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1.
J Mol Model ; 27(11): 341, 2021 Nov 03.
Article in English | MEDLINE | ID: covidwho-1499466

ABSTRACT

From the beginning of pandemic, more than 240 million people have been infected with a death rate higher than 2%. Indeed, the current exit strategy involving the spreading of vaccines must be combined with progress in effective treatment development. This scenario is sadly supported by the vaccine's immune activation time and the inequalities in the global immunization schedule. Bringing the crises under control means providing the world population with accessible and impactful new therapeutics. We screened a natural product library that contains a unique collection of 2370 natural products into the binding site of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). According to the docking score and to the interaction at the active site, three phenylethanoid glycosides (forsythiaside A, isoacteoside, and verbascoside) were selected. In order to provide better insight into the atomistic interaction and test the impact of the three selected compounds at the binding site, we resorted to a half microsecond-long molecular dynamics simulation. As a result, we are showing that forsythiaside A is the most stable molecule and it is likely to possess the highest inhibitory effect against SARS-CoV-2 Mpro. Phenylethanoid glycosides also have been reported to have both protease and kinase activity. This kinase inhibitory activity is very beneficial in fighting viruses inside the body as kinases are required for viral entry, metabolism, and/or reproduction. The dual activity (kinase/protease) of phenylethanoid glycosides makes them very promising anit-COVID-19 agents.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/pharmacology , Glycosides/pharmacology , Antiviral Agents/chemistry , Binding Sites , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Coronavirus Protease Inhibitors/chemistry , Drug Evaluation, Preclinical , Glucosides/chemistry , Glucosides/metabolism , Glucosides/pharmacology , Glycosides/chemistry , Glycosides/metabolism , Hydrogen Bonding , Molecular Docking Simulation , Molecular Dynamics Simulation , Phenols/chemistry , Phenols/metabolism , Phenols/pharmacology
2.
Front Biosci (Landmark Ed) ; 26(10): 789-798, 2021 10 30.
Article in English | MEDLINE | ID: covidwho-1498508

ABSTRACT

Background: The coronavirus disease 2019 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected more than 210 million individuals globally and resulted in over 4 million deaths since the first report in December 2019. The early use of traditional Chinese medicine (TCM) for light and ordinary patients, can rapidly improve symptoms, shorten hospitalization days and reduce severe cases transformed from light and normal. Many TCM formulas and products have a wide application in treating infectious and non-infectious diseases. Polygonum cuspidatum Sieb. et Zucc. (P. cuspidatum), is an important Traditional Chinese Medicine with actions of clearing away heat and eliminating dampness, draining the gallbladder to relieve jaundice, removing blood stasis to alleviate pain, resolving phlegm and arrest cough. In the search for anti-SARS-CoV-2, P. cuspidatum was recommended as as a therapeutic drug of COVID-19 pneumonia.In this study, we aimed to identifies P. cuspidatum is the potential broad-spectrum inhibitor for the treatment of coronaviruses infections. Methods: In the present study , we infected human malignant embryonal rhabdomyoma (RD) cells with the OC43 strain of the coronavirus, which represent an alternative model for SARS-CoV-2 and then employed the cell viability assay kit for the antiviral activity. We combined computer aided virtual screening to predicte the binding site and employed Surface plasmon resonance analysis (SPR) to comfirm the interaction between drugs and coronavirus. We employed fluorescence resonance energy transfer technology to identify drug's inhibition in the proteolytic activity of 3CLpro and Plpro. Results: Based on our results, polydatin and resveratrol derived from P. cuspidatum significantly suppressed HCoV-OC43 replication. 50% inhibitory concentration (IC50) values of polydatin inhibited SARS-CoV-2 Mpro and Plpro, MERS Mpro and Plpro were 18.66, 125, 14.6 and 25.42 µm, respectively. IC50 values of resveratrol inhibited SARS-CoV-2 Mpro and Plpro, MERS Mpro and Plpro were 29.81 ,60.86, 16.35 and19.04 µM, respectively. Finally, SPR assay confirmed that polydatin and resveratrol had high affinity to SARS-CoV-2, SARS-CoV 3Clpro, MERS-CoV 3Clpro and PLpro protein. Conclusions: we identified the antiviral activity of flavonoids polydatin and resveratrol on RD cells. Polydatin and resveratrol were found to be specific and selective inhibitors for SARS-CoV-2, 3CLpro and PLpro, viral cysteine proteases. In summary, this study identifies P. cuspidatum as the potential broad-spectrum inhibitor for the treatment of coronaviruses infections.


Subject(s)
Drugs, Chinese Herbal/chemistry , Fallopia japonica/chemistry , Glucosides/pharmacology , Resveratrol/pharmacology , SARS-CoV-2/drug effects , Stilbenes/pharmacology , Virus Replication/drug effects , Antiviral Agents/pharmacology , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , Cell Line, Tumor , Cell Survival/drug effects , Glucosides/metabolism , HEK293 Cells , Host-Pathogen Interactions/drug effects , Humans , Medicine, Chinese Traditional/methods , Pandemics , Protein Binding , Resveratrol/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Stilbenes/metabolism , Surface Plasmon Resonance/methods , Viral Proteins/metabolism
3.
FASEB J ; 35(9): e21870, 2021 09.
Article in English | MEDLINE | ID: covidwho-1373669

ABSTRACT

COVID-19 is often characterized by dysregulated inflammatory and immune responses. It has been shown that the Traditional Chinese Medicine formulation Qing-Fei-Pai-Du decoction (QFPDD) is effective in the treatment of the disease, especially for patients in the early stage. Our network pharmacology analyses indicated that many inflammation and immune-related molecules were the targets of the active components of QFPDD, which propelled us to examine the effects of the decoction on inflammation. We found in the present study that QFPDD effectively alleviated dextran sulfate sodium-induced intestinal inflammation in mice. It inhibited the production of pro-inflammatory cytokines IL-6 and TNFα, and promoted the expression of anti-inflammatory cytokine IL-10 by macrophagic cells. Further investigations found that QFPDD and one of its active components wogonoside markedly reduced LPS-stimulated phosphorylation of transcription factor ATF2, an important regulator of multiple cytokines expression. Our data revealed that both QFPDD and wogonoside decreased the half-life of ATF2 and promoted its proteasomal degradation. Of note, QFPDD and wogonoside down-regulated deubiquitinating enzyme USP14 along with inducing ATF2 degradation. Inhibition of USP14 with the small molecular inhibitor IU1 also led to the decrease of ATF2 in the cells, indicating that QFPDD and wogonoside may act through regulating USP14 to promote ATF2 degradation. To further assess the importance of ubiquitination in regulating ATF2, we generated mice that were intestinal-specific KLHL5 deficiency, a CUL3-interacting protein participating in substrate recognition of E3s. In these mice, QFPDD mitigated inflammatory reaction in the spleen, but not intestinal inflammation, suggesting CUL3-KLHL5 may function as an E3 for ATF2 degradation.


Subject(s)
Activating Transcription Factor 2/metabolism , Down-Regulation/drug effects , Drugs, Chinese Herbal/pharmacology , Flavanones/pharmacology , Glucosides/pharmacology , Inflammation/drug therapy , Proteolysis/drug effects , Ubiquitin Thiolesterase/deficiency , Animals , Cell Line , Colitis/chemically induced , Colitis/drug therapy , Cullin Proteins/metabolism , Cytokines/metabolism , Dextran Sulfate/pharmacology , Dextran Sulfate/therapeutic use , Drugs, Chinese Herbal/therapeutic use , Flavanones/therapeutic use , Glucosides/therapeutic use , Inflammation/chemically induced , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Phosphorylation/drug effects , Proteasome Endopeptidase Complex/drug effects , Proteasome Endopeptidase Complex/metabolism , Pyrroles/pharmacology , Pyrrolidines/pharmacology , Ubiquitin Thiolesterase/antagonists & inhibitors , Ubiquitination
4.
Int J Mol Sci ; 22(16)2021 Aug 10.
Article in English | MEDLINE | ID: covidwho-1348647

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the development of vaccines, the emergence of SARS-CoV-2 variants and the absence of effective therapeutics demand the continual investigation of COVID-19. Natural products containing active ingredients may be good therapeutic candidates. Here, we investigated the effectiveness of geraniin, the main ingredient in medical plants Elaeocarpus sylvestris var. ellipticus and Nephelium lappaceum, for treating COVID-19. The SARS-CoV-2 spike protein binds to the human angiotensin-converting enzyme 2 (hACE2) receptor to initiate virus entry into cells; viral entry may be an important target of COVID-19 therapeutics. Geraniin was found to effectively block the binding between the SARS-CoV-2 spike protein and hACE2 receptor in competitive enzyme-linked immunosorbent assay, suggesting that geraniin might inhibit the entry of SARS-CoV-2 into human epithelial cells. Geraniin also demonstrated a high affinity to both proteins despite a relatively lower equilibrium dissociation constant (KD) for the spike protein (0.63 µM) than hACE2 receptor (1.12 µM), according to biolayer interferometry-based analysis. In silico analysis indicated geraniin's interaction with the residues functionally important in the binding between the two proteins. Thus, geraniin is a promising therapeutic agent for COVID-19 by blocking SARS-CoV-2's entry into human cells.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Glucosides/pharmacology , Hydrolyzable Tannins/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/chemistry , Glucosides/chemistry , Humans , Hydrolyzable Tannins/chemistry , Ligands , Molecular Dynamics Simulation , Protein Interaction Domains and Motifs , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/chemistry
5.
Biomolecules ; 11(7)2021 07 16.
Article in English | MEDLINE | ID: covidwho-1314581

ABSTRACT

In the search for new therapeutic strategies to contrast SARS-CoV-2, we here studied the interaction of polydatin (PD) and resveratrol (RESV)-two natural stilbene polyphenols with manifold, well known biological activities-with Spike, the viral protein essential for virus entry into host cells, and ACE2, the angiotensin-converting enzyme present on the surface of multiple cell types (including respiratory epithelial cells) which is the main host receptor for Spike binding. Molecular Docking simulations evidenced that both compounds can bind Spike, ACE2 and the ACE2:Spike complex with good affinity, although the interaction of PD appears stronger than that of RESV on all the investigated targets. Preliminary biochemical assays revealed a significant inhibitory activity of the ACE2:Spike recognition with a dose-response effect only in the case of PD.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Glucosides/pharmacology , Resveratrol/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Stilbenes/pharmacology , COVID-19/metabolism , Drug Discovery , Drugs, Chinese Herbal/pharmacology , Enzyme Inhibitors/pharmacology , Host-Pathogen Interactions/drug effects , Humans , Molecular Docking Simulation , Protein Binding/drug effects , SARS-CoV-2/metabolism
6.
Antiviral Res ; 190: 105075, 2021 06.
Article in English | MEDLINE | ID: covidwho-1290345

ABSTRACT

The emerging SARS-CoV-2 infection is the cause of the global COVID-19 pandemic. To date, there are limited therapeutic options available to fight this disease. Here we examined the inhibitory abilities of two broad-spectrum antiviral natural products chebulagic acid (CHLA) and punicalagin (PUG) against SARS-CoV-2 viral replication. Both CHLA and PUG reduced virus-induced plaque formation in Vero-E6 monolayer at noncytotoxic concentrations, by targeting the enzymatic activity of viral 3-chymotrypsin-like cysteine protease (3CLpro) as allosteric regulators. Our study demonstrates the potential use of CHLA and PUG as novel COVID-19 therapies.


Subject(s)
Antiviral Agents/pharmacology , Benzopyrans/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Glucosides/pharmacology , Hydrolyzable Tannins/pharmacology , SARS-CoV-2/drug effects , Allosteric Site , Animals , Antiviral Agents/chemistry , Benzopyrans/chemistry , COVID-19/drug therapy , COVID-19/virology , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Drug Discovery , Glucosides/chemistry , Molecular Docking Simulation , Protease Inhibitors/pharmacology , SARS-CoV-2/metabolism , Vero Cells , Virus Replication/drug effects
7.
Phytomedicine ; 87: 153591, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1240546

ABSTRACT

BACKGROUND: The outbreak of coronavirus (SARS-CoV-2) disease caused more than 100,000,000 people get infected and over 2,200,000 people being killed worldwide. However, the current developed vaccines or drugs may be not effective in preventing the pandemic of COVID-19 due to the mutations of coronavirus and the severe side effects of the newly developed vaccines. Chinese herbal medicines and their active components play important antiviral activities. Corilagin exhibited antiviral effect on human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Epstein-Barr virus (EBV). However, whether it blocks the interaction between SARS-CoV-2 RBD and hACE2 has not been elucidated. PURPOSE: To characterize an active compound, corilagin derived from Phyllanthus urinaria as potential SARS-CoV-2 entry inhibitors for its possible preventive application in daily anti-virus hygienic products. METHODS: Computational docking coupled with bio-layer interferometry, BLI were adopted to screen more than 1800 natural compounds for the identification of SARS-CoV-2 spike-RBD inhibitors. Corilagin was confirmed to have a strong binding affinity with SARS-CoV-2-RBD or human ACE2 (hACE2) protein by the BLI, ELISA and immunocytochemistry (ICC) assay. Furthermore, the inhibitory effect of viral infection of corilagin was assessed by in vitro pseudovirus system. Finally, the toxicity of corilagin was examined by using MTT assay and maximal tolerated dose (MTD) studies in C57BL/6 mice. RESULTS: Corilagin preferentially binds to a pocket that contains residues Cys 336 to Phe 374 of spike-RBD with a relatively low binding energy of -9.4 kcal/mol. BLI assay further confirmed that corilagin exhibits a relatively strong binding affinity to SARS-CoV-2-RBD and hACE2 protein. In addition, corilagin dose-dependently blocks SARS-CoV-2-RBD binding and abolishes the infectious property of RBD-pseudotyped lentivirus in hACE2 overexpressing HEK293 cells, which mimicked the entry of SARS-CoV-2 virus in human host cells. Finally, in vivo studies revealed that up to 300 mg/kg/day of corilagin was safe in C57BL/6 mice. Our findings suggest that corilagin could be a safe and potential antiviral agent against the COVID-19 acting through the blockade of the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors. CONCLUSION: Corilagin could be considered as a safe and environmental friendly anti-SARS-CoV-2 agent for its potential preventive application in daily anti-virus hygienic products.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Glucosides/pharmacology , Host-Pathogen Interactions/drug effects , Hydrolyzable Tannins/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Animals , Antiviral Agents/chemistry , Antiviral Agents/toxicity , COVID-19 , Epstein-Barr Virus Infections/drug therapy , Glucosides/chemistry , Glucosides/toxicity , HEK293 Cells , Humans , Hydrolyzable Tannins/chemistry , Hydrolyzable Tannins/toxicity , Lentivirus Infections/drug therapy , Male , Maximum Tolerated Dose , Mice, Inbred C57BL , Molecular Docking Simulation , Spike Glycoprotein, Coronavirus/chemistry
8.
Clin Nutr ESPEN ; 43: 197-199, 2021 06.
Article in English | MEDLINE | ID: covidwho-1135287

ABSTRACT

The COVID-19 pandemic as the largest global public health crisis is now considered as an emergency at the World Health Organization (WHO). As there is no specific therapy for SARS-CoV-2 infection at present and also because of the long time it takes to discover a new drug and the urgent need to respond urgently to a pandemic infection. Perhaps the best way right now is to find an FDA-approved drug to treat this infection. Oxidative stress and inflammation play a vital role in the progression of tissue injury in COVID-19 patients; furthermore, the G6PD activation is related to increased oxidative inflammation in acute pulmonary injury. In this regard, we propose a new insight that may be a good strategy for this urgency. Exploiting G6PD through inhibiting G6PD activity by modifying redox balance, metabolic switching and protein-protein interactions can be proposed as a new approach to improving patients in severe stage of COVID 19 through various mechanisms. Polydatin is isolated from many plants such as Polygonum, peanuts, grapes, red wines and many daily diets that can be used in severe stage of COVID-19 as a G6PD inhibitor. Furthermore, polydatin possesses various biological activities such as anti-inflammatory, antioxidant, immunoregulatory, nephroprotective, hepatoprotective, anti-arrhythmic and anti-tumor. Our hypothesis is that the consumption of antioxidants such as Polydatin (a glucoside of resveratrol) as a complementary therapeutic approach may be effective in reducing oxidative stress and inflammation in patients with COVID-19.


Subject(s)
Antioxidants/therapeutic use , COVID-19/drug therapy , Glucosephosphate Dehydrogenase/antagonists & inhibitors , Glucosides/therapeutic use , Phytotherapy , Plant Extracts/therapeutic use , Resveratrol/therapeutic use , Stilbenes/therapeutic use , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antioxidants/pharmacology , COVID-19/complications , COVID-19/metabolism , Glucosides/pharmacology , Humans , Inflammation/drug therapy , Inflammation/etiology , Inflammation/metabolism , Lung/drug effects , Magnoliopsida/chemistry , Oxidative Stress/drug effects , Pandemics , Plant Extracts/pharmacology , Resveratrol/pharmacology , SARS-CoV-2 , Stilbenes/pharmacology
9.
J Chem Inf Model ; 60(12): 5771-5780, 2020 12 28.
Article in English | MEDLINE | ID: covidwho-1065771

ABSTRACT

The novel coronavirus (SARS-CoV-2) has infected several million people and caused thousands of deaths worldwide since December 2019. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. Therefore, in this context, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro, and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a database of ∼4600 natural compounds, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including three natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, cannabisin A and isoacteoside, and an HIV-1 PR inhibitor, darunavir, exhibit a large binding free energy to SARS-CoV-2 Mpro, which is larger than that of 13b, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals interaction. We also found that Glu166 forms H-bonds to all of the inhibitors. Replacing Glu166 by an alanine residue leads to ∼2.0 kcal/mol decreases in the affinity of darunavir to SARS-CoV-2 Mpro. Our results could contribute to the development of potential drugs inhibiting SARS-CoV-2.


Subject(s)
Antiviral Agents/chemistry , COVID-19/drug therapy , HIV Protease Inhibitors/chemistry , HIV Protease/metabolism , SARS-CoV-2/drug effects , Amino Acid Sequence , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Binding Sites , Biological Products/chemistry , Biological Products/pharmacology , Darunavir/chemistry , Darunavir/pharmacology , Databases, Factual , Drug Design , Glucosides/chemistry , Glucosides/pharmacology , HIV Protease Inhibitors/metabolism , HIV Protease Inhibitors/pharmacology , Humans , Molecular Docking Simulation , Peptides/chemistry , Phenols/chemistry , Phenols/pharmacology , Protein Binding , Structure-Activity Relationship , Thermodynamics
10.
Curr Atheroscler Rep ; 22(12): 72, 2020 10 03.
Article in English | MEDLINE | ID: covidwho-812523

ABSTRACT

PURPOSE OF REVIEW: The review highlights selected studies related to cardiovascular disease (CVD) prevention that were presented at the 2020 European Society of Cardiology (ESC) Congress-The Digital Experience. RECENT FINDINGS: The studies reviewed include clinical trials on novel RNA interference-based lipid-lowering therapies AKCEA-APOCIII-LRx and vupanorsen (AKCEA-ANGPTL3-LRx); the EVAPORATE trial assessing the effects of icosapent ethyl on coronary plaque volume progression; the LoDoCo2 trial evaluating the efficacy of low-dose colchicine in cardiovascular disease risk reduction among patients with chronic coronary artery disease; as well as the EMPEROR-Reduced trial evaluating cardiovascular and renal outcomes with empagliflozin in patients with heart failure and reduced ejection fraction. In addition, we review the BPLTTC analysis on blood pressure treatment across blood pressure levels and CVD status and discuss findings from the BRACE CORONA study that examined continuing versus suspending angiotensin-converting enzyme inhibitor or angiotensin receptor blockers in patients on these antihypertensive medications who were hospitalized with COVID-19 infection. The studies presented at the 2020 digital ESC Congress highlight the continuing advancements in the field of CVD prevention.


Subject(s)
Betacoronavirus/physiology , Cardiology , Cardiovascular Agents/pharmacology , Cardiovascular Diseases , Coronavirus Infections , Lipid Regulating Agents/pharmacology , Pandemics , Pneumonia, Viral , Benzhydryl Compounds/pharmacology , COVID-19 , Cardiology/methods , Cardiology/trends , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control , Clinical Trials as Topic , Congresses as Topic , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Eicosapentaenoic Acid/analogs & derivatives , Eicosapentaenoic Acid/pharmacology , Europe , Glucosides/pharmacology , Humans , Oligonucleotides/pharmacology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , SARS-CoV-2 , Societies, Medical , Telecommunications
11.
Int J Biol Macromol ; 163: 1687-1696, 2020 Nov 15.
Article in English | MEDLINE | ID: covidwho-793718

ABSTRACT

SARS-CoV-2 has caused COVID-19 outbreak with nearly 2 M infected people and over 100K death worldwide, until middle of April 2020. There is no confirmed drug for the treatment of COVID-19 yet. As the disease spread fast and threaten human life, repositioning of FDA approved drugs may provide fast options for treatment. In this aspect, structure-based drug design could be applied as a powerful approach in distinguishing the viral drug target regions from the host. Evaluation of variations in SARS-CoV-2 genome may ease finding specific drug targets in the viral genome. In this study, 3458 SARS-CoV-2 genome sequences isolated from all around the world were analyzed. Incidence of C17747T and A17858G mutations were observed to be much higher than others and they were on Nsp13, a vital enzyme of SARS-CoV-2. Effect of these mutations was evaluated on protein-drug interactions using in silico methods. The most potent drugs were found to interact with the key and neighbor residues of the active site responsible from ATP hydrolysis. As result, cangrelor, fludarabine, folic acid and polydatin were determined to be the most potent drugs which have potency to inhibit both the wild type and mutant SARS-CoV-2 helicase. Clinical data supporting these findings would be important towards overcoming COVID-19.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Enzyme Inhibitors/pharmacology , Methyltransferases/antagonists & inhibitors , Pneumonia, Viral/drug therapy , RNA Helicases/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Amino Acid Sequence , Betacoronavirus/enzymology , Betacoronavirus/genetics , Binding Sites , COVID-19 , Computer Simulation , Coronavirus Infections/virology , Drug Approval , Drug Repositioning , Folic Acid/pharmacology , Genome, Viral , Glucosides/pharmacology , Humans , Methyltransferases/chemistry , Methyltransferases/genetics , Methyltransferases/metabolism , Molecular Docking Simulation , Mutation , Pandemics , Pneumonia, Viral/virology , RNA Helicases/chemistry , RNA Helicases/genetics , RNA Helicases/metabolism , SARS-CoV-2 , Stilbenes/pharmacology , Vidarabine/analogs & derivatives , Vidarabine/pharmacology , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
12.
Phytomedicine ; 78: 153296, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-747894

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has extensively and rapidly spread in the world, causing an outbreak of acute infectious pneumonia. However, no specific antiviral drugs or vaccines can be used. Phillyrin (KD-1), a representative ingredient of Forsythia suspensa, possesses anti-inflammatory, anti-oxidant, and antiviral activities. However, little is known about the antiviral abilities and mechanism of KD-1 against SARS-CoV-2 and human coronavirus 229E (HCoV-229E). PURPOSE: The study was designed to investigate the antiviral and anti-inflammatory activities of KD-1 against the novel SARS-CoV-2 and HCoV-229E and its potential effect in regulating host immune response in vitro. METHODS: The antiviral activities of KD-1 against SARS-CoV-2 and HCoV-229E were assessed in Vero E6 cells using cytopathic effect and plaque-reduction assay. Proinflammatory cytokine expression levels upon infection with SARS-CoV-2 and HCoV-229E infection in Huh-7 cells were measured by real-time quantitative PCR assays. Western blot assay was used to determine the protein expression of nuclear factor kappa B (NF-κB) p65, p-NF-κB p65, IκBα, and p-IκBα in Huh-7 cells, which are the key targets of the NF-κB pathway. RESULTS: KD-1 could significantly inhibit SARS-CoV-2 and HCoV-229E replication in vitro. KD-1 could also markedly reduce the production of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, MCP-1, and IP-10) at the mRNA levels. Moreover, KD-1 could significantly reduce the protein expression of p-NF-κB p65, NF-κB p65, and p-IκBα, while increasing the expression of IκBα in Huh-7 cells. CONCLUSIONS: KD-1 could significantly inhibit virus proliferation in vitro, the up-regulated expression of proinflammatory cytokines induced by SARS-CoV-2 and HCoV-229E by regulating the activity of the NF-кB signaling pathway. Our findings indicated that KD-1 protected against virus attack and can thus be used as a novel strategy for controlling the coronavirus disease 2019.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus 229E, Human/drug effects , Coronavirus Infections , Glucosides/pharmacology , NF-kappa B/metabolism , Pandemics , Pneumonia, Viral , Animals , COVID-19 , Chlorocebus aethiops , Coronavirus/drug effects , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Cytokines/metabolism , Forsythia/chemistry , Humans , Phytotherapy , Plant Extracts/pharmacology , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/virology , Signal Transduction/drug effects , Vero Cells , Virus Replication/drug effects
13.
Phytomedicine ; 85: 153310, 2021 May.
Article in English | MEDLINE | ID: covidwho-723883

ABSTRACT

BACKGROUND: SARS-CoV-2, an emerging strain of coronavirus, has affected millions of people from all the continents of world and received worldwide attention. This emerging health crisis calls for the urgent development of specific therapeutics against COVID-19 to potentially reduce the burden of this emerging pandemic. PURPOSE: This study aims to evaluate the anti-viral efficacy of natural bioactive entities against COVID-19 via molecular docking and molecular dynamics simulation. METHODS: A library of 27 caffeic-acid derivatives was screened against 5 proteins of SARS-CoV-2 by using Molegro Virtual Docker 7 to obtain the binding energies and interactions between compounds and SARS-CoV-2 proteins. ADME properties and toxicity profiles were investigated via www.swissadme.ch web tools and Toxtree respectively. Molecular dynamics simulation was performed to determine the stability of the lead-protein interactions. RESULTS: Our obtained results has uncovered khainaoside C, 6-O-Caffeoylarbutin, khainaoside B, khainaoside C and vitexfolin A as potent modulators of COVID-19 possessing more binding energies than nelfinavir against COVID-19 Mpro, Nsp15, SARS-CoV-2 spike S2 subunit, spike open state and closed state structure respectively. While Calceolarioside B was identified as pan inhibitor, showing strong molecular interactions with all proteins except SARS-CoV-2 spike glycoprotein closed state. The results are supported by 20 ns molecular dynamics simulations of the best complexes. CONCLUSION: This study will hopefully pave a way for development of phytonutrients-based antiviral therapeutic for treatment or prevention of COVID-19 and further studies are recommended to evaluate the antiviral effects of these phytochemicals against SARS-CoV-2 in in vitro and in vivo models.


Subject(s)
Antiviral Agents/pharmacology , Caffeic Acids/pharmacology , Functional Food , SARS-CoV-2/drug effects , Arbutin/analogs & derivatives , Arbutin/pharmacology , Binding Sites , Glucosides/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Spike Glycoprotein, Coronavirus/antagonists & inhibitors
14.
Biochem Biophys Res Commun ; 530(1): 4-9, 2020 09 10.
Article in English | MEDLINE | ID: covidwho-663155

ABSTRACT

COVID-19 has become one of the worst epidemic in the world, currently already more than four million people have been infected, which probably co-exist with human beings, and has a significant impact on the global economy and political order. In the process of fighting against the epidemic in China, the clinical value of a variety of herbal medicines has been recognized and written into the clinical application guide. However, their effective molecular mechanism and potential targets are still not clear. Pathology and pharmacology research will gradually attract attention in the post-epidemic outbreak term. Here, we constructed a COVID-19 protein microarray of potential therapy targets, which contains the main drug targets to the SARS-CoV-2 virus and the anti-virus, anti-inflammatory cellar targets of the host. Series of quality controls test has been carried out, which showed that it could be applied for drug target screening of bio-active natural products. The establishment of this microarray will provide a useful tool for the study of the molecular pharmacology of natural products.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/pharmacology , Pneumonia, Viral/drug therapy , Proteins/metabolism , Viral Proteins/metabolism , Betacoronavirus/metabolism , Biological Products/pharmacology , COVID-19 , Chlorogenic Acid/pharmacology , Coronavirus Infections/metabolism , Diterpenes/pharmacology , Drug Discovery , Glucosides/pharmacology , HEK293 Cells , Humans , Molecular Docking Simulation , Molecular Targeted Therapy , Pandemics , Pneumonia, Viral/metabolism , Protein Array Analysis , SARS-CoV-2 , Stilbenes/pharmacology
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