ABSTRACT
Background: Coronavirus disease 2019 (COVID-19) has posed a serious threat to human health and there is an urgent need for drug development. In this study, we explored the potential mechanisms underlying the efficacy of polydatin against COVID-19. Methods: A combined approach of network pharmacology, molecular docking, and experimental verification were employed in this study. Potential targets of polydatin for treating COVID-19 were obtained from multiple drug and disease databases. Protein–protein interaction and enrichment analyses were performed to predict the potential mechanism of action of polydatin against COVID-19. The binding potential of polydatin and key targets was evaluated through molecular docking. Furthermore, experimental methods including flow cytometry and luciferase assay were used to validate the results of computational analyses. Results: The main diseases identified as polydatin targets included metabolic diseases, lung diseases, inflammation, infectious diseases, and tumors. Polydatin may be used to treat COVID-19 through interventions that alter the immune and inflammatory responses, including IL-17 signaling pathway, T-cell activation, cytokines and inflammatory response, lipopolysaccharide-mediated signaling pathway, as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) innate immunity evasion and cell-specific immune response. Polydatin can potentially bind to the target proteins related to COVID-19, such as SARS-CoV-2 Mpro, RdRp, and human angiotensin-converting enzyme 2 (ACE2), while directly exerting its regulatory or therapeutic functions. The experimental results showed that polydatin decreased the infectivity of the SARS-CoV-2 spike pseudovirus in HEK293T-ACE2 cells. Accordingly, polydatin may retard the entry of SARS-CoV-2 into cells by competitively binding to human ACE2. Conclusion: The potential targets and signaling pathways of polydatin against COVID-19 were preliminarily identified. The findings may benefit the development and application of polydatin as a treatment for COVID-19.