Withanone from <i>Withania somnifera</i> Attenuates SARS-CoV-2 RBD and Host ACE2 Interactions to Rescue Spike Protein Induced Pathologies in Humanized Zebrafish Model
Balkrishna A, Pokhrel S, Singh H, Joshi M, Mulay VP, Haldar S, Varshney A
Drug design, development and therapy · 64 citations
How it was studied
- Design
- Animal study (classified by our AI screen)
- Studied in
- Animals
- Main outcome
- Health markers and function
Who paid for it
- Funding
- Independent funding
Based on full-text disclosure statement.
Publication
- Published
- 2021-03-01 · Drug Des Devel Ther · vol. Volume 15 · pp. 1111–1133
- Publisher
- Dove Medical Press
- Cited
- 109 citations · more than 100% of similar papers · 26.2× the field average
- Impact
- Top 10% most cited in its field
- References
- 71 works
- Access
- Open access (journal) · CC-BY-NC
- Research areas
- Phytochemicals and Medicinal Plants · Diverse Scientific Research Studies · Andrographolide Research and Applications
- Keywords
- Withania somnifera, Withaferin A, In silico, Docking (animal), In vitro, In vivo, Transmembrane protein, Chemistry, Biology, Cell biology, Biochemistry, Biophysics, Receptor, Genetics, Medicine, Gene
- MeSH
- animals, zebrafish, humans, withania, disease models, animal, antiviral agents, structure-activity relationship, female, male, virus internalization, withanolides, protein interaction domains and motifs, host-pathogen interactions, static electricity, molecular dynamics simulation, molecular docking simulation, spike glycoprotein, coronavirus, a549 cells, covid-19, angiotensin-converting enzyme 2, sars-cov-2, endoplasmic reticulum chaperone bip, covid-19 drug treatment
7 authors
From IN
- Acharya BalkrishnaPatanjali Research Foundation
- Subarna PokhrelPatanjali Research Foundation
- Hoshiyar SinghPatanjali Research Foundation
- Monali JoshiPatanjali Research Foundation
- Vallabh Prakash MulayPatanjali Research Foundation
- Swati HaldarPatanjali Research Foundation
Abstract
Purpose
SARS-CoV-2 engages human ACE2 through its spike (S) protein receptor binding domain (RBD) to enter the host cell. Recent computational studies have reported that withanone and withaferin A, phytochemicals found in Withania somnifera, target viral main protease (MPro) and host transmembrane TMPRSS2, and glucose related protein 78 (GRP78), respectively, implicating their potential as viral entry inhibitors. Absence of specific treatment against SARS-CoV-2 infection has encouraged exploration of phytochemicals as potential antivirals.
Aim
This study aimed at in silico exploration, along with in vitro and in vivo validation of antiviral efficacy of the phytochemical withanone.
Methods
Through molecular docking, molecular dynamic (MD) simulation and electrostatic energy calculation the plausible biochemical interactions between withanone and the ACE2-RBD complex were investigated. These in silico observations were biochemically validated by ELISA-based assays. Withanone-enriched extract from W. somnifera was tested for its ability to ameliorate clinically relevant pathological features, modelled in humanized zebrafish through SARS-CoV-2 recombinant spike (S) protein induction.
Results
Withanone bound efficiently at the interacting interface of the ACE2-RBD complex and destabilized it energetically. The electrostatic component of binding free energies of the complex was significantly decreased. The two intrachain salt bridge interactions (K31-E35) and the interchain long-range ion-pair (K31-E484), at the ACE2-RBD interface were completely abolished by withanone, in the 50 ns simulation. In vitro binding assay experimentally validated that withanone efficiently inhibited (IC50=0.33 ng/mL) the interaction between ACE2 and RBD, in a dose-dependent manner. A withanone-enriched extract, without any co-extracted withaferin A, was prepared from W. somnifera leaves. This enriched extract was found to be efficient in ameliorating human-like pathological responses induced in humanized zebrafish by SARS-CoV-2 recombinant spike (S) protein.
Conclusion
In conclusion, this study provided experimental validation for computational insight into the potential of withanone as a potent inhibitor of SARS-CoV-2 coronavirus entry into the host cells.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY-NC).
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