The Perfect Enemy | Antiviral activity of natural flavonoids against various coronaviruses - News-Medical.Net
April 17, 2024

Antiviral activity of natural flavonoids against various coronaviruses – News-Medical.Net

Antiviral activity of natural flavonoids against various coronaviruses  News-Medical.Net

The enzyme 3-chymotrypsin-like cysteine protease (3CLpro) is a key drug target for the treatment of the coronavirus disease 2019 (COVID-19). Moreover, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CLpro is essential throughout the viral life cycle and exhibits high conservation among coronaviruses.

Recent studies have reported the antiviral activity of flavonoids against different coronaviruses (CoVs), including SARS-CoV-2. A recent Microorganisms journal paper describes the binding affinity and docking sites of several natural compounds and their inhibitory activity against 3CLpro.

Study: Flavonoid Derivates Have Pan-Coronavirus Antiviral Activity. Image Credit: Kitreel /

Study: Flavonoid Derivates Have Pan-Coronavirus Antiviral Activity. Image Credit: Kitreel /


SARS-CoV-2, a positive-strand ribonucleic acid (RNA) virus belonging to the Coronaviridae family, is the causal agent of COVID-19. Distinct viral enzymes, such as papain-like protease (PLpro), 3CLpro, and RNA-dependent RNA polymerase (RdRp), have been used to assess the potential of anti-SARS-CoV-2 drugs.

Research has shown the crucial role of 3CLpro, which is also referred to as Mpro, in antagonizing innate immunity and viral protein maturation. Compared to other human proteases, Mpro is highly conserved and key to proteolytic processing of the viral RNA-polymerase complex.

To date, Molnupiravir and Paxlovid are the only anti-viral agents effective in treating mild-to-moderate COVID-19 in patients susceptible to developing severe disease. Thus, there remains an urgent need to identify new compounds capable of neutralizing SARS-CoV-2 to reduce its infectivity and ability to cause severe disease.

Several in silico, in vitro, and in vivo studies have shown that small natural molecules of the polyphenol family can hinder coronavirus replication. In addition to polyphenols, more information is needed on the antiviral mechanisms of other flavonoids and their potential to mitigate post-COVID-19 syndrome.

About the study

The current study used molecular docking to filter and identify the binding affinities and docking patterns of compounds with structural similarities to flavonoids. Luteolin and 7,8-hydroxyflavone are two flavonoids that have been shown to be active against 3CLpro.

Several enzymatic assays were subsequently used to test the 3CLpro inhibitory effects of compounds that were found to be active in silico. All active compounds were then subjected to an in vitro assay to determine their anti-SARS-CoV-2 activity, as well as their potential anti-pan-coronaviral activity against Human (H)CoVOC43, Feline (F)-CoV, and Bovine (B)-CoV.

Key findings

The first stage of in silico analyses led to the identification of Alnusin, Baicalein, Chrysin, Galangin, Hispidulin, Isokaempferide, Isosakuranetin, Morin, Quercetin, Sakuranetin, Steppogenin, and Taxifolin. Using a 3CLpro enzymatic assay, four flavonoids were found to be active against 3CLpro, of which included Morin, Baicalein, Hispidulin, and Isokaempferide.

Baicalein was the most promising agent, as it inhibited 3CLpro activity above 90%. Hispidulin was associated with Influenza A H1N1 neuraminidase inhibition, whereas the antiviral activity of Morin was observed against the Herpesviridae family.

The identified flavonoids were tested against SARS-CoV-2 replication using an in vitro assay. Consistent with other studies, only Baicalein had greater than 50% activity against virus replication. A crystallographic picture of the molecular interaction between Baicalein and 3CLpro was obtained with SARS-CoV-1 3CLpro, which is very similar to SARS-CoV-2.

Next, the researchers evaluated Baicalein’s inhibitory potency against other members of the Coronaviridae family. To this end, Baicalein was found to be highly active against HCoV-OC43, FCoV, and B-CoV replication.

Given that F-CoV belongs to the alpha coronavirus genus, Baicalein could be effective against human alpha-CoV species, which can cause severe diseases in immunocompromised individuals and newborns. The wide range of anti-pancoronaviral action of Baicalein could be driven by the fact that 3CLpro is highly conserved within the Coronaviridae family.


A key limitation of the current study was the lack of other HCoV models to confirm the anti-pancoronaviral activity of Baicalein. Additionally, several compounds were tested in low concentrations, as they were toxic to the cells. This could have led to a bias in evaluating the true antiviral potency of these molecules.

Taken together, in addition to confirming the in vitro antiviral activity of Baicalein against SARS-CoV-2, the current study demonstrated its anti-pan-coronaviral activity. The researchers also highlighted the utility of the experimental approach of combining in silico and in vitro analyses to identify novel antiviral drugs to treat infection with SARS-CoV-2 or other viral pathogens.

These findings should encourage additional research on exploring naturally occurring flavonoids and identifying more 3CLpro inhibitors of SARS-CoV-2 replication. Future research should also explore the potential activity of Baicalein and its derivatives against other stages of the coronavirus life cycle.

Journal reference: