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1.
Minerva Gastroenterol (Torino) ; 67(2): 190-195, 2021 06.
Article in English | MEDLINE | ID: covidwho-1535066

ABSTRACT

When looking for new antiviral compounds aimed to counteract the COVID-19, a disease caused by the recently identified novel Coronavirus (SARS-CoV-2), the knowledge of the main viral proteins is fundamental. The major druggable targets of SARS-CoV-2 include 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase, and spike (S) protein. Molecular docking studies have highlighted that quercetin, a natural polyphenol belonging to the flavonol class, inhibits 3CLpro, PLpro and S proteins. Biophysical technics have then very recently confirmed that quercetin is reasonably a potent inhibitor of 3CLpro. The likely antiviral properties of quercetin are anyway challenged by its very poor oral bioavailability profile and any attempt to overcome this limit should be welcome. A phospholipid delivery form of quercetin (Quercetin Phytosome®) has been recently tested in humans to evaluate a possible improvement in oral bioavailability. After hydrolysis of the conjugated form (mainly glucuronide) of quercetin found in human plasma, the pharmacokinetics results have demonstrated an increased bioavailability rate by about 20-fold for total quercetin. It has been also observed that the presence of specific glucuronidase could yield free systemic quercetin in human body. Taking also into considerations its anti-inflammatory and thrombin-inhibitory actions, a bioavailable form of quercetin, like Quercetin Phytosome®, should be considered a possible candidate to clinically face COVID-19.


Subject(s)
COVID-19/drug therapy , Quercetin/therapeutic use , Antiviral Agents/therapeutic use , Humans , Molecular Docking Simulation
2.
Minerva Gastroenterol (Torino) ; 67(2): 190-195, 2021 06.
Article in English | MEDLINE | ID: covidwho-1278860

ABSTRACT

When looking for new antiviral compounds aimed to counteract the COVID-19, a disease caused by the recently identified novel Coronavirus (SARS-CoV-2), the knowledge of the main viral proteins is fundamental. The major druggable targets of SARS-CoV-2 include 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase, and spike (S) protein. Molecular docking studies have highlighted that quercetin, a natural polyphenol belonging to the flavonol class, inhibits 3CLpro, PLpro and S proteins. Biophysical technics have then very recently confirmed that quercetin is reasonably a potent inhibitor of 3CLpro. The likely antiviral properties of quercetin are anyway challenged by its very poor oral bioavailability profile and any attempt to overcome this limit should be welcome. A phospholipid delivery form of quercetin (Quercetin Phytosome®) has been recently tested in humans to evaluate a possible improvement in oral bioavailability. After hydrolysis of the conjugated form (mainly glucuronide) of quercetin found in human plasma, the pharmacokinetics results have demonstrated an increased bioavailability rate by about 20-fold for total quercetin. It has been also observed that the presence of specific glucuronidase could yield free systemic quercetin in human body. Taking also into considerations its anti-inflammatory and thrombin-inhibitory actions, a bioavailable form of quercetin, like Quercetin Phytosome®, should be considered a possible candidate to clinically face COVID-19.


Subject(s)
COVID-19/drug therapy , Quercetin/therapeutic use , Antiviral Agents/therapeutic use , Humans , Molecular Docking Simulation
3.
Vet Med Int ; 2021: 9931001, 2021.
Article in English | MEDLINE | ID: covidwho-1268154

ABSTRACT

Since the damage to alveolar tissue due to cigarette smoke exposure (CSE) is lipid peroxidation, antioxidant treatment is needed. The red guava (Psidium guajava L.) fruit contains antioxidants derived from quercetin, lycopene, and vitamin C. This study aimed to determine the effect of red guava fruit extract (RGFE) on the alveolar tissue of rats exposed to cigarette smoke. The 25 rats (Rattus norvegicus) were divided into five groups. The control and T0 groups were only administered placebo, while T1, T2, and T3 groups were orally administered RGFE of 18.9, 37.8, and 56.7 mg/kg body weight daily for 44 days. The CSE dose of 20 suctions daily was conducted on T0, T1, T2, and T3 groups on days 15-44. On day 45, all rats were sacrificed for serum collection and histopathological lung slides with eosin-nigrosin staining. The result showed that CSE caused an increase (p < 0.05) in malondialdehyde (MDA) levels, cell death, apoptosis, and necrosis percentages, congestion and thickening of alveolar septum tissue, and reduction in the alveolar diameter and alveolar number. Administration of RGFE suppressed those effects, and the highest dose of RGFE (T3) restored (p > 0.05) MDA levels, percentage of apoptotic and necrosis, alveolar septal thickening, and alveolar diameter. However, the percentages of cell death, alveolar congestion, and the alveolar number were still worse (p < 0.05) than in normal rats. It could be concluded that RGFE has proved relief and restoration of the alveolar tissue of rats exposed to cigarette smoke.

4.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1246687

ABSTRACT

BACKGROUND: The clinical consequences of SARS-CoV-2 and DENGUE virus co-infection are not promising. However, their treatment options are currently unavailable. Current studies have shown that quercetin is both resistant to COVID-19 and DENGUE; this study aimed to evaluate the possible functional roles and underlying mechanisms of action of quercetin as a potential molecular candidate against COVID-19 and DENGUE co-infection. METHODS: We used a series of bioinformatics analyses to understand and characterize the biological functions, pharmacological targets and therapeutic mechanisms of quercetin in COVID-19 and DENGUE co-infection. RESULTS: We revealed the clinical characteristics of COVID-19 and DENGUE, including pathological mechanisms, key inflammatory pathways and possible methods of intervention, 60 overlapping targets related to the co-infection and the drug were identified, the protein-protein interaction (PPI) was constructed and TNFα, CCL-2 and CXCL8 could become potential drug targets. Furthermore, we disclosed the signaling pathways, biological functions and upstream pathway activity of quercetin in COVID-19 and DENGUE. The analysis indicated that quercetin could inhibit cytokines release, alleviate excessive immune responses and eliminate inflammation, through NF-κB, IL-17 and Toll-like receptor signaling pathway. CONCLUSIONS: This study is the first to reveal quercetin as a pharmacological drug for COVID-19 and DENGUE co-infection. COVID-19 and DENGUE co-infection remain a potential threat to the world's public health system. Therefore, we need innovative thinking to provide admissible evidence for quercetin as a potential molecule drug for the treatment of COVID-19 and DENGUE, but the findings have not been verified in actual patients, so further clinical drug trials are needed.


Subject(s)
COVID-19/drug therapy , Dengue Virus/chemistry , Dengue/drug therapy , Quercetin/chemistry , SARS-CoV-2/chemistry , COVID-19/complications , COVID-19/genetics , COVID-19/virology , Chemokine CCL2/chemistry , Chemokine CCL2/drug effects , Chemokine CCL2/genetics , Coinfection/drug therapy , Coinfection/genetics , Coinfection/virology , Dengue/complications , Dengue/genetics , Dengue/virology , Dengue Virus/drug effects , Humans , Interleukin-17/genetics , Interleukin-8/chemistry , Interleukin-8/drug effects , Interleukin-8/genetics , NF-kappa B/drug effects , NF-kappa B/genetics , Protein Interaction Maps/drug effects , Quercetin/therapeutic use , SARS-CoV-2/drug effects , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/chemistry , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/genetics
5.
Beni Suef Univ J Basic Appl Sci ; 10(1): 21, 2021.
Article in English | MEDLINE | ID: covidwho-1158236

ABSTRACT

BACKGROUND: The world pandemic COVID-19 caused by SARS-CoV-2 is currently claiming thousands of lives. Flavonoids abundantly present in the fruits and vegetables, especially quercetin, are shown to have antiviral activities. MAIN TEXT: This paper reviews the capability of the plant flavonoid quercetin to fight the novel coronavirus and the possibility for drug development based on this. The mode of action explaining the known pathways through which this molecule succeeds in the antiviral activity, action of quercetin on SARS-CoV-2 main protease 3CLpro, antiviral activities of its derivatives on human viruses, effect of combination of zinc co-factor along with quercetin in the COVID-19 treatment, and the regulation of miRNA genes involved in the viral pathogenesis are discussed. Proof for this concept is provided following the virtual screening using ten key enzymes of SARS-CoV-2 and assessing their interactions. Active residues in the 3D structures have been predicted using CASTp and were docked against quercetin. Key proteins 3CLpro, spike glycoprotein/ human ACE2-BOAT1 complex, RNA-dependent RNA polymerase, main peptidase, spike glycoprotein, RNA replicase, RNA binding protein, papain-like protease, SARS papain-like protease/ deubiquitinase, and complex of main peptidase with an additional Ala at the N-terminus of each protomer, have shown the binding energies ranging between - 6.71 and - 3.37 kcal/ Mol, showing that quercetin is a potential drug candidate inhibiting multiple SARS-CoV-2 enzymes. CONCLUSION: The antiviral properties of flavonoid and the molecular mechanisms involved are reviewed. Further, proof for this concept is given by docking of key proteins from SARS-CoV-2 with quercetin.

6.
Pharmaceuticals (Basel) ; 14(3)2021 Mar 09.
Article in English | MEDLINE | ID: covidwho-1143552

ABSTRACT

Although death in malaria is attributed to cerebrovascular blockage and anaemia, overwhelming cytokine production can contribute to the severity of the disease. Therefore, mitigation of dysregulated inflammatory signalling may provide further benefit for malaria treatment. Quercetin (3,3',4',5,7-pentahydroxyflavone) is known to inhibit glycogen synthase kinase-3ß (GSK3ß), a potent regulator of both pro- and anti-inflammatory effects. Quercetin is therefore a potential therapeutic to modulate the imbalanced cytokine production during malarial infection. Anti-malarial effects of quercetin were evaluated in murine models of severe and cerebral malaria using Plasmodium berghei NK65 and ANKA strains, respectively. Western blotting and analysis of cytokines were carried out to determine the GSK3ß-mediated cytokine-modulating effects of quercetin in infected animals. Quercetin (25 mg/kg BW) treatment in P. berghei NK65-infected animals resulted in 60.7 ± 2.4% suppression of parasitaemia and significantly decreased serum levels of TNF-α and IFN-γ, whilst levels of IL-10 and IL-4 were elevated significantly. Western analysis revealed that pGSK3ß (Ser9) increased 2.7-fold in the liver of quercetin-treated NK65-infected animals. Treatment of P. berghei ANKA-infected mice with quercetin (15 mg/kg BW) increased (2.3-fold) pGSK3ß (Ser9) in the brains of infected animals. Quercetin is a potential plant-derived therapeutic for malaria on the basis that it can elicit anti-malarial and GSK3ß-mediated cytokine-modulating effects.

7.
Biomolecules ; 11(1)2020 12 24.
Article in English | MEDLINE | ID: covidwho-1067683

ABSTRACT

The medical burden caused by respiratory manifestations of influenza virus (IV) outbreak as an infectious respiratory disease is so great that governments in both developed and developing countries have allocated significant national budget toward the development of strategies for prevention, control, and treatment of this infection, which is seemingly common and treatable, but can be deadly. Frequent mutations in its genome structure often result in resistance to standard medications. Thus, new generations of treatments are critical to combat this ever-evolving infection. Plant materials and active compounds have been tested for many years, including, more recently, active compounds like flavonoids. Quercetin is a compound belonging to the flavonols class and has shown therapeutic effects against influenza virus. The focus of this review includes viral pathogenesis as well as the application of quercetin and its derivatives as a complementary therapy in controlling influenza and its related symptoms based on the targets. We also touch on the potential of this class of compounds for treatment of SARS-COV-2, the cause of new pandemic.


Subject(s)
COVID-19 , Disease Outbreaks , Influenza A virus/metabolism , Influenza, Human , Quercetin/therapeutic use , SARS-CoV-2/metabolism , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/metabolism , Humans , Influenza, Human/drug therapy , Influenza, Human/epidemiology , Influenza, Human/metabolism
8.
PLoS One ; 16(1): e0245209, 2021.
Article in English | MEDLINE | ID: covidwho-1067409

ABSTRACT

Kidneys are one of the targets for SARS-CoV-2, it is reported that up to 36% of patients with SARS-CoV-2 infection would develop into acute kidney injury (AKI). AKI is associated with high mortality in the clinical setting and contributes to the transition of AKI to chronic kidney disease (CKD). Up to date, the underlying mechanisms are obscure and there is no effective and specific treatment for COVID-19-induced AKI. In the present study, we investigated the mechanisms and interactions between Quercetin and SARS-CoV-2 targets proteins by using network pharmacology and molecular docking. The renal protective effects of Quercetin on COVID-19-induced AKI may be associated with the blockade of the activation of inflammatory, cell apoptosis-related signaling pathways. Quercetin may also serve as SARS-CoV-2 inhibitor by binding with the active sites of SARS-CoV-2 main protease 3CL and ACE2, therefore suppressing the functions of the proteins to cut the viral life cycle. In conclusion, Quercetin may be a novel therapeutic agent for COVID-19-induced AKI. Inhibition of inflammatory, cell apoptosis-related signaling pathways may be the critical mechanisms by which Quercetin protects kidney from SARS-CoV-2 injury.


Subject(s)
Acute Kidney Injury/drug therapy , Acute Kidney Injury/virology , COVID-19/drug therapy , COVID-19/physiopathology , Quercetin/pharmacology , Databases, Factual , Databases, Genetic , Humans , Molecular Docking Simulation , Protein Interaction Mapping/methods , Protein Interaction Maps , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
9.
J Inflamm (Lond) ; 18(1): 3, 2021 Jan 28.
Article in English | MEDLINE | ID: covidwho-1054824

ABSTRACT

SARS-CoV-2 is a betacoronavirus causing severe inflammatory pneumonia, so that excessive inflammation is considered a risk factor for the disease. According to reports, cytokine storm is strongly responsible for death in such patients. Some of the consequences of severe inflammation and cytokine storms include acute respiratory distress syndrome, acute lung injury, and multiple organ dysfunction syndromes. Phylogenetic findings show more similarity of the SARS-CoV-2 virus with bat coronaviruses, and less with SARS-CoV. Quercetin is a carbohydrate-free flavonoid that is the most abundant flavonoid in vegetables and fruits and has been the most studied to determine the biological effects of flavonoids. Inflammasomes are cytosolic multi-protein complexes assembling in response to cytosolic PAMP and DAMPs, whose function is to generate active forms of cytokines IL-1ß and IL-18. Activation or inhibition of the NLRP3 inflammasome is affected by regulators such as TXNIP, SIRT1 and NRF2. Quercetin suppresses the NLRP3 inflammasome by affecting these regulators. Quercetin, as an anti-inflammatory, antioxidant, analgesic and inflammatory compound, is probably a potential treatment for severe inflammation and one of the main life-threatening conditions in patients with COVID-19.

10.
Biosci Rep ; 41(1)2021 01 29.
Article in English | MEDLINE | ID: covidwho-1043444

ABSTRACT

OBJECTIVE: ´Three formulas and three medicines,' namely, Jinhua Qinggan Granule, Lianhua Qingwen Capsule, Xuebijing Injection, Qingfei Paidu Decoction, HuaShi BaiDu Formula, and XuanFei BaiDu Granule, were proven to be effective for coronavirus disease 2019 (COVID-19) treatment. The present study aimed to identify the active chemical constituents of this traditional Chinese medicine (TCM) and investigate their mechanisms through interleukin-6 (IL-6) integrating network pharmacological approaches. METHODS: We collected the compounds from all herbal ingredients of the previously mentioned TCM, but those that could down-regulate IL-6 were screened through the network pharmacology approach. Then, we modeled molecular docking to evaluate the binding affinity between compounds and IL-6. Furthermore, we analyzed the biological processes and pathways of compounds. Finally, we screened out the core genes of compounds through the construction of the protein-protein interaction network and the excavation of gene clusters of compounds. RESULTS: The network pharmacology research showed that TCM could decrease IL-6 using several compounds, such as quercetin, ursolic acid, luteolin, and rutin. Molecular docking results showed that the molecular binding affinity with IL-6 of all compounds except γ-aminobutyric acid was < -5.0 kJ/mol, indicating the potential of numerous active compounds in TCM to directly interact with IL-6, leading to an anti-inflammation effect. Finally, Cytoscape 3.7.2 was used to topologize the biological processes and pathways of compounds, revealing potential mechanisms for COVID-19 treatment. CONCLUSION: These results indicated the positive effect of TCM on the prevention and rehabilitation of COVID-19 in at-risk people. Quercetin, ursolic acid, luteolin, and rutin could inhibit COVID-19 by down-regulating IL-6.


Subject(s)
Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , Drugs, Chinese Herbal/pharmacology , Interleukin-6/immunology , Anti-Inflammatory Agents/chemistry , COVID-19/immunology , Drug Discovery , Drugs, Chinese Herbal/chemistry , Humans , Interleukin-6/antagonists & inhibitors , Luteolin/analysis , Luteolin/pharmacology , Medicine, Chinese Traditional , Molecular Docking Simulation , Protein Interaction Maps/drug effects , Quercetin/analysis , Quercetin/pharmacology , Rutin/analysis , Rutin/pharmacology , Triterpenes/analysis , Triterpenes/pharmacology
12.
Molecules ; 25(23)2020 Dec 07.
Article in English | MEDLINE | ID: covidwho-966360

ABSTRACT

The inflammatory mediator and oxidant agent storm caused by the SARS-CoV-2 infection has been strongly associated with the failure of vital organs observed in critically ill patients with coronavirus disease 2019 (COVID-19) and the death of thousands of infected people around the world. Acute kidney injury (AKI) is a common renal disorder characterized by a sudden and sustained decrease in renal function with a critical influence on poor prognosis and lethal clinical outcomes of various etiologies, including some viral infection diseases. It is known that oxidative stress and inflammation play key roles in the pathogenesis and development of AKI. Quercetin is a natural substance that has multiple pharmacological properties, such as anti-inflammatory action, and is used as a dietary supplement. There is evidence of the anti-coronavirus activities of this compound, including against the target SARS-CoV-2 3CLpro. The ability to inhibit coronavirus and its inflammatory processes is strongly desired in a new drug for the treatment of COVID-19. Therefore, in this review, the dual effect of quercetin is discussed from a mechanistic perspective in relation to AKI kidney injury and its nephroprotective potential to SARS-CoV-2 patients.


Subject(s)
Acute Kidney Injury/drug therapy , COVID-19/complications , Quercetin/pharmacology , Acute Kidney Injury/etiology , Animals , COVID-19/drug therapy , COVID-19/epidemiology , Humans , Morbidity , Protective Agents/pharmacology , Protective Agents/therapeutic use , Quercetin/therapeutic use
13.
Evid Based Complement Alternat Med ; 2020: 7493281, 2020.
Article in English | MEDLINE | ID: covidwho-913872

ABSTRACT

"Three formulas and three medicines," which include Jinhua Qinggan granule, Lianhua Qingwen capsule/granule, Xuebijing injection, Qingfei Paidu decoction, HuaShiBaiDu formula, and XuanFeiBaiDu granule, have been proven to be effective in curbing coronavirus disease 2019 (COVID-19), according to the State Administration of Traditional Chinese Medicine. The aims of this study were to identify the active components of "Three formulas and three medicines" that can be used to treat COVID-19, determine their mechanism of action via angiotensin-converting enzyme 2 (ACE2) by integrating network pharmacological approaches, and confirm the most effective components for COVID-19 treatment or prevention. We investigated all the compounds present in the aforementioned herbal ingredients. Compounds that could downregulate the transcription factors (TFs) of ACE2 and upregulate miRNAs of ACE2 were screened via a network pharmacology approach. Hepatocyte nuclear factor 4 alpha (HNF4A), peroxisome proliferator-activated receptor gamma (PPARG), hsa-miR-2113, and hsa-miR-421 were found to regulate ACE2. Several compounds, such as quercetin, decreased ACE2 expression by regulating the aforementioned TFs or miRNAs. After comparison with the compounds present in Glycyrrhiza Radix et Rhizoma, quercetin, glabridin, and gallic acid present in the herbal formulas and medicines were found to alter ACE2 expression. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to search for possible molecular mechanisms of these compounds. In conclusion, traditional Chinese medicine (TCM) plays a pivotal role in the prevention and treatment of COVID-19. Quercetin, glabridin, and gallic acid, the active components of recommended TCM formulas and medicines, can inhibit COVID-19 by downregulating ACE2.

14.
Phytomedicine ; 85: 153390, 2021 May.
Article in English | MEDLINE | ID: covidwho-912536

ABSTRACT

BACKGROUND: Shufeng Jiedu capsules (SFJDC), a patented herbal drug composed of eight medicinal plants, is used for the treatment of different viral respiratory tract infectious diseases. Based on its antiviral, anti-inflammatory and immunoregulatory activity in acute lung injury, SFJDC might be a promising candidate for the treatment of COVID-19. PURPOSE: To evaluate the antiviral and anti-inflammatory properties and to discover the mechanism of action of SFJDC as a potential drug for the treatment of COVID-19. Furthermore, the study should determine the clinical effectiveness of SFJDC for the treatment of COVID-19. DESIGN: We analyzed the antiviral and anti-inflammatory effects of SFJDC in a HCoV-229E mouse model on lung index, virus load in the lung, the release of cytokines, and on T- and B-lymphocytes. The mechanism of action was further investigated by network analysis. Additionally, we investigated data from a clinical pragmatic real-world study for patients with confirmed COVID-19, to evaluate the clinical effect of SFJDC and to determine the best time to start the treatment. RESULTS: SFJDC significantly reduced the virus load in the lung of HCoV-229E mice (from 1109.29 ± 696.75 to 0 ± 0 copies/ml), decreased inflammatory factors IL-6, IL-10, TNF-α, and IFN-γ in the lung, and increased the amount of CD4+ and CD8+ cells in the blood compared to the model group. Network analysis revealed that SFJDC reduces the activity of NFκB via several signaling pathways. Quercetin, wogonin, and polydatin bind directly to the main protease (Mpro) of SARS-CoV-2. Clinical data showed that SFJDC, added to standard antiviral therapy (AVD), significantly reduced the clinical recovery time of COVID-19 and fatigue (from 3.55 ± 4.09 to 1.19 ± 2.28 days) as well as cough (from 5.67 ± 5.64 to 3.47 ± 3.75) days compared to AVD alone. SFJDC therapy was significantly more effective when used within the first 8 days after the onset of symptoms. CONCLUSION: SFJDC might be a promising drug for the treatment of COVID-19, but large-scale randomized, double-blinded, placebo-controlled clinical trials are needed to complement the real-world evidence. It might be beneficial to start SFJDC treatment as early as possible in suspected cases of COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drugs, Chinese Herbal/therapeutic use , Adult , Animals , Anti-Inflammatory Agents , Coronavirus 229E, Human/drug effects , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Combinations , Female , Humans , Indoles/therapeutic use , Lopinavir/therapeutic use , Lung/virology , Male , Mice , Mice, Inbred BALB C , Middle Aged , Molecular Docking Simulation , NF-kappa B , Ritonavir/therapeutic use , SARS-CoV-2/drug effects , Signal Transduction , Viral Load
15.
Curr Mol Med ; 21(5): 385-391, 2021.
Article in English | MEDLINE | ID: covidwho-789058

ABSTRACT

COVID-19 is an emerging disease that is a major threat to the global community. The main challenge in this disease is the lack of proper or proven medication. The drugs used to treat this disease are only for symptomatic treatment. Studies of other coronaviruses, such as SARS and MERS, suggest that quercetin has sufficient potential to treat COVID-19. Previous studies have shown that quercetin reduces the entry of the virus into the cell by blocking the ACE2 receptor, as well as reducing the level of interleukin-6 in SARS and MERS patients. Therefore, the aim of this review was to scrutinize the potential of quercetin as a drug in the treatment of COVID-19 from a molecular perspective.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Quercetin/pharmacology , Antiviral Agents/therapeutic use , Cytokines/metabolism , Humans , Macrophages/drug effects , Macrophages/metabolism , Quercetin/biosynthesis , Quercetin/therapeutic use , Virus Internalization/drug effects
16.
Drug Dev Ind Pharm ; 46(8): 1345-1353, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-639745

ABSTRACT

PURPOSE: Huashi Baidu formula (HSBDF) was developed to treat the patients with severe COVID-19 in China. The purpose of this study was to explore its active compounds and demonstrate its mechanisms against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through network pharmacology and molecular docking. METHODS: All the components of HSBDF were retrieved from the pharmacology database of TCM system. The genes corresponding to the targets were retrieved using UniProt and GeneCards database. The herb-compound-target network was constructed by Cytoscape. The target protein-protein interaction network was built using STRING database. The core targets of HSBDF were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The main active compounds of HSBDF were docked with SARS-CoV-2 and angiotensin converting enzyme II (ACE2). RESULTS: Compound-target network mainly contained 178 compounds and 272 corresponding targets. Key targets contained MAPK3, MAPK8, TP53, CASP3, IL6, TNF, MAPK1, CCL2, PTGS2, etc. There were 522 GO items in GO enrichment analysis (p < .05) and 168 signaling pathways (p < .05) in KEGG, mainly including TNF signaling pathway, PI3K-Akt signaling pathway, NOD-like receptor signaling pathway, MAPK signaling pathway, and HIF-1 signaling pathway. The results of molecular docking showed that baicalein and quercetin were the top two compounds of HSBDF, which had high affinity with ACE2. CONCLUSION: Baicalein and quercetin in HSBDF may regulate multiple signaling pathways through ACE2, which might play a therapeutic role on COVID-19.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Molecular Docking Simulation/methods , Pharmacology, Clinical/methods , Pneumonia, Viral/drug therapy , Angiotensin-Converting Enzyme 2 , Betacoronavirus/chemistry , Betacoronavirus/genetics , COVID-19 , China , Databases, Factual , Gene Ontology , Gene Targeting , Genes, Viral/drug effects , Genes, Viral/genetics , Humans , Medicine, Chinese Traditional , Pandemics , Peptidyl-Dipeptidase A/drug effects , Peptidyl-Dipeptidase A/genetics , SARS-CoV-2 , Signal Transduction/drug effects , Signal Transduction/genetics
17.
Front Immunol ; 11: 1451, 2020.
Article in English | MEDLINE | ID: covidwho-637661

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) represents an emergent global threat which is straining worldwide healthcare capacity. As of May 27th, the disease caused by SARS-CoV-2 (COVID-19) has resulted in more than 340,000 deaths worldwide, with 100,000 deaths in the US alone. It is imperative to study and develop pharmacological treatments suitable for the prevention and treatment of COVID-19. Ascorbic acid is a crucial vitamin necessary for the correct functioning of the immune system. It plays a role in stress response and has shown promising results when administered to the critically ill. Quercetin is a well-known flavonoid whose antiviral properties have been investigated in numerous studies. There is evidence that vitamin C and quercetin co-administration exerts a synergistic antiviral action due to overlapping antiviral and immunomodulatory properties and the capacity of ascorbate to recycle quercetin, increasing its efficacy. Safe, cheap interventions which have a sound biological rationale should be prioritized for experimental use in the current context of a global health pandemic. We present the current evidence for the use of vitamin C and quercetin both for prophylaxis in high-risk populations and for the treatment of COVID-19 patients as an adjunct to promising pharmacological agents such as Remdesivir or convalescent plasma.


Subject(s)
Antiviral Agents/therapeutic use , Ascorbic Acid/therapeutic use , Betacoronavirus/physiology , Coronavirus Infections/prevention & control , Immunologic Factors/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pre-Exposure Prophylaxis/methods , Quercetin/therapeutic use , Animals , Antiviral Agents/adverse effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Synergism , Drug Therapy, Combination , Humans , Mice , Pneumonia, Viral/virology , Quercetin/adverse effects , Quercetin/chemistry , Quercetin/pharmacokinetics , SARS-CoV-2 , Virus Replication/drug effects
18.
J Biomol Struct Dyn ; 39(14): 5129-5136, 2021 09.
Article in English | MEDLINE | ID: covidwho-619732

ABSTRACT

SARS-CoV-2 or Coronavirus disease 19 (COVID-19) is a rapidly spreading, highly contagious, and sometimes fatal disease for which drug discovery and vaccine development are critical. SARS-CoV-2 papain-like protease (PLpro) was used to virtually screen 1697 clinical FDA-approved drugs. Among the top results expected to bind with SARS-CoV-2 PLpro strongly were three cell protectives and antioxidants (NAD+, quercitrin, and oxiglutatione), three antivirals (ritonavir, moroxydine, and zanamivir), two antimicrobials (doripenem and sulfaguanidine), two anticancer drugs, three benzimidazole anthelmintics, one antacid (famotidine), three anti-hypertensive ACE receptor blockers (candesartan, losartan, and valsartan) and other miscellaneous systemically or topically acting drugs. The binding patterns of these drugs were superior to the previously identified SARS CoV PLpro inhibitor, 6-mercaptopurine (6-MP), suggesting a potential for repurposing these drugs to treat COVID-19. The objective of drug repurposing is the rapid relocation of safe and approved drugs by bypassing the lengthy pharmacokinetic, toxicity, and preclinical phases. The ten drugs with the highest estimated docking scores with favorable pharmacokinetics were subjected to molecular dynamics (MD) simulations followed by molecular mechanics/generalized Born surface area (MM/GBSA) binding energy calculations. Phenformin, quercetin, and ritonavir all demonstrated prospective binding affinities for COVID-19 PLpro over 50 ns MD simulations, with binding energy values of -56.6, -40.9, and -37.6 kcal/mol, respectively. Energetic and structural analyses showed phenformin was more stable than quercetin and ritonavir. The list of the drugs provided herein constitutes a primer for clinical application in COVID-19 patients and guidance for further antiviral studies.Communicated by Ramaswamy H. Sarma.


Subject(s)
Anthelmintics , COVID-19 , Anti-Bacterial Agents , Antioxidants , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Drug Repositioning , Humans , Molecular Docking Simulation , Papain , Peptide Hydrolases , Prospective Studies , SARS-CoV-2
19.
Biomedicines ; 8(5)2020 May 21.
Article in English | MEDLINE | ID: covidwho-327186

ABSTRACT

Genes required for SARS-CoV-2 entry into human cells, ACE2 and FURIN, were employed as baits to build genomic-guided molecular maps of upstream regulatory elements, their expression and functions in the human body, and pathophysiologically relevant cell types. Repressors and activators of the ACE2 and FURIN genes were identified based on the analyses of gene silencing and overexpression experiments as well as relevant transgenic mouse models. Panels of repressors (VDR; GATA5; SFTPC; HIF1a) and activators (HMGA2; INSIG1; RUNX1; HNF4a; JNK1/c-FOS) were then employed to identify existing drugs manifesting in their effects on gene expression signatures of potential coronavirus infection mitigation agents. Using this strategy, vitamin D and quercetin have been identified as putative 2019 coronavirus disease (COVID-19) mitigation agents. Quercetin has been identified as one of top-scoring candidate therapeutics in the supercomputer SUMMIT drug-docking screen and Gene Set Enrichment Analyses (GSEA) of expression profiling experiments (EPEs), indicating that highly structurally similar quercetin, luteolin, and eriodictyol could serve as scaffolds for the development of efficient inhibitors of SARS-CoV-2 infection. In agreement with this notion, quercetin alters the expression of 98 of 332 (30%) of human genes encoding protein targets of SARS-CoV-2, thus potentially interfering with functions of 23 of 27 (85%) of the SARS-CoV-2 viral proteins in human cells. Similarly, Vitamin D may interfere with functions of 19 of 27 (70%) of the SARS-CoV-2 proteins by altering expression of 84 of 332 (25%) of human genes encoding protein targets of SARS-CoV-2. Considering the potential effects of both quercetin and vitamin D, the inference could be made that functions of 25 of 27 (93%) of SARS-CoV-2 proteins in human cells may be altered. GSEA and EPEs identify multiple drugs, smoking, and many disease conditions that appear to act as putative coronavirus infection-promoting agents. Discordant patterns of testosterone versus estradiol impacts on SARS-CoV-2 targets suggest a plausible molecular explanation of the apparently higher male mortality during the coronavirus pandemic. Estradiol, in contrast with testosterone, affects the expression of the majority of human genes (203 of 332; 61%) encoding SARS-CoV-2 targets, thus potentially interfering with functions of 26 of 27 SARS-CoV-2 viral proteins. A hypothetical tripartite combination consisting of quercetin/vitamin D/estradiol may affect expression of 244 of 332 (73%) human genes encoding SARS-CoV-2 targets. Of major concern is the ACE2 and FURIN expression in many human cells and tissues, including immune cells, suggesting that SARS-CoV-2 may infect a broad range of cellular targets in the human body. Infection of immune cells may cause immunosuppression, long-term persistence of the virus, and spread of the virus to secondary targets. Present analyses and numerous observational studies indicate that age-associated vitamin D deficiency may contribute to the high mortality of older adults and the elderly. Immediate availability for targeted experimental and clinical interrogations of potential COVID-19 pandemic mitigation agents, namely vitamin D and quercetin, as well as of the highly selective (Ki, 600 pm) intrinsically specific FURIN inhibitor (a1-antitrypsin Portland (a1-PDX), is considered an encouraging factor. Observations reported in this contribution are intended to facilitate follow-up targeted experimental studies and, if warranted, randomized clinical trials to identify and validate therapeutically viable interventions to combat the COVID-19 pandemic. Specifically, gene expression profiles of vitamin D and quercetin activities and their established safety records as over-the-counter medicinal substances strongly argue that they may represent viable candidates for further considerations of their potential utility as COVID-19 pandemic mitigation agents. In line with the results of present analyses, a randomized interventional clinical trial evaluating effects of estradiol on severity of the coronavirus infection in COVID19+ and presumptive COVID19+ patients and two interventional randomized clinical trials evaluating effects of vitamin D on prevention and treatment of COVID-19 were listed on the ClinicalTrials.gov website.

20.
Virus Res ; 284: 197989, 2020 07 15.
Article in English | MEDLINE | ID: covidwho-141651

ABSTRACT

Coronaviruses are responsible for a growing economic, social and mortality burden, as the causative agent of diseases such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), avian infectious bronchitis virus (IBV) and COVID-19. However, there is a lack of effective antiviral agents for many coronavirus strains. Naturally existing compounds provide a wealth of chemical diversity, including antiviral activity, and thus may have utility as therapeutic agents against coronaviral infections. The PubMed database was searched for papers including the keywords coronavirus, SARS or MERS, as well as traditional medicine, herbal, remedy or plants, with 55 primary research articles identified. The overwhelming majority of publications focussed on polar compounds. Compounds that show promise for the inhibition of coronavirus in humans include scutellarein, silvestrol, tryptanthrin, saikosaponin B2, quercetin, myricetin, caffeic acid, psoralidin, isobavachalcone, and lectins such as griffithsin. Other compounds such as lycorine may be suitable if a therapeutic level of antiviral activity can be achieved without exceeding toxic plasma concentrations. It was noted that the most promising small molecules identified as coronavirus inhibitors contained a conjugated fused ring structure with the majority being classified as being polyphenols.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Phytochemicals/therapeutic use , Pneumonia, Viral/drug therapy , Animals , COVID-19 , Coronavirus, Feline/drug effects , Humans , Infectious bronchitis virus/drug effects , Middle East Respiratory Syndrome Coronavirus/drug effects , Pandemics , Porcine epidemic diarrhea virus/drug effects , SARS Virus/drug effects , SARS-CoV-2
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