Flavonols as potential antiviral drugs targeting SARS-CoV-2 proteases (3CLpro and PLpro), spike protein, RNA-dependent RNA polymerase (RdRp) and angiotensin-converting enzyme II receptor (ACE2)

Eur J Pharmacol. 2021 Jan 15:891:173759. doi: 10.1016/j.ejphar.2020.173759. Epub 2020 Nov 27.


The novel coronavirus outbreak (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents the actual greatest global public health crisis. The lack of efficacious drugs and vaccines against this viral infection created a challenge for scientific researchers in order to find effective solutions. One of the promising therapeutic approaches is the search for bioactive molecules with few side effects that display antiviral properties in natural sources like medicinal plants and vegetables. Several computational and experimental studies indicated that flavonoids especially flavonols and their derivatives constitute effective viral enzyme inhibitors and possess interesting antiviral activities. In this context, the present study reviews the efficacy of many dietary flavonols as potential antiviral drugs targeting the SARS-CoV-2 enzymes and proteins including Chymotrypsin-Like Protease (3CLpro), Papain Like protease (PLpro), Spike protein (S protein) and RNA-dependent RNA polymerase (RdRp), and also their ability to interact with the angiotensin-converting enzyme II (ACE2) receptor. The relationship between flavonol structures and their SARS-CoV-2 antiviral effects were discussed. On the other hand, the immunomodulatory, the anti-inflammatory and the antiviral effects of secondary metabolites from this class of flavonoids were reported. Also, their bioavailability limitations and toxicity were predicted.

Keywords: 3CL(pro); ACE2; Flavonols; PL(pro); RdRp; SARS-CoV-2.

Publication types

  • Review

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism
  • Antiviral Agents / pharmacology
  • COVID-19 Drug Treatment*
  • COVID-19* / metabolism
  • Coronavirus 3C Proteases / metabolism
  • Coronavirus RNA-Dependent RNA Polymerase / metabolism
  • Drug Development
  • Flavonols / pharmacology*
  • Humans
  • Phytochemicals / pharmacology
  • SARS-CoV-2* / drug effects
  • SARS-CoV-2* / physiology
  • Spike Glycoprotein, Coronavirus / metabolism


  • Antiviral Agents
  • Flavonols
  • Phytochemicals
  • Spike Glycoprotein, Coronavirus
  • Coronavirus RNA-Dependent RNA Polymerase
  • Angiotensin-Converting Enzyme 2
  • 3C-like protease, SARS coronavirus
  • 3C-like proteinase, SARS-CoV-2
  • Coronavirus 3C Proteases