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1.
Molecules ; 26(21)2021 Nov 08.
Article in English | MEDLINE | ID: covidwho-1512511

ABSTRACT

This work describes an untargeted analytical approach for the screening, identification, and characterization of the trans-epithelial transport of green tea (Camellia sinensis) catechin extracts with in vitro inhibitory effect against the SARS-CoV-2 papain-like protease (PLpro) activity. After specific catechin extraction, a chromatographic separation obtained six fractions were carried out. The fractions were assessed in vitro against the PLpro target. Fraction 5 showed the highest inhibitory activity against the SARS-CoV-2 PLpro (IC50 of 0.125 µg mL-1). The untargeted characterization revealed that (-)-epicatechin-3-gallate (ECG) was the most abundant compound in the fraction and the primary molecule absorbed by differentiated Caco-2 cells. Results indicated that fraction 5 was approximately 10 times more active than ECG (IC50 value equal to 11.62 ± 0.47 µg mL-1) to inhibit the PLpro target. Overall, our findings highlight the synergistic effects of the various components of the crude extract compared to isolated ECG.


Subject(s)
Catechin/pharmacology , Coronavirus Papain-Like Proteases/metabolism , Tea/metabolism , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/metabolism , Caco-2 Cells , Camellia sinensis/metabolism , Catechin/analogs & derivatives , Catechin/chemistry , Catechin/metabolism , Coronavirus Papain-Like Proteases/drug effects , Epithelium/drug effects , Epithelium/metabolism , Humans , Mass Spectrometry/methods , Plant Extracts/chemistry , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Tea/chemistry , Tea/physiology
2.
Molecules ; 26(21)2021 Oct 30.
Article in English | MEDLINE | ID: covidwho-1488678

ABSTRACT

Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives 34 and 58 were better than the co-crystallized ligand while derivatives 17, 28, 31, 40, 41, 43, 47, 54, and 65 exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives 28, 34, and 47 have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of 28, 34, and 47 against the co-crystallized ligand in a DFT study indicated that 28 is the most promising candidate to interact with the target receptor (PLpro).


Subject(s)
Coronavirus Papain-Like Proteases/metabolism , SARS-CoV-2/drug effects , Virus Replication/drug effects , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Computer Simulation , Coronavirus Papain-Like Proteases/drug effects , Drug Evaluation, Preclinical/methods , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Papain/metabolism , Peptide Hydrolases/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity
3.
J Med Virol ; 93(5): 2722-2734, 2021 05.
Article in English | MEDLINE | ID: covidwho-1196526

ABSTRACT

The 21st century has witnessed three outbreaks of coronavirus (CoVs) infections caused by severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2. Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, spreads rapidly and since the discovery of the first COVID-19 infection in December 2019, has caused 1.2 million deaths worldwide and 226,777 deaths in the United States alone. The high amino acid similarity between SARS-CoV and SARS-CoV-2 viral proteins supports testing therapeutic molecules that were designed to treat SARS infections during the 2003 epidemic. In this review, we provide information on possible COVID-19 treatment strategies that act via inhibition of the two essential proteins of the virus, 3C-like protease (3CLpro ) or papain-like protease (PLpro ).


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Viral Proteases/drug effects , COVID-19/epidemiology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/drug effects , Coronavirus 3C Proteases/genetics , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/drug effects , Coronavirus Papain-Like Proteases/genetics , Humans , Middle East Respiratory Syndrome Coronavirus , Protease Inhibitors/therapeutic use , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics
4.
Future Microbiol ; 15: 1747-1758, 2020 12.
Article in English | MEDLINE | ID: covidwho-1011368

ABSTRACT

COVID-19 caused by SARS-CoV-2, is an international concern. This infection requires urgent efforts to develop new antiviral compounds. To date, no specific drug in controlling this disease has been identified. Developing the new treatment is usually time consuming, therefore using the repurposing broad-spectrum antiviral drugs could be an effective strategy to respond immediately. In this review, a number of broad-spectrum antivirals with potential efficacy to inhibit the virus replication via targeting the virus spike protein (S protein), RNA-dependent RNA polymerase (RdRp), 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) that are critical in the pathogenesis and life cycle of coronavirus, have been evaluated as possible treatment options against SARS-CoV-2 in COVID-19 patients.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , SARS-CoV-2/drug effects , Virus Replication/drug effects , Chymases/drug effects , Coronavirus Papain-Like Proteases/drug effects , Coronavirus RNA-Dependent RNA Polymerase/drug effects , Drug Repositioning , Humans , Virus Internalization/drug effects
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