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The Chinese herb Ephedra (also known as Mahuang) has been extensively utilized for the prevention and treatment of coronavirus-induced diseases, including coronavirus disease 2019 (COVID-19). However, the specific anti-SARS-CoV-2 compounds and mechanisms have not been fully elucidated. The main protease (Mpro) of SARS-CoV-2 is a highly conserved enzyme responsible for proteolytic processing during the viral life cycle, making it a critical target for the development of antiviral therapies. This study aimed to identify naturally occurring covalent inhibitors of SARS-CoV-2 Mpro from Ephedra and to investigate their covalent binding sites. The results demonstrated that the non-alkaloid fraction of Ephedra (ENA) exhibited a potent inhibitory effect against the SARS-CoV-2 Mpro effect, whereas the alkaloid fraction did not. Subsequently, the chemical constituents in ENA were identified, and the major constituents' anti-SARS-CoV-2 Mpro effects were evaluated. Among the tested constituents, herbacetin (HE) and gallic acid (GA) were found to inhibit SARS-CoV-2 Mpro in a time- and dose-dependent manner. Their combination displayed a significant synergistic effect on this key enzyme. Additionally, various techniques, including inhibition kinetic assays, chemoproteomic methods, and molecular dynamics simulations, were employed to further elucidate the synergistic anti-Mpro mechanisms of the combination of HE and GA. Overall, this study deciphers the naturally occurring covalent inhibitors of SARS-CoV-2 Mpro from Ephedra and characterizes their synergistic anti-Mpro synergistic effect, providing robust evidence to support the anti-coronavirus efficacy of Ephedra. [ABSTRACT FROM AUTHOR]

The Chinese herb Ephedra (also known as Mahuang) has been extensively utilized for the prevention and treatment of coronavirus-induced diseases, including coronavirus disease 2019 (COVID-19). However, the specific anti-SARS-CoV-2 compounds and mechanisms have not been fully elucidated. The main protease (M pro ) of SARS-CoV-2 is a highly conserved enzyme responsible for proteolytic processing during the viral life cycle, making it a critical target for the development of antiviral therapies. This study aimed to identify naturally occurring covalent inhibitors of SARS-CoV-2 M pro from Ephedra and to investigate their covalent binding sites. The results demonstrated that the non-alkaloid fraction of Ephedra (ENA) exhibited a potent inhibitory effect against the SARS-CoV-2 M pro effect, whereas the alkaloid fraction did not. Subsequently, the chemical constituents in ENA were identified, and the major constituents' anti-SARS-CoV-2 M pro effects were evaluated. Among the tested constituents, herbacetin (HE) and gallic acid (GA) were found to inhibit SARS-CoV-2 M pro in a time- and dose-dependent manner. Their combination displayed a significant synergistic effect on this key enzyme. Additionally, various techniques, including inhibition kinetic assays, chemoproteomic methods, and molecular dynamics simulations, were employed to further elucidate the synergistic anti-M pro mechanisms of the combination of HE and GA. Overall, this study deciphers the naturally occurring covalent inhibitors of SARS-CoV-2 M pro from Ephedra and characterizes their synergistic anti-M pro synergistic effect, providing robust evidence to support the anti-coronavirus efficacy of Ephedra., (Copyright © 2024 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Introduction: Hepatocellular carcinoma (HCC) accounts for 85% of liver cancer cases and is the third leading cause of cancer death. Regorafenib is a multi-target inhibitor that dramatically prolongs progression-free survival in HCC patients who have failed sorafenib therapy. However, one of the primary factors limiting regorafenib's clinical utilization is toxicity. Using Clinical Trials.gov and PubMed, we gathered clinical data on regorafenib and conducted a extensive analysis of the medication's adverse reactions and mechanisms. Next, we suggested suitable management techniques to improve regorafenib's effectiveness., Areas Covered: We have reviewed the mechanisms by which regorafenib-induced toxicity occurs and general management strategies through clinical trials of regorafenib. Furthermore, by examining the literature on regorafenib and other tyrosine kinase inhibition, we summarized the mechanics of the onset of regorafenib toxicity and mechanism-based intervention strategies by reviewing the literature related to regorafenib and other tyrosine kinase inhibition., Expert Opinion: One of the primary factors restricting regorafenib's clinical utilization and combination therapy is its toxicity reactions. To optimize regorafenib treatment regimens, it is especially important to further understand the specific toxicity mechanisms of regorafenib as a multi-kinase inhibitor.