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

Fitoterapia. 2021 Jul;152:104909. doi: 10.1016/j.fitote.2021.104909. Epub 2021 Apr 22.

Abstract

3-Chymotrypsin-like protease (3CLpro) 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 3CLpro inhibitors from herbal constituents, as well as to investigate the inhibitory mechanism of the newly identified efficacious SARS-CoV-2 3CLpro inhibitors. Following screening of the inhibitory potentials of eighty herbal products against SARS-CoV-2 3CLpro, Ginkgo biloba leaves extract (GBLE) was found with the most potent SARS-CoV-2 3CLpro inhibition activity (IC50 = 6.68 μg/mL). Inhibition assays demonstrated that the ginkgolic acids (GAs) and the bioflavones isolated from GBLE displayed relatively strong SARS-CoV-2 3CLpro inhibition activities (IC50 < 10 μM). Among all tested constituents, GA C15:0, GA C17:1 and sciadopitysin displayed potent 3CLpro inhibition activities, with IC50 values of less than 2 μM. Further inhibition kinetic studies and docking simulations clearly demonstrated that two GAs and sciadopitysin strongly inhibit SARS-CoV-2 3CLprovia 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 3CLpro inhibition activities, which offer several promising leading compounds for developing novel anti-COVID-19 medications via targeting on 3CLpro.

Keywords: Bioflavones; Ginkgo biloba leaves; Ginkgolic acids; Inhibitory mechanism; SARS-CoV-2 3CL(pro).

MeSH terms

  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Biflavonoids / pharmacology
  • Biflavonoids / therapeutic use
  • COVID-19* / drug therapy
  • Coronavirus Protease Inhibitors / pharmacology*
  • Coronavirus Protease Inhibitors / therapeutic use
  • Flavones / pharmacology
  • Flavones / therapeutic use
  • Ginkgo biloba / chemistry*
  • Humans
  • Molecular Structure
  • Phytotherapy
  • Plant Extracts / pharmacology*
  • Plant Extracts / therapeutic use
  • Plant Leaves / chemistry
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / enzymology
  • Salicylates / pharmacology
  • Salicylates / therapeutic use
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Biflavonoids
  • Coronavirus Protease Inhibitors
  • Flavones
  • Plant Extracts
  • Salicylates
  • ginkgolic acid
  • sciadopitysin
  • flavone

Supplementary concepts

  • COVID-19 drug treatment