Flavanols & Dihydroflavonols Inhibit The MPro Activity of SARS-CoV-2 and the Replication of HCoV-229E (Botany)

Human coronavirus 229E (HCoV-229E) is a pathogenic virus in the genus Alpha coronavirus which causes the common cold. The main protease (Mpro) is an essential enzyme required for the multiplication of SARS-CoV-2 and HCoV-229E viruses in the host cells, and thus is an appropriate candidate to screen potential medicinal compounds. Now, Dr. De-Yu Xie and colleagues investigated whether Flavonols and dihydroflavonols, two groups of plant flavonoids can effectively prevent SARS-CoV-2 infection or not. They found that the Flavanols and dihydroflavonols inhibit the main protease activity of SARS-CoV-2 and the replication of human coronaviruses 229 E. Their study recently appeared in BioRxiv.

SARS-CoV-2 is the virus that causes COVID-19, the respiratory illness responsible for the current COVID-19 pandemic. Although, there are many vaccines available in the developed countries to prevent the infection of this virus, there is an urgent need of medicine which can help us control COVID-19 effectively.

Quercetin, kaempferol, and myricetin are three flavonol molecules widely existing in plants. Likewise, dihydroquercetin, dihydrokaempferol, and dihydromyricetin are three dihydroflavonol molecules in plants. In general, flavonols and dihydroflavonols are strong antioxidants with multiple benefits to human health. While, Quercetin is a plant pigment (flavonoid), which have antiviral activity.

In their study, Dr. De-Yu Xie and colleagues hypothesized that flavonols and dihydroflavonols might inhibit the main protease activity of SARS-CoV-2 and HCoV-229E and tested this hypothesis by performing docking simulation for 3 dihydroflavonols (dihydroquercetin, dihydrokaempferol, and dihydromyricetin), 3 flavonols (Quercetin, kaempferol, and myricetin) and 2 glycosylated Quercetins. They also tested these compounds inhibition against the recombinant main protease activity of SARS-CoV-2 in vitro.

Their docking simulation results predicted that dihydrokaempferol, dihydroquercetin, dihydromyricetin, kaempferol, quercetin, myricentin, isoquercetin, and rutin could bind to at least two subsites (S1, S1′, S2, and S4) in the binding pocket and inhibit the activity of SARS-CoV-2 main protease. Their affinity scores ranged from -8.8 to -7.4.

Table 1. Affinity scores of 11 compounds binding to the main proteases of SARS-CoV-2 and HuCoV-229E © De-Yu Xie et al

Likewise, these compounds were predicted to bind and inhibit the HCoV-229E main protease activity with affinity scores ranging from -7.1 to -7.8.

Moreover, In vitro inhibition assays showed that seven available compounds i.e. dihydroquercetin, dihydromyricetin, kaempferol, quercetin, myricentin, isoquercetin, and rutin, effectively inhibited the SARS-CoV-2 main protease activity and their IC50 values ranged from 0.125 to 12.9 uM.

Finally, they tested inhibitory effects of five compounds i.e. Quercetin, isoquercetin, taxifolin, epigallocatechin gallate (EGCG) and epicatechin, on the replication of HCoV-229E in Huh-7 cells. Their resulting data indicated that all five compounds showed an inhibition against the replication of HCoV-229E in Huh-7 cells.

Based on TCID50/ml values, taxifolin started to show its inhibition at 2.5 µM and its inhibitory activity increased as its concentration was increased. Quercetin started to have inhibition at 5 µM. As its concentrations were increased, its inhibitive activities were more effective. At a concentration tested higher 10 µM, quercetin could strongly inhibit the replication of the virus. Its EC50 value was estimated to be 4.88 µM. Isoquercitrin strongly inhibited the replication starting with 2.5 µM. EGCG started to show its inhibition against the replication of the virus at 2.5 µM and its inhibition became stronger as its concentrations were increased. Moreover, epicatechin could strongly inhibit the replication starting at 20 µM.

Their findings indicated that these antioxidative flavonols and dihydroflavonols are promising candidates for curbing the two viruses.

Featured image: Ligand-receptor docking modeling showing the binding of eleven compounds to the substrate pocket of the SARS-CoV-2 main protease (Mpro). The first image shows the 3D surface view of the SARS-CoV-2 Mpro, on which the red rectangular frame indicates the substrate-binding pocket. Eleven flavonoids and ebselen bind to this pocket. Two flavan-3-ols: (+)-catechin (CA) and (-)-epicatechin (EC); three dihydroflavonol aglycones:(+)-dihydroquercetin (DHQ), (+)-dihydrokaempferol (DHK), and (+)-dihydroquercetin (DHM); three flavonols aglycones, kaempferol, quercetin, and myricetin; two glycosylated flavonols: quercetin-3-O-glycoside (isoquercitrin), and rutin. © De-Yu Xie et al.


Reference: Yue Zhu, Frank Scholle, Samantha C. Kisthardt, Deyu Xie, “Flavonols and dihydroflavonols inhibit the main protease activity of SARS-CoV-2 and the replication of human coronavirus 229E”, bioRxiv 2021.07.01.450756; doi: https://doi.org/10.1101/2021.07.01.450756


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