Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea.
S&K Therapeutics, Woncheon Hall 135, Ajou University, Suwon 16499, Korea.
Cells. 2021 Apr 29;10(5):1052. doi: 10.3390/cells10051052.
The rapid spread of the virus, the surge in the number of deaths, and the unavailability of specific SARS-CoV-2 drugs thus far necessitate the identification of drugs with anti-COVID-19 activity. SARS-CoV-2 enters the host cell and assembles a multisubunit RNA-dependent RNA polymerase (RdRp) complex of viral nonstructural proteins that plays a substantial role in the transcription and replication of the viral genome. Therefore, RdRp is among the most suitable targets in RNA viruses. Our aim was to investigate the FDA approved antiviral drugs having potential to inhibit the viral replication. The methodology adopted was virtual screening and docking of FDA-approved antiviral drugs into the RdRp protein. Top hits were selected and subjected to molecular dynamics simulations to understand the dynamics of RdRp in complex with these drugs. The antiviral activity of the drugs against SARS-CoV-2 was assessed in Vero E6 cells. Notably, both remdesivir (half-maximal effective concentration (EC50) 6.6 μM, 50% cytotoxicity concentration (CC) > 100 µM, selectivity index (SI) = 15) and ledipasvir (EC50 34.6 μM, CC > 100 µM, SI > 2.9) exerted antiviral action. This study highlights the use of direct-acting antiviral drugs, alone or in combination, for better treatments of COVID-19.
病毒的迅速传播、死亡人数的增加以及迄今为止缺乏特定的 SARS-CoV-2 药物，这使得我们需要寻找具有抗 COVID-19 活性的药物。SARS-CoV-2 进入宿主细胞并组装由病毒非结构蛋白组成的多亚基 RNA 依赖性 RNA 聚合酶（RdRp）复合物，该复合物在病毒基因组的转录和复制中起着重要作用。因此，RdRp 是 RNA 病毒中最适合的靶标之一。我们的目的是研究具有抑制病毒复制潜力的已批准用于 FDA 的抗病毒药物。采用的方法是虚拟筛选和将 FDA 批准的抗病毒药物对接进入 RdRp 蛋白。选择前几个命中并进行分子动力学模拟，以了解 RdRp 与这些药物结合的动力学。评估了这些药物对 SARS-CoV-2 的抗病毒活性在 Vero E6 细胞中进行。值得注意的是，瑞德西韦（半数最大有效浓度（EC50）为 6.6 μM，50%细胞毒性浓度（CC）> 100 μM，选择性指数（SI）= 15）和利巴韦林（EC50 为 34.6 μM，CC > 100 μM，SI > 2.9）均发挥了抗病毒作用。本研究强调了单独或联合使用直接作用抗病毒药物来更好地治疗 COVID-19。
