The sudden outburst of Coronavirus disease (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses a massive threat to global public health. Currently, no therapeutic drug or vaccine exists to treat COVID-19. Due to the time taking process of new drug development, drug repurposing might be the only viable solution to tackle COVID-19. RNA-dependent RNA polymerase (RdRp) catalyzes SARS-CoV-2 RNA replication and hence, is an obvious target for antiviral drug design. Interestingly, several plant-derived polyphenols effectively inhibit the RdRp of other RNA viruses. More importantly, polyphenols have been used as dietary supplementations for a long time and played beneficial roles in immune homeostasis. We were curious to study the binding of polyphenols with SARS-CoV-2 RdRp and assess their potential to treat COVID-19. Herein, we made a library of polyphenols that have shown substantial therapeutic effects against various diseases. They were successfully docked in the catalytic pocket of RdRp. The investigation reveals that EGCG, theaflavin (TF1), theaflavin-3'-O-gallate (TF2a), theaflavin-3'-gallate (TF2b), theaflavin 3,3'-digallate (TF3), hesperidin, quercetagetin, and myricetin strongly bind to the active site of RdRp. Further, a 150-ns molecular dynamic simulation revealed that EGCG, TF2a, TF2b, TF3 result in highly stable bound conformations with RdRp. The binding free energy components calculated by the MM-PBSA also confirm the stability of the complexes. We also performed a detailed analysis of ADME prediction, toxicity prediction, and target analysis for their druggability. Overall, our results suggest that EGCG, TF2a, TF2b, TF3 can inhibit RdRp and represent an effective therapy for COVID-19.

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Among the synthesized 4′′-alkyl EGCG derivatives, 4′′-C14 EGCG inhibited EGF stimulated phosphorylation of EGFR and its downstream signaling pathways, ERK and Akt. 4′′-C14 EGCG showed significantly improved stability than EGCG and induced apoptosis.

<p>The sudden outburst of Coronavirus disease (COVID-19) has left the entire world to a standstill. COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). As per the report from the WHO, more than 4.5 million people have been infected by SARS-CoV-2 with more than 3,00,000 deaths across the globe. As of now, there is no therapeutic drug or vaccine approved for the treatment of SARS-CoV-2 infection. Hence, the outbreak of COVID-19 poses a massive threat to humans. Due to the time taking process of new drug design and development, drug repurposing might be the only viable solution to tackle COVID-19. RNA‐dependent RNA polymerase (RdRp) catalyzes SARS-CoV-2 RNA replication, <i>i.e.</i> the synthesis of single-stranded RNA genomes, an absolutely necessary step for the survival and growth of the virus. Thus, RdRp is an obvious target for antiviral drug design. Interestingly, several plant-derived polyphenols have been shown to inhibit enzymatic activities of RdRp of various RNA viruses including polio-virus type 1, parainfluenza virus type 3, and respiratory syncytial virus etc. More importantly, natural polyphenols have been used as a dietary supplementation for humans for a long time and played a beneficial role in immune homeostasis. Therefore, we were curious to study the binding of dietary polyphenols with RdRp of SARS-CoV-2 and assess their potential as an effective therapy for COVID-19. In this present work, we made a library of twenty potent polyphenols that have shown substantial therapeutic effects against various diseases. The polyphenols were successfully docked in the catalytic pocket of RdRp of SARS-CoV and SARS-CoV-2, and detailed studies on ADME prediction, toxicity prediction and target analysis were performed. The study reveals that EGCG, quercetagetin, and myricetin strongly bind to the active site of SARS-CoV-2 RdRp. Our studies suggest that EGCG, quercetagetin, and myricetin can inhibit RdRp and represent an effective therapy for COVID-19. </p>