Structure-based discovery of two antiviral inhibitors targeting the NS3 helicase of Japanese encephalitis virus.
Structure-based discovery of two antiviral inhibitors targeting the NS3 helicase of Japanese encephalitis virus.
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基于结构发现两种针对日本脑炎病毒 NS3 解旋酶的抗病毒抑制剂
DOI：
10.1038/srep34550
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发表时间：
2016-09-29
影响因子：
4.6
通讯作者：
Song Y
中科院分区：
文献类型：
--
作者：
Fang J;Li H;Kong D;Cao S;Peng G;Zhou R;Chen H;Song Y
日本脑炎病毒（JEV）是一种黄病毒，威胁着世界上一半以上的人口。接种疫苗可以预防该病，但目前尚无特异性抗病毒药物可用于临床治疗，由JEV引起的死亡率可高达60%。黄病毒非结构蛋白3（NS 3）的C-末端编码解旋酶，并已被鉴定为潜在的药物靶标。在这项研究中，采用高通量分子对接，以确定候选JEV NS 3解旋酶抑制剂在商业图书馆包含250，000化合物。然后测试41种化合物抑制NS 3活性的能力。两种化合物强烈抑制解旋活性，但对蛋白质的ATP酶活性没有影响。蛋白质印迹、IFA和空斑减少试验表明，这两种化合物都能抑制细胞培养物中的病毒。两种化合物的EC 50分别为25.67和23.50 μM。使用模拟对接，显示两种化合物结合并阻断NS 3 RNA解旋通道，与酶抑制试验的结果一致。确定了参与分子内相互作用的原子，以促进未来的化合物优化。
Japanese encephalitis virus (JEV) is a flavivirus that threatens more than half of the world’s population. Vaccination can prevent the disease, but no specific antiviral drug is yet available for clinical therapy, and the death rate caused by JEV can reach as high as 60%. The C-terminus of non-structural protein 3 (NS3) of flavivirus encodes helicase and has been identified as a potential drug target. In this study, high throughput molecular docking was employed to identify candidate JEV NS3 helicase inhibitors in a commercial library containing 250,000 compounds. Forty-one compounds were then tested for their ability to inhibit NS3 activity. Two compounds inhibited unwinding activity strongly but had no effect on the ATPase activity of the protein. Western blots, IFA, and plaque reduction assays demonstrated that both compounds inhibited the virus in cell culture. The EC50s of the two compounds were 25.67 and 23.50 μM, respectively. Using simulated docking, the two compounds were shown to bind and block the NS3 RNA unwinding channel, consistent with the results of the enzyme inhibition tests. The atoms participating in intramolecular interaction were identified to facilitate future compound optimization.
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DOI：
10.1038/nrd1853
发表时间：
2005-10
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
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通讯作者：
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影响因子：
158.5
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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