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 citas
Cómo se estudió
- Diseño
- Estudio en animales (clasificado por nuestro filtro de IA)
- Estudiado en
- Animales
- Resultado principal
- Marcadores de salud y funcionamiento
Quién lo pagó
- Financiación
- Financiación independiente
Según la declaración de financiación del texto completo.
Publicación
- Publicado
- 2021-03-01 · Drug Des Devel Ther · vol. Volume 15 · págs. 1111–1133
- Editorial
- Dove Medical Press
- Citado
- 109 citas · más que el 100% de estudios similares · 26.2× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 71 trabajos
- Acceso
- Acceso abierto (revista) · CC-BY-NC
- Áreas de investigación
- Phytochemicals and Medicinal Plants · Diverse Scientific Research Studies · Andrographolide Research and Applications
- Palabras clave
- 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 autores
- Acharya Balkrishna🇮🇳Patanjali Research Foundation
- Subarna Pokhrel🇮🇳Patanjali Research Foundation
- Hoshiyar Singh🇮🇳Patanjali Research Foundation
- Monali Joshi🇮🇳Patanjali Research Foundation
- Vallabh Prakash Mulay🇮🇳Patanjali Research Foundation
- Swati Haldar🇮🇳Patanjali Research Foundation
- Anurag Varshney🇮🇳Patanjali Research Foundation
Resumen
El texto original del estudio, en el idioma en que se publicó.
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.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial (CC BY-NC).
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