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1.
Comput Biol Med ; 141: 105155, 2022 02.
Article in English | MEDLINE | ID: covidwho-1588033

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is the first target of SARS-CoV-2 and a key functional host receptor through which this virus hooks into and infects human cells. The necessity to block this receptor is one of the essential means to prevent the outbreak of COVID-19. This study was conducted to determine the most eligible natural compound to suppress ACE2 to counterfeit its interaction with the viral infection. To do this, the most known compounds of sixty-six Iraqi medicinal plants were generated and retrieved from PubChem database. After preparing a library for Iraqi medicinal plants, 3663 unique ligands' conformers were docked to ACE2 using the GLIDE tool. Results found that twenty-three compounds exhibited the highest binding affinity with ACE2. The druglikeness and toxicity potentials of these compounds were evaluated using SwissADME and Protox servers respectively. Out of these virtually screened twenty-three compounds, epicatechin and kempferol were predicted to exert the highest druglikeness and lowest toxicity potentials. Extended Molecular dynamics (MD) simulations showed that ACE2-epicatechin complex exhibited a slightly higher binding stability than ACE2-kempferol complex. In addition to the well-known ACE2 inhibitors that were identified in previous studies, this study revealed for the first time that epicatechin from Hypericum perforatum provided a better static and dynamic inhibition for ACE2 with highly favourable pharmacokinetic properties than the other known ACE2 inhibiting compounds. This study entailed the ability of epicatechin to be used as a potent natural inhibitor that can be used to block or at least weaken the SARS-CoV-2 entry and its subsequent invasion. In vitro experiments are required to validate epicatechin effectiveness against the activity of the human ACE2 receptor.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/pharmacology , Catechin , SARS-CoV-2 , Virus Internalization/drug effects , COVID-19 , Catechin/pharmacology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding
2.
Viruses ; 13(12)2021 12 17.
Article in English | MEDLINE | ID: covidwho-1580427

ABSTRACT

The COVID-19 pandemic has resulted in a huge number of deaths from 2020 to 2021; however, effective antiviral drugs against SARS-CoV-2 are currently under development. Recent studies have demonstrated that green tea polyphenols, particularly EGCG, inhibit coronavirus enzymes as well as coronavirus replication in vitro. Herein, we examined the inhibitory effect of green tea polyphenols on coronavirus replication in a mouse model. We used epigallocatechin gallate (EGCG) and green tea polyphenols containing more than 60% catechin (GTP60) and human coronavirus OC43 (HCoV-OC43) as a surrogate for SARS-CoV-2. Scanning electron microscopy analysis results showed that HCoV-OC43 infection resulted in virion particle production in infected cells. EGCG and GTP60 treatment reduced coronavirus protein and virus production in the cells. Finally, EGCG- and GTP60-fed mice exhibited reduced levels of coronavirus RNA in mouse lungs. These results demonstrate that green tea polyphenol treatment is effective in decreasing the level of coronavirus in vivo.


Subject(s)
Antiviral Agents/pharmacology , Catechin/analogs & derivatives , Coronavirus Infections/drug therapy , Polyphenols/pharmacology , Tea/chemistry , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Catechin/pharmacology , Catechin/therapeutic use , Cell Line , Coronavirus Infections/virology , Coronavirus OC43, Human/drug effects , Coronavirus OC43, Human/physiology , Disease Models, Animal , Humans , Mice , Polyphenols/chemistry , Polyphenols/therapeutic use
3.
Pharmacol Res ; 172: 105820, 2021 10.
Article in English | MEDLINE | ID: covidwho-1531713

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which enter the host cells through the interaction between its receptor binding domain (RBD) of spike glycoprotein with angiotensin-converting enzyme 2 (ACE2) receptor on the plasma membrane of host cell. Neutralizing antibodies and peptide binders of RBD can block viral infection, however, the concern of accessibility and affordability of viral infection inhibitors has been raised. Here, we report the identification of natural compounds as potential SARS-CoV-2 entry inhibitors using the molecular docking-based virtual screening coupled with bilayer interferometry (BLI). From a library of 1871 natural compounds, epigallocatechin gallate (EGCG), 20(R)-ginsenoside Rg3 (RRg3), 20(S)-ginsenoside Rg3 (SRg3), isobavachalcone (Ibvc), isochlorogenic A (IscA) and bakuchiol (Bkc) effectively inhibited pseudovirus entry at concentrations up to 100 µM. Among these compounds, four compounds, EGCG, Ibvc, salvianolic acid A (SalA), and isoliensinine (Isl), were effective in inhibiting SARS-CoV-2-induced cytopathic effect and plaque formation in Vero E6 cells. The EGCG was further validated with no observable animal toxicity and certain antiviral effect against SARS-CoV-2 pseudovirus mutants (D614G, N501Y, N439K & Y453F). Interestingly, EGCG, Bkc and Ibvc bind to ACE2 receptor in BLI assay, suggesting a dual binding to RBD and ACE2. Current findings shed some insight into identifications and validations of SARS-CoV-2 entry inhibitors from natural compounds.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/chemistry , Biological Products/chemistry , COVID-19/drug therapy , Enzyme Inhibitors/chemistry , SARS-CoV-2/enzymology , Spike Glycoprotein, Coronavirus/metabolism , Animals , Antiviral Agents/pharmacology , Binding, Competitive , Biological Products/pharmacology , Catechin/analogs & derivatives , Catechin/pharmacology , Cell Membrane/metabolism , Cell Membrane/ultrastructure , Chalcones/pharmacology , Chlorogenic Acid/analogs & derivatives , Chlorogenic Acid/pharmacology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , Ginsenosides/pharmacology , Humans , Interferometry , Mice, Inbred C57BL , Molecular Dynamics Simulation , Phenols/pharmacology , Protein Binding
4.
Phytomedicine ; 96: 153853, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1510181

ABSTRACT

BACKGROUND AND PURPOSE: Previous studies suggest that major Camellia sinensis (tea) catechins can inhibit 3-chymotrypsin-like cysteine protease (3CLpro), inspiring us to study 3CLpro inhibition of the recently discovered catechins from tea by our group. METHODS: Autodock was used to dock 3CLpro and 16 tea catechins. Further, a 3CLpro activity detection system was used to test their intra and extra cellular 3CLpro inhibitory activity. Surface plasmon resonance (SPR) was used to analyze the dissociation constant (KD) between the catechins and 3CLpro. RESULTS: Docking data suggested that 3CLpro interacted with the selected 16 catechins with low binding energy through the key amino acid residues Thr24, Thr26, Asn142, Gly143, His163, and Gln189. The selected catechins other than zijuanin D (3) and (-)-8-(5''R)-N-ethyl-2-pyrrolidinone-3-O-cinnamoylepicatechin (11) can inhibit 3CLpro intracellularly. The extracellular 3CLpro IC50 values of (-)-epicatechin 3-O-caffeoate (EC-C, 1), zijuanin C (2), etc-pyrrolidinone C and D (6), etc-pyrrolidinone A (9), (+)-gallocatechin gallate (GCG), and (-)-epicatechin gallate (ECG) are 1.58 ± 0.21, 41.2 ± 3.56, 0.90 ± 0.03, 46.71 ± 10.50, 3.38 ± 0.48, and 71.78 ± 8.36 µM, respectively. The KD values of 1, 6, and GCG are 4.29, 3.46, and 3.36 µM, respectively. CONCLUSION: Together, EC-C (1), etc-pyrrolidinone C and D (6), and GCG are strong 3CLpro inhibitors. Our results suggest that structural modification of catechins could be conducted by esterificating the 3-OH as well as changing the configuration of C-3, C-3''' or C-5''' to discover strong SARS-CoV-2 inhibitors.


Subject(s)
COVID-19 , Camellia sinensis , Catechin , Catechin/analysis , Catechin/pharmacology , Humans , Molecular Docking Simulation , Protease Inhibitors/pharmacology , SARS-CoV-2 , Tea
5.
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
6.
Comb Chem High Throughput Screen ; 25(1): 197-203, 2022.
Article in English | MEDLINE | ID: covidwho-1502215

ABSTRACT

BACKGROUND: A newly emergent strain of coronavirus (COVID-19) has affected almost the whole of the world's population. Currently, there is no specific vaccine or drug against COVID-19. Xu et al. (2020) built a homolog model of SARS-CoV-2 Mpro based on SARS-CoV Mpro, which is considered as a target to inhibit the replication of CoV. OBJECTIVE: The aim of the current study was to find potential inhibitors of COVID-19 Mpro using docking analysis. METHODS: Autodockvina was used to carry out Protein-Ligand docking. COVID-19 main protease Mpro was docked with catechin and its different synthetic derivatives. Nelfinavir, an antiretroviral drug belonging to protease inhibitors, was taken as the standard. RESULTS: According to the result obtained, it was found that Compound (4) and Compound (1) have more affinity than nelfinavir. CONCLUSION: Compounds were found to have a great potential to become COVID-19 main protease Mpro inhibitor. Nevertheless, for their medicinal use, further investigation is necessary.


Subject(s)
Antiviral Agents , Catechin , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , COVID-19 , Catechin/pharmacology , Humans , Molecular Docking Simulation , Protease Inhibitors/pharmacology
7.
Drug Des Devel Ther ; 15: 4447-4454, 2021.
Article in English | MEDLINE | ID: covidwho-1502185

ABSTRACT

Coronavirus disease-19 (COVID-19) pandemic is currently ongoing worldwide and causes a lot of deaths in many countries. Although different vaccines for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have been developed and are now available, there are no effective antiviral drugs to treat the disease, except for Remdesivir authorized by the US FDA to counteract the emergency. Thus, it can be useful to find alternative therapies based on the employment of natural compounds, with antiviral features, to circumvent SARS-CoV-2 infection. Pre-clinical studies highlighted the antiviral activities of epigallocatechin-3-gallate (EGCG), a catechin primarily found in green tea, against various viruses, including SARS-CoV-2. In this review, we summarize this experimental evidence and highlight the potential use of EGCG as an alternative therapeutic choice for the treatment of SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Catechin/analogs & derivatives , Antiviral Agents/administration & dosage , COVID-19/virology , Catechin/administration & dosage , Catechin/pharmacology , Humans , Tea/chemistry
8.
Food Funct ; 12(20): 9607-9619, 2021 Oct 19.
Article in English | MEDLINE | ID: covidwho-1500759

ABSTRACT

At the end of 2019, the COVID-19 virus spread worldwide, infecting millions of people. Infectious diseases induced by pathogenic microorganisms such as the influenza virus, hepatitis virus, and Mycobacterium tuberculosis are also a major threat to public health. The high mortality caused by infectious pathogenic microorganisms is due to their strong virulence, which leads to the excessive counterattack by the host immune system and severe inflammatory damage of the immune system. This paper reviews the efficacy, mechanism and related immune regulation of epigallocatechin-3-gallate (EGCG) as an anti-pathogenic microorganism drug. EGCG mainly shows both direct and indirect anti-infection effects. EGCG directly inhibits early infection by interfering with the adsorption on host cells, inhibiting virus replication and reducing bacterial biofilm formation and toxin release; EGCG indirectly inhibits infection by regulating immune inflammation and antioxidation. At the same time, we reviewed the bioavailability and safety of EGCG in vivo. At present, the bioavailability of EGCG can be improved to some extent using nanostructured drug delivery systems and molecular modification technology in combination with other drugs. This study provides a theoretical basis for the development of EGCG as an adjuvant drug for anti-pathogenic microorganisms.


Subject(s)
Anti-Infective Agents/pharmacology , Catechin/analogs & derivatives , Catechin/pharmacology , Immunologic Factors/pharmacology , Animals , Antioxidants/pharmacology , COVID-19/drug therapy , Coronavirus/drug effects , Hepatitis Viruses/drug effects , Humans , Inflammation/drug therapy , Mycobacterium tuberculosis/drug effects , Orthomyxoviridae/drug effects , Oxidative Stress/drug effects , SARS-CoV-2/drug effects , Virus Replication/drug effects
9.
Molecules ; 26(19)2021 Sep 30.
Article in English | MEDLINE | ID: covidwho-1444276

ABSTRACT

Data obtained from several intensive care units around the world have provided substantial evidence of the strong association between impairment of the renal function and in-hospital deaths of critically ill COVID-19 patients, especially those with comorbidities and requiring renal replacement therapy (RRT). Acute kidney injury (AKI) is a common renal disorder of various etiologies characterized by a sudden and sustained decrease of renal function. Studies have shown that 5-46% of COVID-19 patients develop AKI during hospital stay, and the mortality of those patients may reach up to 100% depending on various factors, such as organ failures and RRT requirement. Catechins are natural products that have multiple pharmacological activities, including anti-coronavirus and reno-protective activities against kidney injury induced by nephrotoxic agents, obstructive nephropathies and AKI accompanying metabolic and cardiovascular disorders. Therefore, in this review, we discuss the anti-SARS-CoV-2 and reno-protective effects of catechins from a mechanistic perspective. We believe that catechins may serve as promising therapeutics in COVID-19-associated AKI due to their well-recognized anti-SARS-CoV-2, and antioxidant and anti-inflammatory properties that mediate their reno-protective activities.


Subject(s)
Acute Kidney Injury/etiology , Antiviral Agents/pharmacology , COVID-19/complications , Catechin/pharmacology , Protective Agents/pharmacology , Acute Kidney Injury/drug therapy , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Catechin/chemistry , Catechin/therapeutic use , Humans , Protective Agents/chemistry , Protective Agents/therapeutic use , SARS-CoV-2/drug effects
10.
Jpn J Infect Dis ; 74(5): 421-423, 2021 Sep 22.
Article in English | MEDLINE | ID: covidwho-1436359

ABSTRACT

Green tea extracts effectively inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro in a dose-dependent manner. Ten-fold serially diluted solutions of catechin mixture reagent from green tea were mixed with the viral culture fluid at a volume ratio of 9:1, respectively, and incubated at room temperature for 5 min. The solution of 10 mg/mL catechin reagent reduced the viral titer by 4.2 log and 1.0 mg/mL solution by one log. Pre-infection treatment of cells with the reagent alone did not affect viral growth. In addition, cells treated with only the reagent were assayed for host cell viability using the WST-8 system, and almost no host cell damage by the treatment was observed. These findings suggested that the direct treatment of virus with the reagent before inoculation decreased the viral activity and that catechins might have the potential to suppress SARSCoV-2 infection.


Subject(s)
Antiviral Agents/pharmacology , Catechin/pharmacology , SARS-CoV-2/drug effects , Tea/chemistry , Animals , COVID-19/virology , Cell Survival/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Humans , Vero Cells , Viral Load/drug effects
11.
Food Funct ; 12(20): 9607-9619, 2021 Oct 19.
Article in English | MEDLINE | ID: covidwho-1434159

ABSTRACT

At the end of 2019, the COVID-19 virus spread worldwide, infecting millions of people. Infectious diseases induced by pathogenic microorganisms such as the influenza virus, hepatitis virus, and Mycobacterium tuberculosis are also a major threat to public health. The high mortality caused by infectious pathogenic microorganisms is due to their strong virulence, which leads to the excessive counterattack by the host immune system and severe inflammatory damage of the immune system. This paper reviews the efficacy, mechanism and related immune regulation of epigallocatechin-3-gallate (EGCG) as an anti-pathogenic microorganism drug. EGCG mainly shows both direct and indirect anti-infection effects. EGCG directly inhibits early infection by interfering with the adsorption on host cells, inhibiting virus replication and reducing bacterial biofilm formation and toxin release; EGCG indirectly inhibits infection by regulating immune inflammation and antioxidation. At the same time, we reviewed the bioavailability and safety of EGCG in vivo. At present, the bioavailability of EGCG can be improved to some extent using nanostructured drug delivery systems and molecular modification technology in combination with other drugs. This study provides a theoretical basis for the development of EGCG as an adjuvant drug for anti-pathogenic microorganisms.


Subject(s)
Anti-Infective Agents/pharmacology , Catechin/analogs & derivatives , Catechin/pharmacology , Immunologic Factors/pharmacology , Animals , Antioxidants/pharmacology , COVID-19/drug therapy , Coronavirus/drug effects , Hepatitis Viruses/drug effects , Humans , Inflammation/drug therapy , Mycobacterium tuberculosis/drug effects , Orthomyxoviridae/drug effects , Oxidative Stress/drug effects , SARS-CoV-2/drug effects , Virus Replication/drug effects
12.
Drug Res (Stuttg) ; 71(8): 462-472, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1404894

ABSTRACT

BACKGROUND: Replication of SARS-CoV-2 depends on viral RNA-dependent RNA-polymerase (RdRp). Remdesivir, the broad-spectrum RdRp inhibitor acts as nucleoside-analogues (NAs). Remdesivir has initially been repurposed as a promising drug against SARS-CoV-2 infection with some health hazards like liver damage, allergic reaction, low blood-pressure, and breathing-shortness, throat-swelling. In comparison, theaflavin-3'-O-gallate (TFMG), the abundant black tea component has gained importance in controlling viral infection. TFMG is a non-toxic, non-invasive, antioxidant, anticancer and antiviral molecule. RESULTS: Here, we analyzed the inhibitory effect of theaflavin-3'-O-gallate on SARS CoV-2 RdRp in comparison with remdesivir by molecular-docking study. TFMG has been shown more potent in terms of lower Atomic-Contact-Energy (ACE) and higher occupancy of surface area; -393.97 Kcal/mol and 771.90 respectively, favoured with lower desolvation-energy; -9.2: Kcal/mol. TFMG forms more rigid electrostatic and H-bond than remdesivir. TFMG showed strong affinity to RNA primer and template and RNA passage-site of RdRp. CONCLUSIONS: TFMG can block the catalytic residue, NTP entry site, cation binding site, nsp7-nsp12 junction with binding energy of -6. 72 Kcal/mol with Ki value of 11.79, and interface domain with binding energy of -7.72 and -6.16 Kcal/mol with Ki value of 2.21 and 30.71 µM. And most importantly, TFMG shows antioxidant/anti-inflammatory/antiviral effect on human studies.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , Biflavonoids/pharmacology , COVID-19/drug therapy , Catechin/pharmacology , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Gallic Acid/analogs & derivatives , Molecular Docking Simulation , SARS-CoV-2/drug effects , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacology , Alanine/chemistry , Alanine/pharmacology , Antiviral Agents/chemistry , Biflavonoids/chemistry , COVID-19/virology , Catalytic Domain , Catechin/chemistry , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Enzyme Inhibitors/chemistry , Gallic Acid/chemistry , Gallic Acid/pharmacology , Protein Conformation , SARS-CoV-2/enzymology , Structure-Activity Relationship
13.
PLoS One ; 16(6): e0253489, 2021.
Article in English | MEDLINE | ID: covidwho-1388925

ABSTRACT

In the pursuit of suitable and effective solutions to SARS-CoV-2 infection, we investigated the efficacy of several phenolic compounds in controlling key cellular mechanisms involved in its infectivity. The way the SARS-CoV-2 virus infects the cell is a complex process and comprises four main stages: attachment to the cognate receptor, cellular entry, replication and cellular egress. Since, this is a multi-part process, it creates many opportunities to develop effective interventions. Targeting binding of the virus to the host receptor in order to prevent its entry has been of particular interest. Here, we provide experimental evidence that, among 56 tested polyphenols, including plant extracts, brazilin, theaflavin-3,3'-digallate, and curcumin displayed the highest binding with the receptor-binding domain of spike protein, inhibiting viral attachment to the human angiotensin-converting enzyme 2 receptor, and thus cellular entry of pseudo-typed SARS-CoV-2 virions. Both, theaflavin-3,3'-digallate at 25 µg/ml and curcumin above 10 µg/ml concentration, showed binding with the angiotensin-converting enzyme 2 receptor reducing at the same time its activity in both cell-free and cell-based assays. Our study also demonstrates that brazilin and theaflavin-3,3'-digallate, and to a still greater extent, curcumin, decrease the activity of transmembrane serine protease 2 both in cell-free and cell-based assays. Similar pattern was observed with cathepsin L, although only theaflavin-3,3'-digallate showed a modest diminution of cathepsin L expression at protein level. Finally, each of these three compounds moderately increased endosomal/lysosomal pH. In conclusion, this study demonstrates pleiotropic anti-SARS-CoV-2 efficacy of specific polyphenols and their prospects for further scientific and clinical investigations.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/prevention & control , Polyphenols/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , A549 Cells , Benzopyrans/pharmacology , Biflavonoids/pharmacology , COVID-19/virology , Catechin/analogs & derivatives , Catechin/pharmacology , Cell Survival/drug effects , Curcumin/pharmacology , Humans , Protein Binding/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Virion/drug effects , Virion/metabolism , Virion/physiology , Virus Attachment/drug effects
14.
Biochimie ; 191: 27-32, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1347500

ABSTRACT

In the search for anti-SARS-CoV-2 drugs, much attention is given to safe and widely available native compounds. The green tea component epigallocatechin 3 gallate (EGCG) is particularly promising because it reportedly inhibits viral replication and viral entry in vitro. However, conclusive evidence for its predominant activity is needed. We tested EGCG effects on the native virus isolated from COVID-19 patients in two independent series of experiments using VERO cells and two different treatment schemes in each series. The results confirmed modest cytotoxicity of EGCG and its substantial antiviral activity. The preincubation scheme aimed at infection prevention has proven particularly beneficial. We complemented that finding with a detailed investigation of EGCG interactions with viral S-protein subunits, including S2, RBD, and the RBD mutant harboring the N501Y mutation. Molecular modeling experiments revealed N501Y-specific stacking interactions in the RBD-ACE2 complex and provided insight into EGCG interference with the complex formation. Together, these findings provide a molecular basis for the observed EGCG effects and reinforce its prospects in COVID-19 prevention therapy.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Catechin/analogs & derivatives , Mutation , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Animals , Catechin/pharmacology , Chlorocebus aethiops , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2/chemistry , Vero Cells , Viral Proteins/chemistry , Viral Proteins/metabolism , Virus Internalization/drug effects
15.
Molecules ; 26(16)2021 Aug 08.
Article in English | MEDLINE | ID: covidwho-1348676

ABSTRACT

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is producing a large number of infections and deaths globally, the development of supportive and auxiliary treatments is attracting increasing attention. Here, we evaluated SARS-CoV-2-inactivation activity of the polyphenol-rich tea leaf extract TY-1 containing concentrated theaflavins and other virucidal catechins. The TY-1 was mixed with SARS-CoV-2 solution, and its virucidal activity was evaluated. To evaluate the inhibition activity of TY-1 in SARS-CoV-2 infection, TY-1 was co-added with SARS-CoV-2 into cell culture media. After 1 h of incubation, the cell culture medium was replaced, and the cells were further incubated in the absence of TY-1. The viral titers were then evaluated. To evaluate the impacts of TY-1 on viral proteins and genome, TY-1-treated SARS-CoV-2 structural proteins and viral RNA were analyzed using western blotting and real-time RT-PCR, respectively. TY-1 showed time- and concentration-dependent virucidal activity. TY-1 inhibited SARS-CoV-2 infection of cells. The results of western blotting and real-time RT-PCR suggested that TY-1 induced structural change in the S2 subunit of the S protein and viral genome destruction, respectively. Our findings provided basic insights in vitro into the possible value of TY-1 as a virucidal agent, which could enhance the current SARS-CoV-2 control measures.


Subject(s)
COVID-19/virology , Polyphenols/pharmacology , SARS-CoV-2/drug effects , Tea/chemistry , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Biflavonoids/chemistry , Biflavonoids/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Camellia sinensis/metabolism , Catechin/chemistry , Catechin/pharmacology , Cell Line , Chlorocebus aethiops , Genome, Viral/drug effects , Humans , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Polyphenols/isolation & purification , SARS-CoV-2/metabolism , Vero Cells , Viral Load/drug effects
16.
Brief Bioinform ; 22(2): 1346-1360, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343647

ABSTRACT

The global pandemic crisis, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed the lives of millions of people across the world. Development and testing of anti-SARS-CoV-2 drugs or vaccines have not turned to be realistic within the timeframe needed to combat this pandemic. Here, we report a comprehensive computational approach to identify the multi-targeted drug molecules against the SARS-CoV-2 proteins, whichare crucially involved in the viral-host interaction, replication of the virus inside the host, disease progression and transmission of coronavirus infection. Virtual screening of 75 FDA-approved potential antiviral drugs against the target proteins, spike (S) glycoprotein, human angiotensin-converting enzyme 2 (hACE2), 3-chymotrypsin-like cysteine protease (3CLpro), cathepsin L (CTSL), nucleocapsid protein, RNA-dependent RNA polymerase (RdRp) and non-structural protein 6 (NSP6), resulted in the selection of seven drugs which preferentially bind to the target proteins. Further, the molecular interactions determined by molecular dynamics simulation revealed that among the 75 drug molecules, catechin can effectively bind to 3CLpro, CTSL, RBD of S protein, NSP6 and nucleocapsid protein. It is more conveniently involved in key molecular interactions, showing binding free energy (ΔGbind) in the range of -5.09 kcal/mol (CTSL) to -26.09 kcal/mol (NSP6). At the binding pocket, catechin is majorly stabilized by the hydrophobic interactions, displays ΔEvdW values: -7.59 to -37.39 kcal/mol. Thus, the structural insights of better binding affinity and favorable molecular interaction of catechin toward multiple target proteins signify that catechin can be potentially explored as a multi-targeted agent against COVID-19.


Subject(s)
COVID-19/drug therapy , Catechin/pharmacology , Polyphenols/pharmacology , SARS-CoV-2/drug effects , COVID-19/virology , Catechin/chemistry , Catechin/therapeutic use , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Polyphenols/therapeutic use
17.
Biomed Pharmacother ; 142: 112011, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1340557

ABSTRACT

Since the start of the outbreak of coronavirus disease 2019 in Wuhan, China, there have been more than 150 million confirmed cases of the disease reported to the World Health Organization. The beta variant (B.1.351 lineage), the mutation lineages of SARS-CoV-2, had increase transmissibility and resistance to neutralizing antibodies due to multiple mutations in the spike protein. N501Y, K417N and E484K, in the receptor binding domain (RBD) region may induce a conformational change of the spike protein and subsequently increase the infectivity of the beta variant. The L452R mutation in the epsilon variant (the B.1.427/B.1.429 variants) also reduced neutralizing activity of monoclonal antibodies. In this study, we discovered that 300 µg/mL GB-2, from Tian Shang Sheng Mu of Chiayi Puzi Peitian Temple, can inhibit the binding between ACE2 and wild-type (Wuhan type) RBD spike protein. GB-2 can inhibit the binding between ACE2 and RBD with K417N-E484K-N501Y mutation in a dose-dependent manner. GB-2 inhibited the binding between ACE2 and the RBD with a single mutation (K417N or N501Y or L452R) except the E484K mutation. In the compositions of GB-2, glycyrrhiza uralensis Fisch. ex DC., theaflavin and (+)-catechin cannot inhibit the binding between ACE2 and wild-type RBD spike protein. Theaflavin 3-gallate can inhibit the binding between ACE2 and wild-type RBD spike protein. Our results suggest that GB-2 could be a potential candidate for the prophylaxis of some SARS-CoV-2 variants infection in the further clinical study because of its inhibition of binding between ACE2 and RBD with K417N-E484K-N501Y mutations or L452R mutation.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Biflavonoids/pharmacology , COVID-19 , Catechin/pharmacology , Gallic Acid/analogs & derivatives , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Antibodies, Neutralizing/immunology , Antioxidants/pharmacology , Antiviral Agents/pharmacology , COVID-19/immunology , COVID-19/virology , Drug Discovery , Gallic Acid/pharmacology , HEK293 Cells , Humans , Medicine, East Asian Traditional , Mutation , Protein Binding/physiology , Protein Interaction Domains and Motifs/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
18.
Molecules ; 26(13)2021 Jun 29.
Article in English | MEDLINE | ID: covidwho-1288963

ABSTRACT

(-)-Epigallocatechin-3-O-gallate (EGCG), the most abundant component of catechins in tea (Camellia sinensis (L.) O. Kuntze), plays a role against viruses through inhibiting virus invasiveness, restraining gene expression and replication. In this paper, the antiviral effects of EGCG on various viruses, including DNA virus, RNA virus, coronavirus, enterovirus and arbovirus, were reviewed. Meanwhile, the antiviral effects of the EGCG epi-isomer counterpart (+)-gallocatechin-3-O-gallate (GCG) were also discussed.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Catechin/analogs & derivatives , Tea/chemistry , Animals , Antiviral Agents/therapeutic use , Catechin/pharmacology , Catechin/therapeutic use , Humans , Virus Internalization/drug effects , Viruses/drug effects
19.
Molecules ; 26(12)2021 Jun 11.
Article in English | MEDLINE | ID: covidwho-1270089

ABSTRACT

Potential effects of tea and its constituents on SARS-CoV-2 infection were assessed in vitro. Infectivity of SARS-CoV-2 was decreased to 1/100 to undetectable levels after a treatment with black tea, green tea, roasted green tea, or oolong tea for 1 min. An addition of (-) epigallocatechin gallate (EGCG) significantly inactivated SARS-CoV-2, while the same concentration of theasinensin A (TSA) and galloylated theaflavins including theaflavin 3,3'-di-O-gallate (TFDG) had more remarkable anti-viral activities. EGCG, TSA, and TFDG at 1 mM, 40 µM, and 60 µM, respectively, which are comparable to the concentrations of these compounds in tea beverages, significantly reduced infectivity of the virus, viral RNA replication in cells, and secondary virus production from the cells. EGCG, TSA, and TFDG significantly inhibited interaction between recombinant ACE2 and RBD of S protein. These results suggest potential usefulness of tea in prevention of person-to-person transmission of the novel coronavirus.


Subject(s)
Antiviral Agents/pharmacology , Biflavonoids/chemistry , Catechin/chemistry , Gallic Acid/analogs & derivatives , SARS-CoV-2/physiology , Tea/chemistry , Virus Replication/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/chemistry , Biflavonoids/pharmacology , COVID-19/pathology , COVID-19/virology , Catechin/analogs & derivatives , Catechin/pharmacology , Cell Survival/drug effects , Chlorocebus aethiops , Gallic Acid/chemistry , Gallic Acid/pharmacology , Humans , Protein Interaction Maps/drug effects , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Tea/metabolism , Vero Cells
20.
Comput Biol Med ; 135: 104560, 2021 08.
Article in English | MEDLINE | ID: covidwho-1263240

ABSTRACT

BACKGROUND: The global pandemic caused by a RNA virus capable of infecting humans and animals, has resulted in millions of deaths worldwide. Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infects the lungs, and the gastrointestinal tract to some extent. Rapid structural mutations have increased the virulence and infectivity of the virus drastically. One such mutated strain known as the UK variant has caused many deaths in the United Kingdom. HYPOTHESIS: Among several indigenous natural ingredients used for prevention and cure of many diseases, the catechins have been reported for their antiviral activity, even against SARS-CoV-2. Characteristic mutations present on the spike protein have presented the newer strain its enhanced infectivity. The spike protein helps the virus bind to ACE2 receptor of the host cell and hence is a drug target. Catechins have been reported for their entry-inhibitory activity against several viruses. METHOD: In this study, we performed molecular docking of different catechins with the wild and mutant variants of the spike protein of SARS-CoV-2. The stability of the best docked complexes was validated using molecular dynamics simulation. RESULTS: The in-silico studies show that the catechins form favourable interactions with the spike protein and can potentially impair its function. Epigallocatechin gallate (EGCG) showed the best binding among the catechins against both the strains. Both the protein-ligand complexes were stable throughout the simulation time frame. CONCLUSION: The outcomes should encourage further exploration of the antiviral activity of EGCG against SARS-CoV-2 and its variants.


Subject(s)
Catechin , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Catechin/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding
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