Graphical abstract This work screened 125 compounds from the Chinese herbal medicine licorice. Licorice-saponin A3 and glycyrrhetinic acid potently inhibit SARS-CoV-2 infection, targeting the nsp7 protein and the spike protein receptor binding domain, respectively, with EC 50 of 0.075 and 3.17 µM. Highlights • Systemic approach to discover SARS-CoV-2 inhibitors from the herbal medicine licorice. • Licorice-saponin A3 and glycyrrhetinic acid inhibit SARS-CoV-2 by targeting nsp7 and the S-RBD, respectively. • Drug potential of these compounds was confirmed by cell models and PK studies. • The “multi-component, multi-target” mode of action was demonstrated for herbal medicines. • Licorice triterpenoids could be promising candidates for anti-SARS-CoV-2 drug development. Introduction The COVID-19 global epidemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a great public health emergency. Discovering antiviral drug candidates is urgent for the prevention and treatment of COVID-19. Objectives This work aims to discover natural SARS-CoV-2 inhibitors from the traditional Chinese herbal medicine licorice. Methods We screened 125 small molecules from Glycyrrhiza uralensis Fisch. (licorice, Gan-Cao) by virtual ligand screening targeting the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. Potential hit compounds were further evaluated by ELISA, SPR, luciferase assay, antiviral assay and pharmacokinetic study. Results The triterpenoids licorice-saponin A3 (A3) and glycyrrhetinic acid (GA) could potently inhibit SARS-CoV-2 infection, with EC 50 of 75 nM and 3.17 µM, respectively. Moreover, we reveal that A3 mainly targets the nsp7 protein, and GA binds to the spike protein RBD of SARS-CoV-2. Conclusion In this work, we found GA and A3 from licorice potently inhibit SARS-CoV-2 infection by affecting entry and replication of the virus. Our findings indicate that these triterpenoids may contribute to the clinical efficacy of licorice for COVID-19 and could be promising candidates for antiviral drug development.
【저자키워드】 COVID-19, SARS-CoV-2, Glycyrrhetinic acid, licorice, Licorice-saponin A3,