Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of <i>Plasmodium falciparum</i> (<i>Pf</i>NDH2) with Small Molecule To Eliminate Drug-Resistant Malaria

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 <i>Plasmodium falciparum</i> (<i>Pf</i>NDH2) represents a viable target for antimalarial drug development. However, the absence of structural information on <i>Pf</i>NDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the <i>Pf</i>NDH2 protein for the first time in Apo-, NADH-, and RYL-552 (a new inhibitor)-bound states. The <i>Pf</i>NDH2 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 <i>Pf</i>NDH2 protein-based drug development but could also have broad implications for other NDH2-containing pathogenic microorganisms such as <i>Mycobacterium tuberculosis</i>