Discovery of naturally occurring inhibitors against SARS-CoV-2 3CLpro from Ginkgo biloba leaves via large-scale screening

3-Chymotrypsin-like protease (3CL(pro)) is a virally encoded main proteinase that is pivotal for the viral replication across a broad spectrum of coronaviruses. This study aims to discover the naturally occurring SARS-CoV-2 3CL(pro) inhibitors from herbal constituents, as well as to investigate the inhibitory mechanism of the newly identified efficacious SARS-CoV-2 3CL(pro) inhibitors. Following screening of the inhibitory potentials of eighty herbal products against SARS-CoV-2 3CL(pro), Ginkgo biloba leaves extract (GBLE) was found with the most potent SARSCoV-2 3CL(pro) inhibition activity (IC50 = 6.68 mu g/mL). Inhibition assays demonstrated that the ginkgolic acids (GAs) and the bioflavones isolated from GBLE displayed relatively strong SARS-CoV-2 3CL(pro) inhibition activities (IC50 < 10 mu M). Among all tested constituents, GA C15:0, GA C17:1 and sciadopitysin displayed potent 3CL(pro) inhibition activities, with IC50 values of less than 2 mu M. Further inhibition kinetic studies and docking simulations clearly demonstrated that two GAs and sciadopitysin strongly inhibit SARS-CoV-2 3CL(pro) via a reversible and mixed inhibition manner. Collectively, this study found that both GBLE and the major constituents in this herbal product exhibit strong SARS-CoV-2 3CL(pro) inhibition activities, which offer several promising leading compounds for developing novel anti-COVID-19 medications via targeting on 3CL(pro).

Automated summary

This study aimed to discover naturally occurring SARS-CoV-2 3CL(pro) inhibitors from herbal constituents, with Ginkgo biloba leaves extract (GBLE) identified as the most potent inhibitor. The major constituents in GBLE exhibited strong SARS-CoV-2 3CL(pro) inhibition activities, offering promising compounds for developing novel anti-COVID-19 medications.