Quercetin and other plant flavonols show anti-SARS-CoV-2 activity

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019 and ultimately led to the current coronavirus disease 2019 (COVID-19) pandemic.

While COVID-19 vaccines were developed and subsequently distributed in record time to help build population immunity, newer SARS-CoV-2 variants have shown evidence of immune escape, thus reducing vaccine effectiveness. Moreover, the slow rollout of vaccines in many parts of developing and developed nations have also allowed for the continued transmission of SARS-CoV-2.

Taken together, these factors demonstrate the urgent need to develop effective and safe antiviral medications. A new Virology journal study discusses the potential of certain plant compounds to block SARS-CoV-2 replication within host cells.

Study: Flavonols and Dihydroflavonols Inhibit the Main Protease Activity Of SARS-Cov-2 And the Replication of Human Coronavirus 229E. Image Credit: photo_gonzo / Shutterstock.com

Study: Flavonols and Dihydroflavonols Inhibit the Main Protease Activity Of SARS-Cov-2 And the Replication of Human Coronavirus 229E. Image Credit: photo_gonzo / Shutterstock.com


Plants contain many chemicals that have biological activity in human cells, which has supported research into the use of these chemicals in COVID-19 prevention and treatment.

Both SARS-CoV-2 and the human coronavirus 229E (HCoV-229E) are coronaviruses that share many similarities, including a surface spike protein that is required for cell attachment and entry, and the cleavage of a single large polyprotein product by the viral main protease enzyme (Mpro).

The SARS-CoV-2 Mpro is a cysteine protease containing a cysteine-histidine dyad as a catalytic site. This enzyme is an attractive drug target, as it plays a crucial role in the viral life cycle but is non-homologous to any human enzyme.

HCoV-229E is a suitable model virus, as it is significantly less pathogenic than SARS-CoV-2 and can be screened in biosafety level 2 (BSL2) laboratories. In the current study, scientists screened existing and new antivirals that inhibit Mpro activity through a carbonyl-thiol covalent linkage involving the drug molecule’s ketone or aldehyde group and the Mpro 145-cysteine thiol group.

Previous work by these authors showed Mpro inhibition by flavonols such as (−)-epigallotechin-3-gallate, (−)-catechin-3-gallate, and (−)-epicatechin-3-gallate, along with procyanidins in dimeric form. Docking simulations showed that this was likely due to the formation of hydrogen bonds between the enzyme and these molecules.

Plant flavonoids include other flavonols like quercetin, kaempferol, and myricetin, as well as their dihydroflavonols. These are potent antioxidants with antiviral activity; thus, these agents have the potential to inhibit Mpro of both SARS-CoV-2 and HCoV-229E, as this enzyme shows 48% sequence identity in these viruses.

In the current study, the investigators carried out docking simulations to test this hypothesis, as well as direct inhibition assays using recombinant Mpro of SARS-CoV-2.

Study findings

The researchers found that eight compounds were able to inhibit SARS-CoV-2 Mpro activity, while five suppressed HCoV-229E replication in cell culture.

The SARS-CoV-2 Mpro has a substrate-binding pocket. There were 11 compounds bound to this binding pocket, eight of which showed higher affinity than the already tested drug ebselen. These included dihydroflavonols, flavonols, and glycosylated flavonols. 

These flavonols bound to two or more subsites in the substrate-binding pocket, thus blocking Mpro activity. The affinity scores were between −8.8 to −7.4 (kcal/mol) lower than those of ebselen. In contrast, two different types of glycosylation were observed to reduce the binding affininty of these molecules to the SARS-CoV-2 Mpro, without affecting HCoV-229E Mpro binding.

Inhibition assays showed that seven of these compounds effectively inhibited the SARS-CoV-2 Mpro activity and their half-maximum inhibitory concentrations (IC50) were between 0.125–20.3 μM. Correspondingly, ebselen was found to have an IC50 of 0.5 μM, while among the tested compounds, rutin had the lowest IC50.

Quercetin, isoquercitrin, dihydro quercetin, epigallocatechin gallate (EGCG) and epicatechin were also tested for their ability to inhibit the replication of HCoV-229E in cell culture. All five compounds effectively inhibited the virus starting at a concentration of 2.5 μM in a dose-dependent manner.

Notably, the data from the current study indicate that HCoV-229E can also be used to screen for SARS-CoV-2 Mpro inhibitors.


The study findings indicate that these antioxidative flavonols and dihydroflavonols are worthy of further development as potential antivirals in the treatment of these coronaviruses. The mode of inhibition here exploits the Cys145 residue, to which the small molecule ebselen was found to bind, causing inhibition of the Mpro enzyme.

In the current study, the researchers used plant flavonols and related compounds to form hydrogen bonds with the enzyme’s binding pocket, thus inhibiting its activity. Docking simulations showed flavonols and dihydroflavonols bind to the substrate-binding pocket of Mpro. Glycosylation of one compound, quercetin, increased the ability of the flavonol to stay at the binding site.

Another quercetin derivative, rutin, had the lowest affinity score, thereby indicating stronger Mpro inhibition. These findings were repeated in the in vitro inhibition assays.

Quercetin, rutin, and isoquercetin are nutraceuticals that are already widely used and known for being safe and nutritionally valuable. Furthermore, quercetin is easily absorbed after oral administration, inhibits lipid oxidation, reduces the risk of cardiovascular disease, and possesses potent anti-inflammatory activity.

Journal reference:
  • Zhu, Y., Scholle, F., Kisthardt, S. C., & Xie, D. (2022). Flavonols and Dihydroflavonols Inhibit the Main Protease Activity Of SARS-Cov-2 And the Replication of Human Coronavirus 229E. Virology. doi:10.1016/j.virol.2022.04.005.
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Thomas, Liji. (2022, April 24). Quercetin and other plant flavonols show anti-SARS-CoV-2 activity. News-Medical. Retrieved on June 27, 2022 from https://www.news-medical.net/news/20220424/Quercetin-and-other-plant-flavonols-show-anti-SARS-CoV-2-activity.aspx.

  • MLA

    Thomas, Liji. "Quercetin and other plant flavonols show anti-SARS-CoV-2 activity". News-Medical. 27 June 2022. <https://www.news-medical.net/news/20220424/Quercetin-and-other-plant-flavonols-show-anti-SARS-CoV-2-activity.aspx>.

  • Chicago

    Thomas, Liji. "Quercetin and other plant flavonols show anti-SARS-CoV-2 activity". News-Medical. https://www.news-medical.net/news/20220424/Quercetin-and-other-plant-flavonols-show-anti-SARS-CoV-2-activity.aspx. (accessed June 27, 2022).

  • Harvard

    Thomas, Liji. 2022. Quercetin and other plant flavonols show anti-SARS-CoV-2 activity. News-Medical, viewed 27 June 2022, https://www.news-medical.net/news/20220424/Quercetin-and-other-plant-flavonols-show-anti-SARS-CoV-2-activity.aspx.


  1. Principia Newton Principia Newton United States says:

    Solubility of quercetin in water is low, and it is poorly bioavailable orally.  EMIQ is the only formulated quercetin that is water soluble and bioavailable but the concentration of quercetin in EMIQ is low, and the authentic EMIQ made in Japan is unfortunately expensive.  Quercetin is an important molecule in light of D+Q discovery in the anti-aging field. Solubility problem ought to be solved.

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
You might also like...
Nanoparticles may be the next-generation solution for teeth whitening