Kumar Deepak, Sharma Nitin, Aarthy Murali, Singh Sanjeev Kumar, Giri Rajanish
School of Basic Sciences, Indian Institute of Technology Mandi, VPO Kamand, Mandi, Himachal Pradesh 175005, India.
Department of Bioinformatics, Computer Aided Drug Design and Molecular Modeling Lab, Alagappa University, Science Block, Karaikudi 630003, Tamilnadu, India.
ACS Omega. 2020 May 4;5(19):11217-11226. doi: 10.1021/acsomega.0c01353. eCollection 2020 May 19.
Since 2007, repeated outbreaks of Zika virus (ZIKV) have affected millions of people worldwide and created a global health concern with major complications like microcephaly and Guillain Barre's syndrome. To date, there is not a single Zika-specific licensed drug present in the market. However, in recent months, several antiviral molecules have been screened against ZIKV. Among those, (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol, has shown great virucidal potential against flaviviruses including ZIKV. The mechanistic understanding of EGCG-targeting viral proteins is not yet entirely deciphered except that little is known about its interaction with viral envelope protein and viral protease. We designed our current study to find inhibitory actions of EGCG against ZIKV NS3 helicase. NS3 helicase performs a significant role in viral replication by unwinding RNA after hydrolyzing NTP. We employed molecular docking and simulation approach and found significant interactions at the ATPase site and also at the RNA binding site. Further, the enzymatic assay has shown significant inhibition of NTPase activity with an IC value of 295.7 nM and Ki of 0.387 ± 0.034 μM. Our study suggests the possibility that EGCG could be considered as a prime backbone molecule for further broad-spectrum inhibitor development against ZIKV and other flaviviruses.
自2007年以来，寨卡病毒（ZIKV）反复爆发，影响了全球数百万人，并引发了对小头畸形和格林-巴利综合征等主要并发症的全球健康关注。迄今为止，市场上还没有一种专门针对寨卡病毒的获批药物。然而，近几个月来，已经针对寨卡病毒筛选了几种抗病毒分子。其中，绿茶多酚（-）-表没食子儿茶素-3-没食子酸酯（EGCG）对包括寨卡病毒在内的黄病毒显示出巨大的杀病毒潜力。除了对其与病毒包膜蛋白和病毒蛋白酶的相互作用了解甚少外，对EGCG靶向病毒蛋白的机制理解尚未完全破译。我们开展当前的研究以发现EGCG对寨卡病毒NS3解旋酶的抑制作用。NS3解旋酶在水解NTP后通过解开RNA在病毒复制中发挥重要作用。我们采用分子对接和模拟方法，发现在ATP酶位点以及RNA结合位点存在显著相互作用。此外，酶活性测定显示对NTP酶活性有显著抑制，IC值为295.7 nM，Ki为0.387±0.034μM。我们的研究表明，EGCG有可能被视为进一步开发针对寨卡病毒和其他黄病毒的广谱抑制剂的主要骨架分子。
