State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
Biochem Biophys Res Commun. 2022 May 14;604:76-82. doi: 10.1016/j.bbrc.2022.03.052. Epub 2022 Mar 10.
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and seriously threatened public health and safety. Despite COVID-19 vaccines being readily popularized worldwide, targeted therapeutic agents for the treatment of this disease remain very limited. Here, we studied the inhibitory activity of the scutellarein and its methylated derivatives against SARS-CoV-2 main protease (M) by the fluorescence resonance energy transfer (FRET) assay. Among all the methylated derivatives we studied, 4'-O-methylscutellarein exhibited the most promising enzyme inhibitory activity in vitro, with the half-maximal inhibitory concentration value (IC) of 0.40 ± 0.03 μM. Additionally, the mechanism of action of the hits was further characterized through enzyme kinetic studies and molecular docking. Overall, our results implied that 4'-O-methylscutellarein could be a primary lead compound with clinical potential for the development of inhibitors against the SARS-CoV-2 M.
新型冠状病毒病（COVID-19）是由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引起的，导致数百万人死亡，严重威胁公众健康和安全。尽管 COVID-19 疫苗在全球范围内得到广泛推广，但针对该疾病的靶向治疗药物仍然非常有限。在这里，我们通过荧光共振能量转移（FRET）测定法研究了白杨素及其甲基化衍生物对 SARS-CoV-2 主蛋白酶（M）的抑制活性。在我们研究的所有甲基化衍生物中，4'-O-甲基白杨素在体外表现出最有前途的酶抑制活性，其半数最大抑制浓度值（IC）为 0.40±0.03μM。此外，通过酶动力学研究和分子对接进一步表征了命中物的作用机制。总的来说，我们的结果表明，4'-O-甲基白杨素可能是一种具有临床潜力的先导化合物，可用于开发针对 SARS-CoV-2 M 的抑制剂。
