Plant flavonoid inhibition of SARS-CoV-2 main protease and viral replication

• Published in: iScience Vol. 26; no. 9; p. 107602
• Main Authors: Lin, Lin, Chen, Da-Yuan, Scartelli, Christina, Xie, Huanzhang, Merrill-Skoloff, Glenn, Yang, Moua, Sun, Lijun, Saeed, Mohsan, Flaumenhaft, Robert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.09.2023; Elsevier
• Subjects: Biochemistry; Biological sciences; Cell biology; Chemistry; Natural product chemistry; Natural sciences; Pharmacology; Chemistry; Natural sciences; Cell biology; Pharmacology; Biological sciences; Biochemistry; Natural product chemistry
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.107602

Plant-based flavonoids have been evaluated as inhibitors of β-coronavirus replication and as therapies for COVID-19 on the basis of their safety profile and widespread availability. The SARS-CoV-2 main protease (Mpro) has been implicated as a target for flavonoids in silico. Yet no comprehensive in vitro testing of flavonoid activity against SARS-CoV-2 Mpro has heretofore been performed. We screened 1,019 diverse flavonoids for their ability to inhibit SARS-CoV-2 Mpro. Multiple structure-activity relationships were identified among active compounds such as enrichment of galloylated flavonoids and biflavones, including multiple biflavone analogs of apigenin. In a cell-based SARS-CoV-2 replication assay, the most potent inhibitors were apigenin and the galloylated pinocembrin analog, pinocembrin 7-O-(3''-galloyl-4'',6''-(S)-hexahydroxydiphenoyl)-beta-D-glucose (PGHG). Molecular dynamic simulations predicted that PGHG occludes the S1 binding site via a galloyl group and induces a conformational change in Mpro. These studies will advance the development of plant-based flavonoids—including widely available natural products—to target β-coronaviruses. [Display omitted] •HTS of a large flavonoid library identified SARS-CoV-2 main protease inhibitors•Galloylated compounds and biflavones were enriched among active compounds•The galloylated pinocembrin, PGHG, occluded the S1 binding site via its galloyl group•PGHG and apigenin were the most potent inhibitors of SARS-CoV-2 replication Pharmacology; Natural sciences; Chemistry; Natural product chemistry; Biological sciences; Biochemistry; Cell biology