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

Lin Lin; Da-Yuan Chen; Christina Scartelli; Huanzhang Xie; Glenn Merrill-Skoloff; Moua Yang; Lijun Sun; Mohsan Saeed; Robert Flaumenhaft

doi:10.1016/j.isci.2023.107602

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

iScience. 2023 Aug 10;26(9):107602. doi: 10.1016/j.isci.2023.107602. eCollection 2023 Sep 15.

Authors

Lin Lin^{1

2}, Da-Yuan Chen^{3

4}, Christina Scartelli¹, Huanzhang Xie², Glenn Merrill-Skoloff¹, Moua Yang¹, Lijun Sun⁵, Mohsan Saeed^{3

4}, Robert Flaumenhaft¹

Affiliations

¹ Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
² College of Materials and Chemical Engineering, Minjiang University, Fuzhou Institute of Oceanography, Fuzhou, China.
³ National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, USA.
⁴ Department of Biochemistry & Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
⁵ Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Abstract

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.

Keywords: Biochemistry; Biological sciences; Cell biology; Chemistry; Natural product chemistry; Natural sciences; Pharmacology.

Grants and funding

K99 HL164888/HL/NHLBI NIH HHS/United States