Journal
PHYTOCHEMISTRY
Volume 193, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phytochem.2021.112984
Keywords
SARS-CoV-2; Papain-like protease; Natural biflavone; deISGylation; Antiviral
Categories
Funding
- National Mega-Project for Innovative Drugs [2019ZX09735002]
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This study discovered natural biflavones as potent inhibitors of SARS-CoV-2 PLpro by investigating the national compound library of traditional Chinese medicines, revealing their inhibitory effects on viral replication and immune evasion processes. Further evaluation included structure-activity relationship elucidation and molecular docking investigation to understand the mechanism of action.
Papain-like protease (PLpro) 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 PLpro, revealing an inspiring strategy for COVID-19 treatment. This study aimed to discover PLpro 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 PLpro inhibitors with IC50 values ranging from 9.5 to 43.2 mu M. Pro-ISG15 cleavage assays further demonstrated that several biflavones exhibited potent inhibitory effects against PLpro-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 PLpro.
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