Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
Int J Biol Macromol. 2021 Jul 31;183:182-192. doi: 10.1016/j.ijbiomac.2021.04.129. Epub 2021 Apr 24.
After the emergence of the pandemic, repurposed drugs have been considered as a quicker way of finding potential antiviral agents. SARS-CoV-2 3CL is essential for processing the viral polyproteins into mature non-structural proteins, making it an attractive target for developing antiviral agents. Here we show that Vitamin K3 screened from the FDA-Approved Drug Library containing an array of 1,018 compounds has potent inhibitory activity against SARS-CoV-2 3CL with the IC value of 4.78 ± 1.03 μM, rather than Vitamin K1, K2 and K4. Next, the time-dependent inhibitory experiment was carried out to confirm that Vitamin K3 could form the covalent bond with SARS-CoV-2 3CL. Then we analyzed the structure-activity relationship of Vitamin K3 analogues and identified 5,8-dihydroxy-1,4-naphthoquinone with 9.8 times higher inhibitory activity than Vitamin K3. Further mass spectrometric analysis and molecular docking study verified the covalent binding between Vitamin K3 or 5,8-dihydroxy-1,4-naphthoquinone and SARS-CoV-2 3CL. Thus, our findings provide valuable information for further optimization and design of novel inhibitors based on Vitamin K3 and its analogues, which may have the potential to fight against SARS-CoV-2.
在大流行出现后，人们认为重新利用药物是寻找潜在抗病毒药物的一种更快的方法。SARS-CoV-2 3CL 对于将病毒多蛋白加工成成熟的非结构蛋白至关重要，使其成为开发抗病毒药物的有吸引力的靶标。在这里，我们展示了从包含 1018 种化合物的 FDA 批准药物库中筛选出的维生素 K3 对 SARS-CoV-2 3CL 具有很强的抑制活性，IC 值为 4.78±1.03 μM，而不是维生素 K1、K2 和 K4。接下来，进行了时程抑制实验以确认维生素 K3 可以与 SARS-CoV-2 3CL 形成共价键。然后，我们分析了维生素 K3 类似物的结构-活性关系，并确定 5,8-二羟基-1,4-萘醌对 SARS-CoV-2 3CL 的抑制活性比维生素 K3 高 9.8 倍。进一步的质谱分析和分子对接研究证实了维生素 K3 或 5,8-二羟基-1,4-萘醌与 SARS-CoV-2 3CL 之间的共价结合。因此，我们的研究结果为进一步基于维生素 K3 及其类似物优化和设计新型抑制剂提供了有价值的信息，这可能有潜力对抗 SARS-CoV-2。
