Research suggests plant flavonols could serve as effective antivirals for SARS-CoV-2

Researchers in Algeria have reviewed some of the evidence suggesting that flavonols commonly found in many plants and vegetables could be used as a therapeutic approach to coronavirus disease 2019 (COVID-19).

In an article recently published in the European Journal of Pharmacology, the team describes a number of studies suggesting that these naturally occurring molecules exert antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes COVID-19.

The studies have demonstrated that many dietary flavonols disrupt the ability of SARS-CoV-2 to bind to its target host cell receptor angiotensin-converting enzyme 2 (ACE2) and gain viral entry.

The reviewers also discuss how some flavonols can inhibit the activity of SARS-CoV-2 proteins that are involved in viral replication.

“These molecules may alleviate the severity of COVID‐19 symptoms and modulate the immune response,” say Chaima Mouffouk and colleagues from the University of Batna.

Researchers race to identify treatment approaches

Since SARS-CoV-2 was first identified in Wuhan, China, late December 2019, the COVID-19 pandemic has led to more than 63.37 million infections and caused more than 1.47 million deaths.

In the absence of any effective vaccine or treatment, researchers are racing to identify potential treatment approaches

The antioxidant, anti-inflammatory, and antiviral activities of flavonoids have led many researchers to investigate the effects of these biomolecules on SARS-CoV-2.

Flavonols – the most prevalent group of flavonoids – are of particular interest to researchers and their antiviral activity against SARS-CoV-2 has been well documented, say Mouffouk and colleagues.

The researchers have now reviewed some of the evidence published between January and August this year (2020) demonstrating the potential of flavonols as antiviral agents for targeting SARS-CoV-2.

These molecules can target essential viral proteins, including 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), Spike protein (S protein) and RNA-dependent RNA polymerase (RdRp). They can also interact with the ACE2 receptor that SARs-CoV-2 uses to enter host cells.

Targeting 3CLpro and PLpro

Also referred to as the main protease, 3CLpro is an enzyme involved in the proteolytic maturation of viral polypeptides that form a protein complex called RNA replicase-transcriptase complex. This complex is essential for viral transcription and replication.  

Molecules that target 3CLpro may be able to prevent post-translational processing of SARS-CoV-2 polypeptides and reduce the risk of mutation-mediated drug resistance, say the researchers.

PLpro is also an important proteolytic enzyme that cleaves viral polyproteins to form a number of nonstructural viral proteins. In addition, PLpro has been shown to inhibit the production of interferons, which exert antiviral activity.  

Molecules that inhibit PLpro would induce an antiviral response in host cells and also disrupt the replication cycle, says the team.

According to a study that tested 32,297 molecules used in traditional Chinese medicine, the flavonols myricitrin and myricetin-3-O-β-D-glucopyranoside showed a strong binding affinity for the receptor-binding site of 3CLpro.

“These compounds are also non-toxic, biologically active and naturally found in many medicinal species,” writes Mouffouk and team.

The study also showed that the flavonols astragalin, kaempferol, and quercetin, all consistently interacted with both 3CLpro and PLpro. These molecules all exhibited stronger binding affinities for the two enzymes than the drug remdesivir.

Remdesivir is an immunomodulatory agent approved for emergency use as a COVID‑19 treatment in around fifty countries.

Flavonols that can target the S protein and ACE2

The S protein is the main viral structure that SARS-CoV-2 uses to bind to ACE2 and fuse with the host cell membrane. Molecules that could block this binding of S to ACE2 would prevent the virus from entering host cells.

One study recently reported that the flavonols fisetin, quercetin, isorhamnetin and kaempferol had a higher binding affinity for the S protein than the drug hydroxychloroquine, which has been investigated as a potential treatment for COVID-19.

Furthermore, another study found that the myricetin could interact with ACE2 and cause conformational changes that inhibited viral entry.

Flavonols that can target RdRp

RdRp is an enzyme involved in the synthesis of viral RNA and is essential to viral replication and transcription.

One molecular docking study showed that quercetin and kaempferol, as well as the glucuronide and sulfate derivatives of these flavonols, potently inhibited the RdRp protein. An analysis of binding energy values showed that a number of quercetin derivatives demonstrated higher binding affinities than quercetin itself, says the team.

A promising new therapeutic strategy for COVID-19

Mouffouk and colleagues say the evidence reviewed in this study suggests that flavonols may represent a promising new therapeutic strategy for COVID-19.

“Flavonols have the ability to disturb and destabilize the binding between S protein and ACE2, leading to the inhibition of virus entry, and halt the activity of several enzymes involved in viral replication including 3CLpro, PLpro and RdRp,” they write.

“Due to their large spectrum of biological activities, these molecules may alleviate the severity of COVID‐19 symptoms and modulate the immune response,” concludes the team.

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.


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