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EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-309267


The infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in a pandemic with huge death toll and economic consequences. The virus attaches itself to the human epithelial cells through noncovalent bonding of its spike protein with the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. We hypothesized that perturbing the functionally active conformation of spike protein through reduction of its solvent accessible disulfide bond, thereby disintegrating its structural architecture, may be a feasible strategy to prevent infection. Proteomics data showed that N-acetyl cysteine (NAC), an antioxidant and mucolytic agent been widely in use in clinical medicine, forms covalent conjugates with solvent accessible cysteine residues of spike protein that were disulfide bonded in the native state. In silico analysis indicated that this covalent conjugation perturbed the stereo specific orientations of the interacting key residues of spike protein that resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. Antiviral assay using VeroE6 cells showed that NAC caused 54.3% inhibition in SARS-CoV-2 replication. Interestingly, almost all SARS-Cov-2 variants conserved cystine residues in the spike protein. Our observed results open avenues for exploring in vivo pharmaco-preventive and therapeutic potential of NAC for Coronavirus Disease 2019 (COVID-19).

Int J Biol Macromol ; 184: 297-312, 2021 Aug 01.
Article in English | MEDLINE | ID: covidwho-1265684


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 Mpro) that is essential for virus replication. We report that the withanolides possess capacity to inhibit the activity of TMPRSS2 and Mpro. 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.

Antiviral Agents/pharmacology , Plant Extracts/chemistry , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Viral Matrix Proteins/metabolism , Withanolides/pharmacology , A549 Cells , Antiviral Agents/chemistry , Cell Line , Cell Survival/drug effects , Computer Simulation , Down-Regulation , Gene Expression Regulation/drug effects , Humans , MCF-7 Cells , Models, Molecular , Molecular Dynamics Simulation , Protein Conformation , SARS-CoV-2/drug effects , Serine Endopeptidases/chemistry , Viral Matrix Proteins/chemistry , Virus Internalization/drug effects , Withanolides/chemistry