Quercetin: A promising drug candidate against the potential SARS-CoV-2-Spike mutants with high viral infectivity

The emergence of SARS-CoV-2-Spike mutants not only enhances viral infectivity but also lead to treatment failure. Gaining a comprehensive understanding of the molecular binding mode between the mutant SARS-CoV-2-Spike and human ACE2 receptor is crucial for therapeutic development against this virus. Building upon our previous predictions and verifications regarding heightened viral infectivity of six potential SARS-CoV-2-Spike mutants, this study aims to further investigate the potential disruption of the interaction between these mutants and ACE2 by quercetin, a Chinese herbal compound. Molecular docking and dynamics simulations results reveal that the binding sites of quercetin particularly enriched around a specific “cavity” at the interface of Spike/ACE2 complex, indicating a favorable region for quercetin to interfere with Spike/ACE2 interaction. Virus infection assay confirms that quercetin not only attenuates wild-type virus infectivity but also suppresses the infectivity of all six tested SARS-CoV-2-Spike mutants. Therefore, quercetin represents a promising therapeutic candidate against both wild-type and potential future variants of SARS-CoV-2 exhibiting high viral infectivity. •Understanding of the impact of emerging Spike variants on therapeutics is crucial for developing drugs against COVID-19.•A specific "cavity" at the interface of the Spike/ACE2 complex is identified as a favorable binding region for quercetin.•Quercetin attenuates the infectivity of pseudotyped SARS-CoV-2 and the tested Spike-mutant viruses towards host cells.•Quercetin shows promising potential in combating both the wild-type SARS-CoV-2 and forthcoming emerging variants.