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Withanone from Withania somnifera Attenuates SARS-CoV-2 RBD and Host ACE2 Interactions to Rescue Spike Protein Induced Pathologies in Humanized Zebrafish Model.
Balkrishna, Acharya; Pokhrel, Subarna; Singh, Hoshiyar; Joshi, Monali; Mulay, Vallabh Prakash; Haldar, Swati; Varshney, Anurag.
  • Balkrishna A; Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India.
  • Pokhrel S; Department of Allied and Applied Sciences, University of Patanjali, Haridwar, 249405, Uttarakhand, India.
  • Singh H; Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India.
  • Joshi M; Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India.
  • Mulay VP; Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India.
  • Haldar S; Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India.
  • Varshney A; Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, 249405, Uttarakhand, India.
Drug Des Devel Ther ; 15: 1111-1133, 2021.
Article in English | MEDLINE | ID: covidwho-1150609
Semantic information from SemMedBD (by NLM)
1. ACE2 gene|ACE2 PART_OF Homo sapiens
Subject
ACE2 gene|ACE2
Predicate
PART_OF
Object
Homo sapiens
2. TMPRSS2 gene|TMPRSS2 PART_OF integral to membrane
Subject
TMPRSS2 gene|TMPRSS2
Predicate
PART_OF
Object
integral to membrane
3. Phytochemicals COEXISTS_WITH WITHANIA SOMNIFERA
Subject
Phytochemicals
Predicate
COEXISTS_WITH
Object
WITHANIA SOMNIFERA
4. withaferin A INTERACTS_WITH Peptide Hydrolases
Subject
withaferin A
Predicate
INTERACTS_WITH
Object
Peptide Hydrolases
5. withanone INTERACTS_WITH Peptide Hydrolases
Subject
withanone
Predicate
INTERACTS_WITH
Object
Peptide Hydrolases
6. ACE2 gene|ACE2 PART_OF Homo sapiens
Subject
ACE2 gene|ACE2
Predicate
PART_OF
Object
Homo sapiens
7. TMPRSS2 gene|TMPRSS2 PART_OF integral to membrane
Subject
TMPRSS2 gene|TMPRSS2
Predicate
PART_OF
Object
integral to membrane
8. Phytochemicals COEXISTS_WITH WITHANIA SOMNIFERA
Subject
Phytochemicals
Predicate
COEXISTS_WITH
Object
WITHANIA SOMNIFERA
9. withaferin A INTERACTS_WITH Peptide Hydrolases
Subject
withaferin A
Predicate
INTERACTS_WITH
Object
Peptide Hydrolases
10. withanone INTERACTS_WITH Peptide Hydrolases
Subject
withanone
Predicate
INTERACTS_WITH
Object
Peptide Hydrolases
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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Withania / Withanolides / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Limits: Animals / Female / Humans / Male Language: English Journal: Drug Des Devel Ther Journal subject: Pharmacology / Drug Therapy Year: 2021 Document Type: Article Affiliation country: Dddt.S292805

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Withania / Withanolides / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Limits: Animals / Female / Humans / Male Language: English Journal: Drug Des Devel Ther Journal subject: Pharmacology / Drug Therapy Year: 2021 Document Type: Article Affiliation country: Dddt.S292805