Plant flavonoid inhibition of SARS-CoV-2 main protease and viral replication
Summary: 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 comprehe...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223016796 |
| _version_ | 1797738920816934912 |
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| author | Lin Lin Da-Yuan Chen Christina Scartelli Huanzhang Xie Glenn Merrill-Skoloff Moua Yang Lijun Sun Mohsan Saeed Robert Flaumenhaft |
| author_facet | Lin Lin Da-Yuan Chen Christina Scartelli Huanzhang Xie Glenn Merrill-Skoloff Moua Yang Lijun Sun Mohsan Saeed Robert Flaumenhaft |
| author_sort | Lin Lin |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-12T13:50:49Z |
| format | Article |
| id | doaj.art-39b04371d6844ffb8a5d50a2ddaf2484 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-12T13:50:49Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-39b04371d6844ffb8a5d50a2ddaf24842023-08-23T04:33:51ZengElsevieriScience2589-00422023-09-01269107602Plant flavonoid inhibition of SARS-CoV-2 main protease and viral replicationLin Lin0Da-Yuan Chen1Christina Scartelli2Huanzhang Xie3Glenn Merrill-Skoloff4Moua Yang5Lijun Sun6Mohsan Saeed7Robert Flaumenhaft8Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; College of Materials and Chemical Engineering, Minjiang University, Fuzhou Institute of Oceanography, Fuzhou, ChinaNational Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, USA; Department of Biochemistry & Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USADivision of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USACollege of Materials and Chemical Engineering, Minjiang University, Fuzhou Institute of Oceanography, Fuzhou, ChinaDivision of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADivision of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USACenter for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USANational Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, USA; Department of Biochemistry & Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USADivision of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004223016796PharmacologyNatural sciencesChemistryNatural product chemistryBiological sciencesBiochemistry |
| spellingShingle | Lin Lin Da-Yuan Chen Christina Scartelli Huanzhang Xie Glenn Merrill-Skoloff Moua Yang Lijun Sun Mohsan Saeed Robert Flaumenhaft Plant flavonoid inhibition of SARS-CoV-2 main protease and viral replication iScience Pharmacology Natural sciences Chemistry Natural product chemistry Biological sciences Biochemistry |
| title | Plant flavonoid inhibition of SARS-CoV-2 main protease and viral replication |
| title_full | Plant flavonoid inhibition of SARS-CoV-2 main protease and viral replication |
| title_fullStr | Plant flavonoid inhibition of SARS-CoV-2 main protease and viral replication |
| title_full_unstemmed | Plant flavonoid inhibition of SARS-CoV-2 main protease and viral replication |
| title_short | Plant flavonoid inhibition of SARS-CoV-2 main protease and viral replication |
| title_sort | plant flavonoid inhibition of sars cov 2 main protease and viral replication |
| topic | Pharmacology Natural sciences Chemistry Natural product chemistry Biological sciences Biochemistry |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223016796 |
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