying-wang@nagasaki-u.ac.jp.
² School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. xinying-wang@nagasaki-u.ac.jp.
³ Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. y.miyazaki@lumc.nl.
⁴ Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. danielken@nagasaki-u.ac.jp.
⁵ School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. danielken@nagasaki-u.ac.jp.
⁶ Department of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. danielken@nagasaki-u.ac.jp.
⁷ Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. endah.dwi08@yahoo.co.id.
⁸ Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ywatanab@m.u-tokyo.ac.jp.
⁹ Department of Applied Biology, Graduate School of Science Technology, Kyoto Institute of Technology, Matsugasaki, Hashikamicho, Sakyo-ku, Kyoto 606-8585, Japan. tshiba@kit.ac.jp.
¹⁰ Department of Applied Biology, Graduate School of Science Technology, Kyoto Institute of Technology, Matsugasaki, Hashikamicho, Sakyo-ku, Kyoto 606-8585, Japan. harada@kit.ac.jp.
¹¹ Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-cho Minami, Tottori 680-8550, Japan. saimoto@chem.tottori-u.ac.jp.
¹² Medicines for Malaria Venture, Route de Pré Bois 20, 1215 Geneva, Switzerland. burrowsj@mmv.org.
¹³ GlaxoSmithKline (GSK), Tres Cantos Medicine Development Campus, Severo Ochoa, 28760 Madrid, Spain. francisco-javier.b.gamo@gsk.com.
¹⁴ Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. nozaki@m.u-tokyo.ac.jp.
¹⁵ Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. kitak@nagasaki-u.ac.jp.
¹⁶ School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. kitak@nagasaki-u.ac.jp.
¹⁷ Department of Host-Defense Biochemistry, Institute of Tropical Medicine (NEKKEN), Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. kitak@nagasaki-u.ac.jp.

PMID: 31234346
PMCID: PMC6627850
DOI: 10.3390/genes10060471

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

Xinying Wang et al. Genes (Basel). 2019.

. 2019 Jun 21;10(6):471.

doi: 10.3390/genes10060471.

Authors

Affiliations

¹ Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. xinying-wang@nagasaki-u.ac.jp.
² School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. xinying-wang@nagasaki-u.ac.jp.
³ Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. y.miyazaki@lumc.nl.
⁴ Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. danielken@nagasaki-u.ac.jp.
⁵ School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. danielken@nagasaki-u.ac.jp.
⁶ Department of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. danielken@nagasaki-u.ac.jp.
⁷ Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. endah.dwi08@yahoo.co.id.
⁸ Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ywatanab@m.u-tokyo.ac.jp.
⁹ Department of Applied Biology, Graduate School of Science Technology, Kyoto Institute of Technology, Matsugasaki, Hashikamicho, Sakyo-ku, Kyoto 606-8585, Japan. tshiba@kit.ac.jp.
¹⁰ Department of Applied Biology, Graduate School of Science Technology, Kyoto Institute of Technology, Matsugasaki, Hashikamicho, Sakyo-ku, Kyoto 606-8585, Japan. harada@kit.ac.jp.
¹¹ Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-cho Minami, Tottori 680-8550, Japan. saimoto@chem.tottori-u.ac.jp.
¹² Medicines for Malaria Venture, Route de Pré Bois 20, 1215 Geneva, Switzerland. burrowsj@mmv.org.
¹³ GlaxoSmithKline (GSK), Tres Cantos Medicine Development Campus, Severo Ochoa, 28760 Madrid, Spain. francisco-javier.b.gamo@gsk.com.
¹⁴ Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. nozaki@m.u-tokyo.ac.jp.
¹⁵ Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. kitak@nagasaki-u.ac.jp.
¹⁶ School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. kitak@nagasaki-u.ac.jp.
¹⁷ Department of Host-Defense Biochemistry, Institute of Tropical Medicine (NEKKEN), Nagasaki University, 1-12-4, Sakamoto, Nagasaki 852-8523, Japan. kitak@nagasaki-u.ac.jp.

PMID: 31234346
PMCID: PMC6627850
DOI: 10.3390/genes10060471

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: Plasmodium falciparum; drug target; energy metabolism; inhibitor screening; membrane protein; mitochondria.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Scheme of the biological pathways in *Plasmodium falciparum* cells that PfMQO is involved with. Abbreviations, Q: ubiquinone; QH₂: ubiquinol; FH: fumarate hydratase; AAT: aspartate aminotransferase; MDH: malate dehydrogenase.

**Figure 2**
Overview of all the compounds from the Pathogen Box and their inhibition percentages against recombinant PfMQO at 10 μM.

**Figure 3**
The IC₅₀ against recombinant PfMQO and the chemical structure of each hit identified from the Pathogen Box.

**Figure 4**
IC₅₀ of each strong hit compound from the Pathogen Box which showed inhibition against the asexual blood stage (ABS) parasite.

See this image and copyright information in PMC

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

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

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