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1.
Inflammopharmacology ; 30(1): 173-184, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1648298

ABSTRACT

In the current scenario, most countries are affected by COVID-19, a pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has a massive impact on human health. Previous studies showed that some traditionally used medicinal herbs and their combinations showed synergistic anti-viral and anti-inflammatory activity against SARS-CoV-2 type infections. Therefore, the goal of this study is to demonstrate the anti-viral and anti-inflammatory effects of a novel polyherbal formulation, hereinafter referred to as Imusil, on Vero E6 cell lines and Raw 264.7 murine macrophage cells respectively. The Imusil was subjected to identify its chemical characterisations such as UV-Visible spectrum profile, Fourier transform infrared spectroscopy (FT-IR) and gas chromatography-mass spectroscopic (GC-MS) analysis. FT-IR analysis of Imusil peak values with various functional compounds such as alcohol, esters, aliphatic and carboxylic acids. GC-MS analysis of compounds with totally 87 compounds major chemical compounds were identified, such as 3-(Octanoyloxy) propane-1,2-diyl bis(decanoate), Succinic acid, 2-methylhex-3-yl 2,2,2-trifluoroethyl ester, Neophytadiene, 3,5,9-Trioxa-4-phosphaheneicosan-1-aminium, 4-hydroxy-N,N,N-trimethyl-10-oxo-7-[(1-oxododecyl)oxy]-, hydroxide, inner salt, 4-oxide, (R)-. The anti-viral activity of Imusil against SARS-CoV-2 was assessed using plaque reduction assay and anti-inflammatory study was conducted on lipopolysaccharide (LPS)-induced RAW 264.7 cells. The results obtained from the study reveal that Imusil significantly inhibited SARS-CoV-2 replication in Vero E6 cells and the production of inflammatory mediator's cyclooxygenase-2 and pro-inflammatory cytokines like tumour necrosis factor-α and interleukin- 6 were significantly reduced, along with thwarting the significant oxidative stress by preventing the expression of NOX-2 thereby inhibiting the reactive oxygen species formation. Hence, considering the current study as a novel strategy for mediating the COVID-19 associated aliments, inceptive scientific evidence of Imusil promises its potential therapeutic implications against COVID-19 and inflammatory conditions.


Subject(s)
COVID-19 , Cytokine Release Syndrome , Animals , Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , Humans , Inflammation Mediators , Mice , Oxidative Stress , SARS-CoV-2 , Spectroscopy, Fourier Transform Infrared
2.
J Biomol Struct Dyn ; : 1-11, 2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1585533

ABSTRACT

Phytochemicals with potential to competitively bind to the host receptors or inhibit SARS-CoV-2 replication, may prove to be useful as adjunct therapeutics for COVID-19. We profiled and investigated the phytochemicals of Rhododendron arboreum petals sourced from Himalayan flora, undertook in vitro studies and found it as a promising candidate against SARS-CoV-2. The phytochemicals were reported in various scientific investigations to act against a range of virus in vitro and in vivo, which prompted us to test against SARS-CoV-2. In vitro assays of R. arboreum petals hot aqueous extract confirmed dose dependent reduction in SARS-CoV-2 viral load in infected Vero E6 cells (80% inhibition at 1 mg/ml; IC50 = 173 µg/ml) and phytochemicals profiled were subjected to molecular docking studies against SARS CoV-2 target proteins. The molecules 5-O-Feruloyl-quinic acid, 3-Caffeoyl-quinic acid, 5-O-Coumaroyl-D-quinic acid, Epicatechin and Catechin showed promising binding affinity with SARS-CoV-2 Main protease (MPro; PDB ID: 6LU7; responsible for viral replication) and Human Angiotensin Converting Enzyme-2 (ACE2; PDB ID: 1R4L; mediate viral entry in the host). Molecular dynamics (MD) simulation of 5-O-Feruloyl-quinic acid, an abundant molecule in the extract complexed with the target proteins showed stable interactions. Taken together, the phytochemical profiling, in silico analysis and in vitro anti-viral assay revealed that the petals extract act upon MPro and may be inhibiting SARS-CoV-2 replication. This is the first report highlighting R. arboreum petals as a reservoir of antiviral phytochemicals with potential anti-SARS-CoV-2 activity using an in vitro system.

3.
Chem Commun (Camb) ; 57(78): 10083-10086, 2021 Sep 30.
Article in English | MEDLINE | ID: covidwho-1404890

ABSTRACT

Zinc deficiency is linked to poor prognosis in COVID-19 patients while clinical trials with zinc demonstrate better clinical outcomes. The molecular targets and mechanistic details of the anti-coronaviral activity of zinc remain obscure. We show that zinc not only inhibits the SARS-CoV-2 main protease (Mpro) with nanomolar affinity, but also viral replication. We present the first crystal structure of the Mpro-Zn2+ complex at 1.9 Å and provide the structural basis of viral replication inhibition. We show that Zn2+ coordinates with the catalytic dyad at the enzyme active site along with two previously unknown water molecules in a tetrahedral geometry to form a stable inhibited Mpro-Zn2+ complex. Further, the natural ionophore quercetin increases the anti-viral potency of Zn2+. As the catalytic dyad is highly conserved across SARS-CoV, MERS-CoV and all variants of SARS-CoV-2, Zn2+ mediated inhibition of Mpro may have wider implications.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Zinc/chemistry , Animals , Binding Sites , COVID-19/pathology , Catalytic Domain , Chlorocebus aethiops , Coordination Complexes/chemistry , Coordination Complexes/metabolism , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Humans , Ions/chemistry , Kinetics , Molecular Dynamics Simulation , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , SARS-CoV-2/isolation & purification , Surface Plasmon Resonance , Thermodynamics , Vero Cells , Virus Replication/drug effects
4.
Front Med (Lausanne) ; 8: 631769, 2021.
Article in English | MEDLINE | ID: covidwho-1389197

ABSTRACT

Background: SARS-CoV-2 infection may not provide long lasting post-infection immunity. While hundreds of reinfections have reported only a few have been confirmed. Whole genome sequencing (WGS) of the viral isolates from the different episodes is mandatory to establish reinfection. Methods: Nasopharyngeal (NP), oropharyngeal (OP) and whole blood (WB) samples were collected from paired samples of four individuals who were suspected of SARS-CoV-2 reinfection based on distinct clinical episodes and RT-PCR tests. Details from their case record files and investigations were documented. RNA was extracted from the NP and OP samples and subjected to WGS, and the nucleotide and amino acid sequences were subjected to genome and protein-based functional annotation analyses. Serial serology was performed for Anti-N IgG, Anti- S1 RBD IgG, and sVNT (surrogate virus neutralizing test). Findings: Three patients were more symptomatic with lower Ct values and longer duration of illness. Seroconversion was detected soon after the second episode in three patients. WGS generated a genome coverage ranging from 80.07 to 99.7%. Phylogenetic analysis revealed sequences belonged to G, GR and "Other" clades. A total of 42mutations were identified in all the samples, consisting of 22 non-synonymous, 17 synonymous, two in upstream, and one in downstream regions of the SARS-CoV-2 genome. Comparative genomic and protein-based annotation analyses revealed differences in the presence and absence of specific mutations in the virus sequences from the two episodes in all four paired samples. Interpretation: Based on the criteria of genome variations identified by whole genome sequencing and supported by clinical presentation, molecular and serological tests, we were able to confirm reinfections in two patients, provide weak evidence of reinfection in the third patient and unable to rule out a prolonged infection in the fourth. This study emphasizes the importance of detailed analyses of clinical and serological information as well as the virus's genomic variations while assessing cases of SARS-CoV-2 reinfection.

5.
Int J Mol Sci ; 22(1)2020 Dec 30.
Article in English | MEDLINE | ID: covidwho-1006614

ABSTRACT

Being opportunistic intracellular pathogens, viruses are dependent on the host for their replication. They hijack host cellular machinery for their replication and survival by targeting crucial cellular physiological pathways, including transcription, translation, immune pathways, and apoptosis. Immediately after translation, the host and viral proteins undergo a process called post-translational modification (PTM). PTMs of proteins involves the attachment of small proteins, carbohydrates/lipids, or chemical groups to the proteins and are crucial for the proteins' functioning. During viral infection, host proteins utilize PTMs to control the virus replication, using strategies like activating immune response pathways, inhibiting viral protein synthesis, and ultimately eliminating the virus from the host. PTM of viral proteins increases solubility, enhances antigenicity and virulence properties. However, RNA viruses are devoid of enzymes capable of introducing PTMs to their proteins. Hence, they utilize the host PTM machinery to promote their survival. Proteins from viruses belonging to the family: Togaviridae, Flaviviridae, Retroviridae, and Coronaviridae such as chikungunya, dengue, zika, HIV, and coronavirus are a few that are well-known to be modified. This review discusses various host and virus-mediated PTMs that play a role in the outcome during the infection.


Subject(s)
Protein Processing, Post-Translational , RNA Virus Infections/enzymology , RNA Virus Infections/virology , RNA Viruses/metabolism , RNA Viruses/pathogenicity , Viral Proteins/metabolism , Acetylation , Chikungunya virus/metabolism , Coronavirus/metabolism , Coronavirus/pathogenicity , Cytopathogenic Effect, Viral , Glycosylation , HIV/metabolism , HIV/pathogenicity , Host Microbial Interactions , Humans , Phosphorylation , RNA Virus Infections/immunology , RNA Virus Infections/metabolism , RNA Viruses/immunology , Ubiquitination , Virus Replication/physiology , Zika Virus/metabolism , Zika Virus/pathogenicity
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