Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
1.
Biosci Rep ; 41(10)2021 10 29.
Article in English | MEDLINE | ID: covidwho-1510636

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a global health emergency. Although new vaccines have been generated and being implicated, discovery and application of novel preventive and control measures are warranted. We aimed to identify compounds that may possess the potential to either block the entry of virus to host cells or attenuate its replication upon infection. Using host cell surface receptor expression (angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS2)) analysis as an assay, we earlier screened several synthetic and natural compounds and identified candidates that showed ability to down-regulate their expression. Here, we report experimental and computational analyses of two small molecules, Mortaparib and MortaparibPlus that were initially identified as dual novel inhibitors of mortalin and PARP-1, for their activity against SARS-CoV-2. In silico analyses showed that MortaparibPlus, but not Mortaparib, stably binds into the catalytic pocket of TMPRSS2. In vitro analysis of control and treated cells revealed that MortaparibPlus caused down-regulation of ACE2 and TMPRSS2; Mortaparib did not show any effect. Furthermore, computational analysis on SARS-CoV-2 main protease (Mpro) that also predicted the inhibitory activity of MortaparibPlus. However, cell-based antiviral drug screening assay showed 30-60% viral inhibition in cells treated with non-toxic doses of either MortaparibPlus or Mortaparib. The data suggest that these two closely related compounds possess multimodal anti-COVID-19 activities. Whereas MortaparibPlus works through direct interactions/effects on the host cell surface receptors (ACE2 and TMPRSS2) and the virus protein (Mpro), Mortaparib involves independent mechanisms, elucidation of which warrants further studies.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Computational Biology/methods , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/immunology , COVID-19/immunology , Cell Line, Tumor , Drug Evaluation, Preclinical/methods , HSP70 Heat-Shock Proteins/antagonists & inhibitors , Humans , Mitochondrial Proteins/antagonists & inhibitors , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , SARS-CoV-2/immunology , Serine Endopeptidases/immunology , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
2.
Biosci Rep ; 2021 Oct 04.
Article in English | MEDLINE | ID: covidwho-1450299

ABSTRACT

COVID-19 pandemic caused by SARS-CoV-2 virus has become a global health emergency. Although new vaccines have been generated and being implicated, discovery and application of novel preventive and control measures are warranted. We aimed to identify compound/s that may possess the potential to either block the entry of virus to host cells or attenuate its replication upon infection. Using host cell surface receptor expression (Angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS2) analysis as an assay, we earlier screened several synthetic and natural compounds and identified candidates that showed ability to downregulate their expression. Here, we report experimental and computational analyses of two small molecules, Mortaparib and MortaparibPlus that were initially identified as dual novel inhibitors of mortalin and PARP-1, for their activity against SARS-CoV-2. In silico analyses showed that MortaparibPlus, but not Mortaparib, stably binds into the catalytic pocket of TMPRSS2. In vitro analysis of control and treated cells revealed that MortaparibPlus caused downregulation of ACE2 and TMPRSS2; Mortaparib did not show any effect. Furthermore, computational analysis on SARS-CoV-2 main protease (Mpro) that also predicted the inhibitory activity of MortaparibPlus.  However, cell based anti-virus drug screening assay showed 30~60% viral inhibition in cells treated with non-toxic doses of either MortaparibPlus or Mortaparib. The data suggests that these two closely related compounds possess multimodal anti-COVID 19 activities. Whereas MortaparibPlus works through direct interactions/effects on the host cell surface receptors (ACE2 and TMPRSS2) and the virus protein (Mpro), Mortaparib involves independent mechanisms, elucidation of which warrants further studies.

3.
Front Aging Neurosci ; 13: 662786, 2021.
Article in English | MEDLINE | ID: covidwho-1278422

ABSTRACT

The spectrum of health complications instigated by coronavirus disease 2019 (COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) pandemic has been diverse and complex. Besides the evident pulmonary and cardiovascular threats, accumulating clinical data points to several neurological complications, which are more common in elderly COVID-19 patients. Recent pieces of evidence have marked events of neuro infection and neuroinvasion, producing several neurological complications in COVID-19 patients; however, a systematic understanding of neuro-pathophysiology and manifested neurological complications, more specifically in elderly COVID-19 patients is largely elusive. Since the elderly population gradually develops neurological disorders with aging, COVID-19 inevitably poses a higher risk of neurological manifestations to the aged patients. In this report, we reviewed SARS-CoV-2 infection and its role in neurological manifestations with an emphasis on the elderly population. We reviewed neuropathological events including neuroinfection, neuroinvasion, and their underlying mechanisms affecting neuromuscular, central- and peripheral- nervous systems. We further assessed the imminent neurological challenges in the COVID-19 exposed population, post-SARS-CoV-2-infection. Given the present state of clinical preparedness, the emerging role of AI and machine learning was also discussed concerning COVID-19 diagnostics and its management. Taken together, the present review summarizes neurological outcomes of SARS-CoV-2 infection and associated complications, specifically in elderly patients, and underlines the need for their clinical management in advance.

4.
Int J Biol Macromol ; 184: 297-312, 2021 Aug 01.
Article in English | MEDLINE | ID: covidwho-1265684

ABSTRACT

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.


Subject(s)
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
5.
J Biomol Struct Dyn ; : 1-14, 2021 Apr 02.
Article in English | MEDLINE | ID: covidwho-1165102

ABSTRACT

SARS-CoV-2 outbreak in China in December 2019 and its spread as worldwide pandemic has been a major global health crisis. Extremely high infection and mortality rate has severely affected all sectors of life and derailed the global economy. While drug and vaccine development have been prioritized and have made significant progression, use of phytochemicals and herbal constituents is deemed as a low-cost, safer and readily available alternative. We investigated therapeutic efficacy of eight withanolides (derived from Ashwagandha) against the angiotensin-converting enzyme 2 (ACE2) proteins, a target cell surface receptor for SARS-CoV-2 and report results on the (i) computational analyses including binding affinity and stable interactions with ACE2, occupancy of ACE2 residues in making polar and nonpolar interactions with different withanolides/ligands and (2) in vitro mRNA and protein analyses using human cancer (A549, MCF7 and HSC3) cells. We found that among all withanolides, Withaferin-A, Withanone, Withanoside-IV and Withanoside-V significantly inhibited the ACE2 expression. Analysis of withanolides-rich aqueous extracts derived from Ashwagandha leaves and stem showed a higher ACE2 inhibitory potency of stem-derived extracts. Taken together, we demonstrated the inhibitory potency of Ashwagandha withanolides and its aqueous extracts against ACE2.Communicated by Ramaswamy H. Sarma.

6.
J Biomol Struct Dyn ; 40(1): 1-13, 2022 01.
Article in English | MEDLINE | ID: covidwho-436584

ABSTRACT

Coronavirus disease 2019 (COVID-19) initiated in December 2019 in Wuhan, China and became pandemic causing high fatality and disrupted normal life calling world almost to a halt. Causative agent is a novel coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2/2019-nCoV). While new line of drug/vaccine development has been initiated world-wide, in the current scenario of high infected numbers, severity of the disease and high morbidity, repurposing of the existing drugs is heavily explored. Here, we used a homology-based structural model of transmembrane protease serine 2 (TMPRSS2), a cell surface receptor, required for entry of virus to the target host cell. Using the strengths of molecular docking and molecular dynamics simulations, we examined the binding potential of Withaferin-A (Wi-A), Withanone (Wi-N) and caffeic acid phenethyl ester to TPMRSS2 in comparison to its known inhibitor, Camostat mesylate. We found that both Wi-A and Wi-N could bind and stably interact at the catalytic site of TMPRSS2. Wi-N showed stronger interactions with TMPRSS2 catalytic residues than Wi-A and was also able to induce changes in its allosteric site. Furthermore, we investigated the effect of Wi-N on TMPRSS2 expression in MCF7 cells and found remarkable downregulation of TMPRSS2 mRNA in treated cells predicting dual action of Wi-N to block SARS-CoV-2 entry into the host cells. Since the natural compounds are easily available/affordable, they may even offer a timely therapeutic/preventive value for the management of SARS-CoV-2 pandemic. We also report that Wi-A/Wi-N content varies in different parts of Ashwagandha and warrants careful attention for their use.Communicated by Ramaswamy H. Sarma.


Subject(s)
SARS-CoV-2 , Serine Proteinase Inhibitors/pharmacology , Virus Internalization/drug effects , Withanolides/pharmacology , Binding Sites , COVID-19 , Humans , MCF-7 Cells , Molecular Docking Simulation , Plant Extracts/chemistry , Serine , Serine Endopeptidases/genetics
7.
J Biomol Struct Dyn ; 39(11): 3842-3854, 2021 07.
Article in English | MEDLINE | ID: covidwho-324383

ABSTRACT

The recent novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2/2019-nCoV) has caused a large number of deaths around the globe. There is an urgent need to understand this new virus and develop prophylactic and therapeutic drugs. Since drug development is an expensive, intense and time-consuming path, timely repurposing of the existing drugs is often explored wherein the research avenues including genomics, bioinformatics, molecular modeling approaches offer valuable strengths. Here, we have examined the binding potential of Withaferin-A (Wi-A), Withanone (Wi-N) (active withanolides of Ashwagandha) and Caffeic Acid Phenethyl Ester (CAPE, bioactive ingredient of propolis) to a highly conserved protein, Mpro of SARS-CoV-2. We found that Wi-N and CAPE, but not Wi-A, bind to the substrate-binding pocket of SARS-CoV-2 Mpro with efficacy and binding energies equivalent to an already claimed N3 protease inhibitor. Similar to N3 inhibitor, Wi-N and CAPE were interacting with the highly conserved residues of the proteases of coronaviruses. The binding stability of these molecules was further analyzed using molecular dynamics simulations. The binding free energies calculated using MM/GBSA for N3 inhibitor, CAPE and Wi-N were also comparable. Data presented here predicted that these natural compounds may possess the potential to inhibit the functional activity of SARS-CoV-2 protease (an essential protein for virus survival), and hence (i) may connect to save time and cost required for designing/development, and initial screening for anti-COVID drugs, (ii) may offer some therapeutic value for the management of novel fatal coronavirus disease, (iii) warrants prioritized further validation in the laboratory and clinical tests.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , SARS-CoV-2 , Caffeic Acids , Humans , Molecular Docking Simulation , Peptide Hydrolases , Phenylethyl Alcohol/analogs & derivatives , Protease Inhibitors/pharmacology , Withanolides
SELECTION OF CITATIONS
SEARCH DETAIL