Department of Life Science, Shiv Nadar University, Greater Noida, UP 201314, India.
Department of Chemistry, Presidency University, Kolkata 700073, India.
J Nat Prod. 2022 Oct 28;85(10):2340-2350. doi: 10.1021/acs.jnatprod.2c00521. Epub 2022 Sep 13.
The current COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) created a global health crisis. The ability of vaccines to protect immunocompromised individuals and from emerging new strains are major concerns. Hence antiviral drugs against SARS-CoV-2 are essential. The SARS-CoV-2 main protease M is vital for replication and an important target for antivirals. Using CMap analysis and docking studies, withaferin A (wifA) and withanone (win), two natural products from the medicinal herb (ashwagandha), were identified as promising candidates that can covalently inhibit the viral protease M. Cell culture, enzymatic, LC-MS/MS, computational, and equilibrium dialysis based assays were performed. DFT calculations indicated that wifA and win can form stable adducts with thiols. The cytotoxicity of M was significantly reduced by wifA and win. Both wifA and win were found to irreversibly inhibit 0.5 μM M with IC values of 0.54 and 1.8 μM, respectively. LC-MS/MS analysis revealed covalent adduct formation with wifA at cysteines 145 and 300 of M. The natural products wifA and win can irreversibly inhibit the SARS-CoV-2 main protease M. Based on the work presented here we propose that both wifA and win have the potential to be safely used as preventative and therapeutic interventions for COVID-19.
当前由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的 COVID-19 大流行造成了全球卫生危机。疫苗保护免疫功能低下个体和预防新出现的病毒株的能力是主要关注点。因此，针对 SARS-CoV-2 的抗病毒药物至关重要。SARS-CoV-2 主要蛋白酶 M 对于复制至关重要，是抗病毒药物的重要靶标。通过 CMap 分析和对接研究，从药用植物（印度人参）中发现了两种天然产物，即醉茄素 A (wifA) 和醉茄酮 (win)，它们是具有潜力的候选药物，可以共价抑制病毒蛋白酶 M。进行了细胞培养、酶、LC-MS/MS、计算和平衡透析测定。DFT 计算表明，wifA 和 win 可以与硫醇形成稳定的加合物。wifA 和 win 显著降低了 M 的细胞毒性。wifA 和 win 均可不可逆地抑制 0.5 μM 的 M，IC 值分别为 0.54 和 1.8 μM。LC-MS/MS 分析显示，wifA 与 M 的半胱氨酸 145 和 300 形成共价加合物。天然产物 wifA 和 win 可不可逆地抑制 SARS-CoV-2 主要蛋白酶 M。基于目前的工作，我们提出 wifA 和 win 都有可能作为 COVID-19 的预防和治疗干预措施安全使用。
