Publication date: Sep 15, 2023
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.
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| Concepts | Keywords |
|---|---|
| Coronaviruses | Biochemistry |
| Flavonoids | Biological sciences |
| Hexahydroxydiphenoyl | Cell biology |
| Therapy | Chemistry |
| Natural product chemistry | |
| Natural sciences | |
| Pharmacology |
Semantics
| Type | Source | Name |
|---|---|---|
| pathway | KEGG | Viral replication |
| disease | IDO | replication |
| disease | MESH | COVID-19 |
| drug | DRUGBANK | Apigenin |
| disease | IDO | cell |
| disease | IDO | assay |
| drug | DRUGBANK | Beta-D-Glucose |
| disease | IDO | site |
| drug | DRUGBANK | Dextrose unspecified form |
| drug | DRUGBANK | Chymotrypsin |
| drug | DRUGBANK | L-Cysteine |
| disease | VO | effective |
| drug | DRUGBANK | Ritonavir |
| disease | IDO | host |
| pathway | REACTOME | Metabolism |
| disease | MESH | Thrombosis |
| disease | VO | USA |
| disease | MESH | Emerging Infectious Diseases |
| drug | DRUGBANK | Dimethyl sulfoxide |
| disease | VO | URE |
| disease | VO | dose |
| drug | DRUGBANK | Coenzyme M |
| disease | IDO | production |
| drug | DRUGBANK | Flavone |