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The Natural Products Withaferin A and Withanone from the Medicinal Herb Withania somnifera Are Covalent Inhibitors of the SARS-CoV-2 Main Protease
Mallick D., Goswami M., Guengerich F.P., Chowdhury G., , S. Chakraborty
Published in American Chemical Society
2022
PMID: 36098617
Volume: 85
   
Issue: 10
Pages: 2340 - 2350
Abstract
The current COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) created a global health crisis. The ability of vaccines to protect immunocompromised individuals and from emerging new strains are major concerns. Hence antiviral drugs against SARS-CoV-2 are essential. The SARS-CoV-2 main protease Mprois vital for replication and an important target for antivirals. Using CMap analysis and docking studies, withaferin A (wifA) and withanone (win), two natural products from the medicinal herb Withania somnifera (ashwagandha), were identified as promising candidates that can covalently inhibit the viral protease Mpro. Cell culture, enzymatic, LC-MS/MS, computational, and equilibrium dialysis based assays were performed. DFT calculations indicated that wifA and win can form stable adducts with thiols. The cytotoxicity of Mprowas significantly reduced by wifA and win. Both wifA and win were found to irreversibly inhibit 0.5 μM Mprowith IC50values of 0.54 and 1.8 μM, respectively. LC-MS/MS analysis revealed covalent adduct formation with wifA at cysteines 145 and 300 of Mpro. The natural products wifA and win can irreversibly inhibit the SARS-CoV-2 main protease Mpro. Based on the work presented here we propose that both wifA and win have the potential to be safely used as preventative and therapeutic interventions for COVID-19. © 2022 American Chemical Society. All rights reserved.
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Published in American Chemical Society
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