Natural biflavones are potent inhibitors against SARS-CoV-2 papain-like protease

Lingyu Li; Liyan Ma; Yue Hu; Xiaoxue Li; Meng Yu; Hai Shang; Zhongmei Zou

doi:10.1016/j.phytochem.2021.112984

Natural biflavones are potent inhibitors against SARS-CoV-2 papain-like protease

Phytochemistry. 2022 Jan:193:112984. doi: 10.1016/j.phytochem.2021.112984. Epub 2021 Oct 12.

Authors

Lingyu Li¹, Liyan Ma¹, Yue Hu¹, Xiaoxue Li², Meng Yu¹, Hai Shang³, Zhongmei Zou⁴

Affiliations

¹ Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, PR China.
² Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
³ Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, PR China. Electronic address: shanghai0503@163.com.
⁴ Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, PR China. Electronic address: zmzou@implad.ac.cn.

Abstract

Papain-like protease (PL^pro) is a key enzyme encoded by SARS-CoV-2 that is essential for viral replication and immune evasion. Significant suppression of viral spread and promotion of antiviral immunity can be achieved by inhibition of PL^pro, revealing an inspiring strategy for COVID-19 treatment. This study aimed to discover PL^pro inhibitors by investigating the national compound library of traditional Chinese medicines (NCLTCMs), a phytochemical library comprising over 9000 TCM-derived compounds. Through virtual screening and enzymatic evaluations, nine natural biflavones were confirmed to be effective PL^pro inhibitors with IC₅₀ values ranging from 9.5 to 43.2 μM. Pro-ISG15 cleavage assays further demonstrated that several biflavones exhibited potent inhibitory effects against PL^pro-mediated deISGylation, a key process involved in viral immune evasion. Herein, we report the discovery, antiviral evaluation, structure-activity relationship elucidation and molecular docking investigation of biflavones as potent inhibitors of SARS-CoV-2 PL^pro.

Keywords: Antiviral; Natural biflavone; Papain-like protease; SARS-CoV-2; deISGylation.

MeSH terms

Antiviral Agents / pharmacology
COVID-19 Drug Treatment*
Coronavirus Papain-Like Proteases
Humans
Molecular Docking Simulation
Protease Inhibitors / pharmacology
SARS-CoV-2

Substances

Antiviral Agents
Protease Inhibitors
Coronavirus Papain-Like Proteases
papain-like protease, SARS-CoV-2