2. Academic Validation
  3. Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria

Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria

  • J Med Chem. 2017 Mar 9;60(5):1994-2005. doi: 10.1021/acs.jmedchem.6b01733.
Yiqing Yang 1 2,  You Yu 2,  Xiaolu Li 3,  Jing Li 2,  Yue Wu 1,  Jie Yu 2,  Jingpeng Ge 2,  Zhenghui Huang 4,  Lubin Jiang 4,  Yu Rao 1,  Maojun Yang 2
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Tsinghua University , Beijing 100084, China.
  • 2 MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University , Beijing 100084, China.
  • 3 Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College , Beijing 100005, China.
  • 4 Institut Pasteur of Shanghai, CAS Key Laboratory of Molecular Virology and Immunology, Chinese Academy of Sciences , Shanghai 200031, China.
PMID: 28195463 DOI: 10.1021/acs.jmedchem.6b01733
Abstract

Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new antimalarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for antimalarial drug development. However, the absence of structural information on PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH-, and RYL-552 (a new inhibitor)-bound states. The PfNDH2 inhibitor exhibits excellent potency against both drug-resistant strains in vitro and parasite-infected mice in vivo via a potential allosteric mechanism. Furthermore, it was found that the inhibitor can be used in combination with dihydroartemisinin (DHA) synergistically. These findings not only are important for malarial PfNDH2 protein-based drug development but could also have broad implications for other NDH2-containing pathogenic Microorganisms such as Mycobacterium tuberculosis.

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