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Molecular mechanism of anti-SARS-CoV2 activity of Ashwagandha-derived withanolides.

ABSTRACT: COVID-19 caused by SARS-CoV-2 corona virus has become a global pandemic. In the absence of drugs and vaccine, and premises of time, efforts and cost required for their development, natural resources such as herbs are anticipated to provide some help and may also offer a promising resource for drug development. Here, we have investigated the therapeutic prospective of Ashwagandha for the COVID-19 pandemic. Nine withanolides were tested in silico for their potential to target and inhibit (i) cell surface receptor protein (TMPRSS2) that is required for entry of virus to host cells and (ii) viral protein (the main protease M^pro) that is essential for virus replication. We report that the withanolides possess capacity to inhibit the activity of TMPRSS2 and M^pro. Furthermore, withanolide-treated cells showed downregulation of TMPRSS2 expression and inhibition of SARS-CoV-2 replication in vitro, suggesting that Ashwagandha may provide a useful resource for COVID-19 treatment.

SUBMITTER: Dhanjal JK

PROVIDER: S-EPMC8188803 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Molecular mechanism of anti-SARS-CoV2 activity of Ashwagandha-derived withanolides.

Dhanjal Jaspreet Kaur JK Kumar Vipul V Garg Sukant S Subramani Chandru C Agarwal Shubhra S Wang Jia J Zhang Huayue H Kaul Ashish A Kalra Rajkumar Singh RS Kaul Sunil C SC Vrati Sudhanshu S Sundar Durai D Wadhwa Renu R

International journal of biological macromolecules 20210609

COVID-19 caused by SARS-CoV-2 corona virus has become a global pandemic. In the absence of drugs and vaccine, and premises of time, efforts and cost required for their development, natural resources such as herbs are anticipated to provide some help and may also offer a promising resource for drug development. Here, we have investigated the therapeutic prospective of Ashwagandha for the COVID-19 pandemic. Nine withanolides were tested in silico for their potential to target and inhibit (i) cell ...[more]

PMID: 34118289

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Project description:BackgroundTumor suppressor p53 protein is frequently mutated in a large majority of cancers. These mutations induce local or global changes in protein structure thereby affecting its binding to DNA. The structural differences between the wild type and mutant p53 thus provide an opportunity to selectively target mutated p53 harboring cancer cells. Restoration of wild type p53 activity in mutants using small molecules that can revert the structural changes have been considered for cancer therapeutics.MethodsWe used bioinformatics and molecular docking tools to investigate the structural changes between the wild type and mutant p53 proteins (p53V143A, p53R249S, p53R273H and p53Y220C) and explored the therapeutic potential of Withaferin A and Withanone for restoration of wild type p53 function in cancer cells. Cancer cells harboring the specific mutant p53 proteins were used for molecular assays to determine the mutant or wild type p53 functions.ResultsWe found that p53V143A mutation does not show any significant structural changes and was also refractory to the binding of withanolides. p53R249S mutation critically disturbed the H-bond network and destabilized the DNA binding site. However, withanolides did not show any selective binding to either this mutant or other similar variants. p53Y220C mutation created a cavity near the site of mutation with local loss of hydrophobicity and water network, leading to functionally inactive conformation. Mutated structure could accommodate withanolides suggesting their conformational selectivity to target p53Y220C mutant. Using human cell lines containing specific p53 mutant proteins, we demonstrated that Withaferin A, Withanone and the extract rich in these withanolides caused restoration of wild type p53 function in mutant p53Y220C cells. This was associated with induction of p21WAF-1-mediated growth arrest/apoptosis.ConclusionThe study suggested that withanolides may serve as highly potent anticancer compounds for treatment of cancers harboring a p53Y220C mutation.

Dataset Information

Molecular mechanism of anti-SARS-CoV2 activity of Ashwagandha-derived withanolides.

Publications

Molecular mechanism of anti-SARS-CoV2 activity of Ashwagandha-derived withanolides.

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