Discovery of 4'-O-methylscutellarein as a potent SARS-CoV-2 main protease inhibitor

Qianqian Wu; Shiqiang Yan; Yujie Wang; Maotian Li; Yibei Xiao; Yingxia Li

doi:10.1016/j.bbrc.2022.03.052

Discovery of 4'-O-methylscutellarein as a potent SARS-CoV-2 main protease inhibitor

Biochem Biophys Res Commun. 2022 May 14:604:76-82. doi: 10.1016/j.bbrc.2022.03.052. Epub 2022 Mar 10.

Authors

Qianqian Wu¹, Shiqiang Yan², Yujie Wang², Maotian Li³, Yibei Xiao⁴, Yingxia Li⁵

Affiliations

¹ 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.
² Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
³ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China.
⁴ 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. Electronic address: yibei.xiao@cpu.edu.cn.
⁵ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: liyx417@fudan.edu.cn.

Abstract

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^pro) 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 (IC₅₀) 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^pro.

Keywords: COVID-19; M(pro) inhibitor; SARS-CoV-2; Scutellarein.

MeSH terms

Alkaloids* / pharmacology
Coronavirus 3C Proteases* / antagonists & inhibitors
Humans
Indoles* / pharmacology
Kinetics
Molecular Docking Simulation
SARS-CoV-2* / drug effects
SARS-CoV-2* / enzymology
Viral Protease Inhibitors* / pharmacology

Substances

Alkaloids
Indoles
Viral Protease Inhibitors
4'-O-methylstephavanine
3C-like proteinase, SARS-CoV-2
Coronavirus 3C Proteases