HU Qing, ZHANG Yiwen, CHEN Pengcheng, ZHANG Yani, ZHU Guanghao, LIU Wei, WANG Chaoran, ZHENG Shuilian, SHEN Nonger, WANG Haonan, HUANG Ping, GE Guangbo. Discovery and characterization of naturally occurring covalent inhibitors of SARS-CoV-2 Mpro from the anti-viral herb Ephedra [J].Chin J Nat Med, 2024, 22(0): 1-12. doi: 10.1016/S1875-5364(24)60577-7
Citation: HU Qing, ZHANG Yiwen, CHEN Pengcheng, ZHANG Yani, ZHU Guanghao, LIU Wei, WANG Chaoran, ZHENG Shuilian, SHEN Nonger, WANG Haonan, HUANG Ping, GE Guangbo. Discovery and characterization of naturally occurring covalent inhibitors of SARS-CoV-2 Mpro from the anti-viral herb Ephedra [J].Chin J Nat Med, 2024, 22(0): 1-12. doi: 10.1016/S1875-5364(24)60577-7
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Discovery and characterization of naturally occurring covalent inhibitors of SARS-CoV-2 Mpro from the anti-viral herb Ephedra

    Abstract
  • The Chinese herb Ephedra (also termed Mahuang) has been widely used for the prevention and treatment of coronavirus-caused diseases, including coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ephedra is a key material for preparing some famous anti-viral Chinese medicines that have been used for combating COVID-19, but its anti-SARS-CoV-2 substances and underlying mechanisms have not been fully revealed. The main protease (Mpro) is a highly conserved protease responsible for proteolytic processing during the viral life cycle, making it a key target for anti-coronavirus therapy development. This study aimed to find the naturally occurring covalent inhibitors of SARS-CoV-2 Mpro from the anti-viral herb Ephedra, as well as to investigate their covalent binding sites and anti-SARS-CoV-2 Mpro mechanisms. The results demonstrated that the Ephedra non-alkaloid fraction (ENA) showed potent anti-SARS-CoV-2 Mpro effect, while the alkaloid fraction of Ephedra did not inhibit Mpro. The chemical constituents in ENA were then identified and the anti-SARS-CoV-2 Mpro effects of the major constituents in ENA were evaluated. Among all tested constituents, herbacetin and gallic acid in ENA time- and dose-dependently inhibited SARS-CoV-2 Mpro, while their combination exhibited significant synergistic effect on this key enzyme. Moreover, a series of techniques, such as inhibition kinetic assays, chemoproteomic methods, and molecular dynamics simulations, were employed to further elucidate the synergistic anti-Mpro mechanisms of the combination of two identified natural Mpro inhibitors (herbacetin and gallic acid). Overall, this study deciphers the naturally occurring covalent inhibitors of SARS-CoV-2 Mpro from the anti-viral herb Ephedra and characterizes their anti-Mpro synergistic effect, which offers powerful evidence to support the anti-coronavirus effects of the Chinese herb Ephedra.
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