The current COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has created an unprecedented global crisis since December 2019. Because of emerging new strains, virulence, and morbidity of SARS-CoV-2, there is an urgent need for an effective cure. Although vaccines have been approved, there are concerns regarding the time frame of their effectiveness and against emerging new strains. SARS-CoV-2 being an RNA virus is prone to accrue mutations. With the extensive spread of SARS-CoV-2 infection and the selection pressure coming from vaccines and currently used drugs, the evolution of new virulent strains is inevitable. Moreover, there are numerous coronaviruses in nature that have the potential to mutate and jump species to infect humans. Hence, a broad-spectrum antiviral effective against coronaviruses, in general, is necessary. New drug candidates including those designed using AI, mini-, and decoy-proteins are being pursued although it might take years to reach the clinics. Repurposing existing drugs is a quicker approach, however, considering they are typically designed and developed for specific diseases, success depends on a rare “chance” factor. Herbal medicines, extracts, and their active ingredients, which are used for years, provide a reasonably safe alternative. Withania somnifera (Ashwagandha), is a medicinal plant used for thousands of years in India against various diseases. Withanone (win) and withaferin A (wifA) are two metabolites of Withania somnifera having epoxide and Michael acceptor functional groups. MPro is a ubiquitous coronavirus protein with no human homolog which renders it a lucrative target for antiviral drug development. Although a plethora of potential reversible and irreversible inhibitors (including aldehydes, Michael acceptors, and epoxides) of Mpro has been identified, none has been approved. Herein, using experimental and docking studies, we show that not only win and wifA can for adducts with cysteine and glutathione (GSH) but can also act as covalent inhibitors of Mpro. Our studies also show that the GSH adducts of win and wifA has the potential to inhibit Mpro. We propose to win, wifA and Withania somnifera extract as preventative and therapeutic interventions for COVID-19.

Withania somnifera metabolites withanone, withaferin A, and their GSH conjugates are potential irreversible inhibitors of the SARS-CoV-2 protease Mpro

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.