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
复制标题
通过小分子恶性疟原虫 NADH-泛醌氧化还原酶 (PfNDH2) 的共晶结构阐明消除耐药性疟疾的靶点。
DOI：
10.1021/acs.jmedchem.6b01733
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发表时间：
2017-03-09
影响因子：
7.3
通讯作者：
Yang, Maojun
中科院分区：
文献类型：
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作者：
Yang, Yiqing;Yu, You;Yang, Maojun
近年来，疟疾耐药株不断涌现，对全球健康提出了巨大挑战。因此，迫切需要具有新的靶向机制的新的抗疟疾药物来对抗耐药疟疾。恶性疟原虫NADH-泛醌氧化还原酶(PfNDH2)是抗疟疾药物开发的有效靶点。然而，缺乏关于PfNDH2的结构信息限制了合理的药物设计和进一步的开发。在此，我们首次报道了PfNDH2蛋白在Apo-、NADH-和RYL-552(一种新的抑制剂)结合状态下的高分辨晶体结构。PfNDH2抑制剂在体外通过潜在的变构机制对耐药菌株和体内寄生虫感染的小鼠显示出良好的效力。此外，还发现该缓蚀剂可以与双氢青蒿素(DHA)协同使用。这些发现不仅对基于疟疾PfNDH2蛋白的药物开发很重要，而且可能对其他含有NDH2的病原微生物，如结核分枝杆菌也有广泛的影响。
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.