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1.
Curr Drug Targets ; 23(4): 420-436, 2022.
Article in English | MEDLINE | ID: covidwho-1799012

ABSTRACT

Chrysin (a flavonoid) has shown various promising pharmacological activities viz. anticancer, anti-diabetic, immune-modulation, antidepressant, and anti-asthmatic. Additionally, it exhibited potential protective effects against various toxins on different organs like the liver, brain, kidney, and heart. A multitude of studies have been conducted to explore the possible targets for its possible mechanism of action. However, its therapeutic applications have been limited due to its poor oral bioavailability. The major reason for its poor bioavailability is its extensive first-pass metabolism. A critical review of the pharmacological properties of chrysin and its associated molecular targets has not been discussed as yet comprehensively. Therefore, the emphasis of the present work is to provide an in-depth understanding of molecular targets accountable for the pharmacological actions of chrysin. Moreover, a schematic diagram was made for the first time to represent the comprehensive pharmacokinetic properties of chrysin, which helps to understand the biopharmaceutical aspect for its successful delivery. An in-depth understanding of the biopharmaceutical properties of chrysin will help in adopting a suitable formulation approach to overcome poor oral bioavailability. Additionally, it facilitates to study the possible pharmacokinetic interactions of chrysin with other drugs. Hence, we found that chrysin is a miraculous natural agent with myriad therapeutic properties, and its benefit can be exploited with an in-depth understanding of molecular targets, pharmacological actions, and biopharmaceutical attributes.


Subject(s)
Biological Products , Flavonoids , Biological Availability , Flavonoids/pharmacology , Flavonoids/therapeutic use , Humans , Pharmaceutical Preparations
2.
J Mol Model ; 28(4): 82, 2022 Mar 05.
Article in English | MEDLINE | ID: covidwho-1729317

ABSTRACT

Novel SARS coronavirus or SARS-CoV-2 is a novel coronavirus that was identified and spread from Wuhan in 2019. On January 30th, the World Health Organization declared the coronavirus outbreak as a Global Public Health Emergency. Although Remdesivir and Molnupiravir are FDA-approved drugs for COVID-19, finding new efficient and low-cost antiviral drugs against COVID-19 for applying in more countries can still be helpful. One of the potential sources for finding new and low-cost drugs is the herbal compounds in addition to repurposing FDA-approved drugs. So, in this study, we focused on finding effective drug candidates against COVID-19 based on the computational approaches. As ACE2 serves as a critical receptor for cell entry of this virus. Inhibiting the binding site of SARS-CoV-2 on human ACE2 provides a promising therapeutic approach for developing drugs against SARS-CoV-2. Herein, we applied a bioinformatics approach to identify possible potential inhibitors of SARS-CoV-2. A library of FDA-approved compounds and five natural compounds was screened using Smina docking. Top-docking compounds are then applied in Molecular Dynamics (MD) simulation to assess the stability of ACE2-inhibitor complexes. Results indicate that Luteolin and Chrysin represent high conformation stability with ACE2 during 120 ns of Molecular Dynamics simulation. The binding free energies of Luteolin and Chrysin were calculated by the Molecular Mechanics/Poisson-Boltzmann Surface Area method (MM/PBSA) which confirmed the relative binding free energy of these drugs to ACE2 in favor of the effective binding. So, Luteolin and Chrysin could sufficiently interact with ACE2 and block the Spike binding pocket of ACE2 and can be a potential inhibitor against the binding of SARS-CoV-2 to ACE2 receptor which is an early stage of infection. Luteolin and Chrysin could be suggestive as beneficial compounds for preventing or reducing SARS-CoV-2 transmission and infection which need experimental work to prove.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/prevention & control , Flavonoids/pharmacology , Luteolin/pharmacology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/metabolism , COVID-19/transmission , Drug Repositioning , Flavonoids/therapeutic use , Humans , Luteolin/therapeutic use , Molecular Dynamics Simulation , Protein Binding
3.
Molecules ; 27(5)2022 Mar 01.
Article in English | MEDLINE | ID: covidwho-1715570

ABSTRACT

A new flavonoid, Jusanin, (1) has been isolated from the aerial parts of Artemisia commutata. The chemical structure of Jusanin has been elucidated using 1D, 2D NMR, and HR-Ms spectroscopic methods to be 5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone. Being new in nature, the inhibition potential of 1 has been estimated against SARS-CoV-2 using different in silico techniques. Firstly, molecular similarity and fingerprint studies have been conducted for Jusanin against co-crystallized ligands of eight different SARS-CoV-2 essential proteins. The studies indicated the similarity between 1 and X77, the co-crystallized ligand SARS-CoV-2 main protease (PDB ID: 6W63). To confirm the obtained results, a DFT study was carried out and indicated the similarity of (total energy, HOMO, LUMO, gap energy, and dipole moment) between 1 and X77. Accordingly, molecular docking studies of 1 against the target enzyme have been achieved and showed that 1 bonded correctly in the protein's active site with a binding energy of -19.54 Kcal/mol. Additionally, in silico ADMET in addition to the toxicity evaluation of Jusanin against seven models have been preceded and indicated the general safety and the likeness of Jusanin to be a drug. Finally, molecular dynamics simulation studies were applied to investigate the dynamic behavior of the Mpro-Jusanin complex and confirmed the correct binding at 100 ns. In addition to 1, three other metabolites have been isolated and identified to be сapillartemisin A (2), methyl-3-[S-hydroxyprenyl]-cumarate (3), and ß-sitosterol (4).


Subject(s)
Artemisia/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Flavonoids/chemistry , SARS-CoV-2/enzymology , Animals , Artemisia/metabolism , Binding Sites , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Coronavirus 3C Proteases/metabolism , Density Functional Theory , Flavonoids/isolation & purification , Flavonoids/metabolism , Flavonoids/pharmacology , Humans , Lethal Dose 50 , Male , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , Rats , SARS-CoV-2/isolation & purification , Skin/drug effects , Skin/pathology
4.
Molecules ; 27(5)2022 Mar 01.
Article in English | MEDLINE | ID: covidwho-1715569

ABSTRACT

COVID-19 is an endothelial disease. All the major comorbidities that increase the risk for severe SARS-CoV-2 infection and severe COVID-19 including old age, obesity, diabetes, hypertension, respiratory disease, compromised immune system, coronary artery disease or heart failure are associated with dysfunctional endothelium. Genetics and environmental factors (epigenetics) are major risk factors for endothelial dysfunction. Individuals with metabolic syndrome are at increased risk for severe SARS-CoV-2 infection and poor COVID-19 outcomes and higher risk of mortality. Old age is a non-modifiable risk factor. All other risk factors are modifiable. This review also identifies dietary risk factors for endothelial dysfunction. Potential dietary preventions that address endothelial dysfunction and its sequelae may have an important role in preventing SARS-CoV-2 infection severity and are key factors for future research to address. This review presents some dietary bioactives with demonstrated efficacy against dysfunctional endothelial cells. This review also covers dietary bioactives with efficacy against SARS-CoV-2 infection. Dietary bioactive compounds that prevent endothelial dysfunction and its sequelae, especially in the gastrointestinal tract, will result in more effective prevention of SARS-CoV-2 variant infection severity and are key factors for future food research to address.


Subject(s)
Endothelium/drug effects , Flavonoids/pharmacology , Functional Food/analysis , SARS-CoV-2/drug effects , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Endothelium/metabolism , Flavonoids/metabolism , Flavonoids/therapeutic use , Humans , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , Risk Factors , SARS-CoV-2/isolation & purification , Stilbenes/pharmacology , Stilbenes/therapeutic use , Terpenes/pharmacology , Terpenes/therapeutic use
5.
Molecules ; 27(4)2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1715568

ABSTRACT

Baicalin is a major active ingredient of traditional Chinese medicine Scutellaria baicalensis, and has been shown to have antiviral, anti-inflammatory, and antitumor activities. However, the protein targets of baicalin have remained unclear. Herein, a chemical proteomics strategy was developed by combining baicalin-functionalized magnetic nanoparticles (BCL-N3@MNPs) and quantitative mass spectrometry to identify the target proteins of baicalin. Bioinformatics analysis with the use of Gene Ontology, STRING and Ingenuity Pathway Analysis, was performed to annotate the biological functions and the associated signaling pathways of the baicalin targeting proteins. Fourteen proteins in human embryonic kidney cells were identified to interact with baicalin with various binding affinities. Bioinformatics analysis revealed these proteins are mainly ATP-binding and/or ATPase activity proteins, such as CKB, HSP86, HSP70-1, HSP90, ATPSF1ß and ACTG1, and highly associated with the regulation of the role of PKR in interferon induction and the antiviral response signaling pathway (P = 10-6), PI3K/AKT signaling pathway (P = 10-5) and eNOS signaling pathway (P = 10-4). The results show that baicalin exerts multiply pharmacological functions, such as antiviral, anti-inflammatory, antitumor, and antioxidant functions, through regulating the PKR and PI3K/AKT/eNOS signaling pathways by targeting ATP-binding and ATPase activity proteins. These findings provide a fundamental insight into further studies on the mechanism of action of baicalin.


Subject(s)
Flavonoids/pharmacology , HSP70 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Nitric Oxide Synthase Type III/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Animals , Dose-Response Relationship, Drug , Flavonoids/administration & dosage , Flavonoids/chemistry , Humans , Magnetite Nanoparticles/chemistry , Magnetite Nanoparticles/ultrastructure , Protein Interaction Mapping
6.
Phytother Res ; 36(1): 266-278, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1640375

ABSTRACT

Quercetin, widely distributed in fruits and vegetables, is a flavonoid known for its antioxidant, antiviral, antimicrobial, and antiinflammatory properties. Several studies highlight the potential use of quercetin as an antiviral, due to its ability to inhibit the initial stages of virus infection, to be able to interact with proteases important for viral replication, and to reduce inflammation caused by infection. Quercetin could also be useful in combination with other drugs to potentially enhance the effects or synergistically interact with them, in order to reduce their side effects and related toxicity. Since there is no comprehensive compilation about antiviral activities of quercetin and derivates, the aim of this review is providing a summary of their antiviral activities on a set of human viral infections along with mechanisms of action. Thus, the following family of viruses are examined: Flaviviridae, Herpesviridae, Orthomyxoviridae, Coronaviridae, Hepadnaviridae, Retroviridae, Picornaviridae, Pneumoviridae, and Filoviridae.


Subject(s)
Antiviral Agents , Virus Diseases , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Flavonoids/pharmacology , Humans , Quercetin/pharmacology , Quercetin/therapeutic use , Virus Diseases/drug therapy , Virus Replication
7.
Comput Biol Med ; 142: 105231, 2022 03.
Article in English | MEDLINE | ID: covidwho-1616436

ABSTRACT

The advent and persistence of the Severe Acute Respiratory Syndrome Coronavirus - 2 (SARS-CoV-2)-induced Coronavirus Disease (COVID-19) pandemic since December 2019 has created the largest public health emergency in over a century. Despite the administration of multiple vaccines across the globe, there continues to be a lack of approved efficacious non-prophylactic interventions for the disease. Flavonoids are a class of phytochemicals with historically established antiviral, anti-inflammatory and antioxidative properties that are effective against cancers, type 2 diabetes mellitus, and even other human coronaviruses. To identify the most promising bioactive flavonoids against the SARS-CoV-2, this article screened a virtual library of 46 bioactive flavonoids against three promising targets in the SARS-CoV-2 life cycle: human TMPRSS2 protein, 3CLpro, and PLpro. By examining the effects of glycosylation and other structural-activity relationships, the presence of sugar moiety in flavonoids significantly reduces its binding energy. It increases the solubility of flavonoids leading to reduced toxicity and higher bioavailability. Through protein-ligand contact profiling, it was concluded that naringin formed more hydrogen bonds with TMPRSS2 and 3CLpro. In contrast, hesperidin formed a more significant number of hydrogen bonds with PLpro. These observations were complimented by the 100 ns molecular dynamics simulation and binding free energy analysis, which showed a considerable stability of docked bioflavonoids in the active site of SARS-CoV-2 target proteins. Finally, the binding affinity and stability of the selected docked complexes were compared with the reference ligands (camostat for TMPRSS2, GC376 for 3CLpro, and GRL0617 for PLpro) that strongly inhibit their respective SARS-COV-2 targets. Overall analysis revealed that the selected flavonoids could be potential therapeutic agents against SARS-CoV-2. Naringin showed better affinity and stability for TMPRSS2 and 3CLpro, whereas hesperidin showed a better binding relationship and stability for PLpro.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Aniline Compounds , Animals , Benzamides , Flavonoids/pharmacology , Humans , Life Cycle Stages , Molecular Docking Simulation , Naphthalenes , SARS-CoV-2
8.
Molecules ; 27(1)2021 Dec 30.
Article in English | MEDLINE | ID: covidwho-1580564

ABSTRACT

The COVID-19 pandemic has caused millions of fatalities since 2019. Despite the availability of vaccines for this disease, new strains are causing rapid ailment and are a continuous threat to vaccine efficacy. Here, molecular docking and simulations identify strong inhibitors of the allosteric site of the SARS-CoV-2 virus RNA dependent RNA polymerase (RdRp). More than one hundred different flavonoids were docked with the SARS-CoV-2 RdRp allosteric site through computational screening. The three top hits were Naringoside, Myricetin and Aureusidin 4,6-diglucoside. Simulation analyses confirmed that they are in constant contact during the simulation time course and have strong association with the enzyme's allosteric site. Absorption, distribution, metabolism, excretion and toxicity (ADMET) data provided medicinal information of these top three hits. They had good human intestinal absorption (HIA) concentrations and were non-toxic. Due to high mutation rates in the active sites of the viral enzyme, these new allosteric site inhibitors offer opportunities to drug SARS-CoV-2 RdRp. These results provide new information for the design of novel allosteric inhibitors against SARS-CoV-2 RdRp.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Computational Biology/methods , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Drug Evaluation, Preclinical , Flavonoids/pharmacology , SARS-CoV-2/enzymology , Allosteric Site , COVID-19/virology , Catalytic Domain , Drug Design , Humans , Intestinal Absorption , Molecular Docking Simulation
9.
Curr Pharm Biotechnol ; 22(15): 2054-2070, 2021.
Article in English | MEDLINE | ID: covidwho-1551391

ABSTRACT

BACKGROUND: In December 2019, an outbreak of a pneumonia-like illness, Corona virus disease 2019 (COVID-19), originating from Wuhan, China, was linked to novel coronavirus, now termed SARS-CoV-2. Unfortunately, no effective drugs or vaccines have been reported yet. The main protease (MPRO) remains the most validated pharmacological target for the design and discovery of inhibitors. OBJECTIVE: The purpose of the study was to find a prospective natural scaffold as an inhibitor for MPRO main protease in SARS-CoV-2 and compare it with repurposed antiviral drugs lopinavir and nelfinavir. METHODS: Natural compound libraries were screened for potential scaffold against MPRO main protease. Molecular dynamics simulation, MM-GBSA and principal component analyses of enzyme- ligand complexes were carried out with the top-ranking hits and compared with the repurposed antiviral drugs lopinavir and nelfinavir. RESULTS: The structure-based virtual screening indicated phenylbenzopyrone of flavonoids as one of the top-ranking scaffolds that have the potential to inhibit the main protease with the Oglycosidic form, performing better than the corresponding aglyconic form. Simulation studies indicated that glycosidic form of flavonoid is a more suitable inhibitor with compounds rutin, procyanidin B6, baicalin and galloylquercetin, demonstrating high affinity and stability, and rutin, emerging as one of the best candidate compounds. Interestingly, rutin was reported to have inhibitory activity against similar protease (3Cprotease of enterovirus A71) and implicated in lung fibrosis. CONCLUSION: The present study on flavonoids, possessing a potential scaffold for inhibiting main protease activity for all betacoronavirus is an attempt to provide new and safe drug leads within a reasonably short period.


Subject(s)
Antiviral Agents , Coronavirus 3C Proteases/antagonists & inhibitors , Flavonoids , Protease Inhibitors , SARS-CoV-2/enzymology , Antiviral Agents/pharmacology , COVID-19 , Flavonoids/pharmacology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Prospective Studies , Protease Inhibitors/pharmacology , SARS-CoV-2/physiology , Virus Replication/drug effects
10.
Int J Mol Sci ; 22(22)2021 Nov 09.
Article in English | MEDLINE | ID: covidwho-1512384

ABSTRACT

Coronaviruses cause diseases in humans and livestock. The SARS-CoV-2 is infecting millions of human beings, with high morbidity and mortality worldwide. The main protease (Mpro) of coronavirus plays a pivotal role in viral replication and transcription, which, in theory, is an attractive drug target for antiviral drug development. It has been extensively discussed whether Xanthohumol is able to help COVID-19 patients. Here, we report that Xanthohumol, a small molecule in clinical trials from hops (Humulus lupulus), was a potent pan-inhibitor for various coronaviruses by targeting Mpro, for example, betacoronavirus SARS-CoV-2 (IC50 value of 1.53 µM), and alphacoronavirus PEDV (IC50 value of 7.51 µM). Xanthohumol inhibited Mpro activities in the enzymatical assays, while pretreatment with Xanthohumol restricted the SARS-CoV-2 and PEDV replication in Vero-E6 cells. Therefore, Xanthohumol is a potent pan-inhibitor of coronaviruses and an excellent lead compound for further drug development.


Subject(s)
3C Viral Proteases/antagonists & inhibitors , Flavonoids/chemistry , Propiophenones/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , 3C Viral Proteases/chemistry , 3C Viral Proteases/metabolism , Alphacoronavirus/enzymology , Alphacoronavirus/physiology , Amino Acid Sequence , Animals , Binding Sites , Biological Products/chemistry , Biological Products/metabolism , Biological Products/pharmacology , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Catalytic Domain , Chlorocebus aethiops , Coronavirus/enzymology , Coronavirus/physiology , Flavonoids/metabolism , Flavonoids/pharmacology , Flavonoids/therapeutic use , Humans , Molecular Docking Simulation , Propiophenones/metabolism , Propiophenones/pharmacology , Propiophenones/therapeutic use , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , SARS-CoV-2/isolation & purification , Sequence Alignment , Vero Cells , Virus Replication/drug effects
11.
Molecules ; 26(21)2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1488677

ABSTRACT

Flavonoids are important secondary plant metabolites that have been studied for a long time for their therapeutic potential in inflammatory diseases because of their cytokine-modulatory effects. Five flavonoid aglycones were isolated and identified from the hydrolyzed aqueous methanol extracts of Anastatica hierochuntica L., Citrus reticulata Blanco, and Kickxia aegyptiaca (L.) Nabelek. They were identified as taxifolin (1), pectolinarigenin (2), tangeretin (3), gardenin B (4), and hispidulin (5). These structures were elucidated based on chromatographic and spectral analysis. In this study, molecular docking studies were carried out for the isolated and identified compounds against SARS-CoV-2 main protease (Mpro) compared to the co-crystallized inhibitor of SARS-CoV-2 Mpro (α-ketoamide inhibitor (KI), IC50 = 66.72 µg/mL) as a reference standard. Moreover, in vitro screening against SARS-CoV-2 was evaluated. Compounds 2 and 3 showed the highest virus inhibition with IC50 12.4 and 2.5 µg/mL, respectively. Our findings recommend further advanced in vitro and in vivo studies of the examined isolated flavonoids, especially pectolinarigenin (2), tangeretin (3), and gardenin B (4), either alone or in combination with each other to identify a promising lead to target SARS-CoV-2 effectively. This is the first report of the activity of these compounds against SARS-CoV-2.


Subject(s)
Coronavirus 3C Proteases/drug effects , Flavones/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/pharmacology , Brassicaceae/metabolism , COVID-19/drug therapy , Chlorocebus aethiops , Chromones/pharmacology , Coronavirus 3C Proteases/metabolism , Drug Discovery/methods , Flavones/metabolism , Flavonoids/pharmacology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Plant Extracts/pharmacology , Protease Inhibitors/chemistry , Quercetin/analogs & derivatives , Quercetin/pharmacology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Vero Cells
12.
Int J Biol Macromol ; 187: 976-987, 2021 Sep 30.
Article in English | MEDLINE | ID: covidwho-1474606

ABSTRACT

Coronavirus 3C-like protease (3CLpro) is a crucial target for treating coronavirus diseases including COVID-19. Our preliminary screening showed that Ampelopsis grossedentata extract (AGE) displayed potent SARS-CoV-2-3CLpro inhibitory activity, but the key constituents with SARS-CoV-2-3CLpro inhibitory effect and their mechanisms were unrevealed. Herein, a practical strategy via integrating bioactivity-guided fractionation and purification, mass spectrometry-based peptide profiling and time-dependent biochemical assay, was applied to identify the crucial constituents in AGE and to uncover their inhibitory mechanisms. The results demonstrated that the flavonoid-rich fractions (10-17.5 min) displayed strong SARS-CoV-2-3CLpro inhibitory activities, while the constituents in these fractions were isolated and their SARS-CoV-2-3CLpro inhibitory activities were investigated. Among all isolated flavonoids, dihydromyricetin, isodihydromyricetin and myricetin strongly inhibited SARS-CoV-2 3CLpro in a time-dependent manner. Further investigations demonstrated that myricetin could covalently bind on SARS-CoV-2 3CLpro at Cys300 and Cys44, while dihydromyricetin and isodihydromyricetin covalently bound at Cys300. Covalent docking coupling with molecular dynamics simulations showed the detailed interactions between the orthoquinone form of myricetin and two covalent binding sites (surrounding Cys300 and Cys44) of SARS-CoV-2 3CLpro. Collectively, the flavonoids in AGE strongly and time-dependently inhibit SARS-CoV-2 3CLpro, while the newly identified SARS-CoV-2 3CLpro inhibitors in AGE offer promising lead compounds for developing novel antiviral agents.


Subject(s)
3C Viral Proteases/chemistry , 3C Viral Proteases/metabolism , Ampelopsis/chemistry , Antiviral Agents/pharmacology , Flavonoids/pharmacology , SARS-CoV-2/enzymology , Antiviral Agents/chemistry , Binding Sites/drug effects , Cysteine/metabolism , Flavonoids/chemistry , Flavonols/chemistry , Flavonols/pharmacology , Mass Spectrometry , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Plant Extracts/chemistry , Plant Extracts/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protein Binding/drug effects , Protein Conformation/drug effects , SARS-CoV-2/drug effects
13.
Int J Mol Sci ; 22(20)2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1470888

ABSTRACT

The ongoing COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a globally leading public health concern over the past two years. Despite the development and administration of multiple vaccines, the mutation of newer strains and challenges to universal immunity has shifted the focus to the lack of efficacious drugs for therapeutic intervention for the disease. As with SARS-CoV, MERS-CoV, and other non-respiratory viruses, flavonoids present themselves as a promising therapeutic intervention given their success in silico, in vitro, in vivo, and more recently, in clinical studies. This review focuses on data from in vitro studies analyzing the effects of flavonoids on various key SARS-CoV-2 targets and presents an analysis of the structure-activity relationships for the same. From 27 primary papers, over 69 flavonoids were investigated for their activities against various SARS-CoV-2 targets, ranging from the promising 3C-like protease (3CLpro) to the less explored nucleocapsid (N) protein; the most promising were quercetin and myricetin derivatives, baicalein, baicalin, EGCG, and tannic acid. We further review promising in silico studies featuring activities of flavonoids against SARS-CoV-2 and list ongoing clinical studies involving the therapeutic potential of flavonoid-rich extracts in combination with synthetic drugs or other polyphenols and suggest prospects for the future of flavonoids against SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Flavonoids/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/virology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Coronavirus Nucleocapsid Proteins/antagonists & inhibitors , Coronavirus Nucleocapsid Proteins/metabolism , Flavonoids/chemistry , Flavonoids/pharmacology , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/physiology , Phosphoproteins/antagonists & inhibitors , Phosphoproteins/metabolism , Rhinovirus/drug effects , Rhinovirus/physiology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Virus Internalization/drug effects
14.
Mol Cell Biochem ; 477(1): 225-240, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1469743

ABSTRACT

Severe acute respiratory syndrome-coronavirus-2 (COVID-19) virus uses Angiotensin-Converting Enzyme 2 (ACE2) as a gateway for their entry into the human body. The ACE2 with cleaved products have emerged as major contributing factors to multiple physiological functions and pathogenic complications leading to the clinical consequences of the COVID-19 infection Decreased ACE2 expression restricts the viral entry into the human cells and reduces the viral load. COVID-19 infection reduces the ACE2 expression and induces post-COVID-19 complications like pneumonia and lung injury. The modulation of the ACE2-Ang (1-7)-Mas (AAM) axis is also being explored as a modality to treat post-COVID-19 complications. Evidence indicates that specific food components may modulate the AAM axis. The variations in the susceptibility to COVID-19 infection and the post-COVID its complications are being correlated with varied dietary habits. Some of the food substances have emerged to have supportive roles in treating post-COVID-19 complications and are being considered as adjuvants to the COVID-19 therapy. It is possible that some of their active ingredients may emerge as the direct treatment for the COVID-19.


Subject(s)
Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/diet therapy , Peptide Fragments/metabolism , /metabolism , Cardiovascular Diseases/pathology , Cardiovascular Diseases/virology , Dietary Proteins/pharmacology , Flavonoids/pharmacology , Humans , Lung/pathology , Lung/virology , Plant Oils/pharmacology , Polyphenols/pharmacology , Terpenes/pharmacology , Virus Internalization , Vitamins/pharmacology
15.
Molecules ; 26(19)2021 Oct 07.
Article in English | MEDLINE | ID: covidwho-1463771

ABSTRACT

3CL-Pro is the SARS-CoV-2 main protease (MPro). It acts as a homodimer to cleave the large polyprotein 1ab transcript into proteins that are necessary for viral growth and replication. 3CL-Pro has been one of the most studied SARS-CoV-2 proteins and a main target of therapeutics. A number of drug candidates have been reported, including natural products. Here, we employ elaborate computational methods to explore the dimerization of the 3CL-Pro protein, and we formulate a computational context to identify potential inhibitors of this process. We report that fortunellin (acacetin 7-O-neohesperidoside), a natural flavonoid O-glycoside, and its structural analogs are potent inhibitors of 3CL-Pro dimerization, inhibiting viral plaque formation in vitro. We thus propose a novel basis for the search of pharmaceuticals as well as dietary supplements in the fight against SARS-CoV-2 and COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Flavonoids/pharmacology , Glycosides/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Flavonoids/chemistry , Glycosides/chemistry , Humans , Molecular Docking Simulation , Polyphenols/chemistry , Polyphenols/pharmacology , Protease Inhibitors/chemistry , Protein Multimerization/drug effects , SARS-CoV-2/metabolism , Vero Cells
16.
Molecules ; 25(8)2020 Apr 18.
Article in English | MEDLINE | ID: covidwho-1450861

ABSTRACT

(1) Background: Viral respiratory infections cause life-threatening diseases in millions of people worldwide every year. Human coronavirus and several picornaviruses are responsible for worldwide epidemic outbreaks, thus representing a heavy burden to their hosts. In the absence of specific treatments for human viral infections, natural products offer an alternative in terms of innovative drug therapies. (2) Methods: We analyzed the antiviral properties of the leaves and stem bark of the mulberry tree (Morus spp.). We compared the antiviral activity of Morus spp. on enveloped and nonenveloped viral pathogens, such as human coronavirus (HCoV 229E) and different members of the Picornaviridae family-human poliovirus 1, human parechovirus 1 and 3, and human echovirus 11. The antiviral activity of 12 water and water-alcohol plant extracts of the leaves and stem bark of three different species of mulberry-Morus alba var. alba, Morus alba var. rosa, and Morus rubra-were evaluated. We also evaluated the antiviral activities of kuwanon G against HCoV-229E. (3) Results: Our results showed that several extracts reduced the viral titer and cytopathogenic effects (CPE). Leaves' water-alcohol extracts exhibited maximum antiviral activity on human coronavirus, while stem bark and leaves' water and water-alcohol extracts were the most effective on picornaviruses. (4) Conclusions: The analysis of the antiviral activities of Morus spp. offer promising applications in antiviral strategies.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Morus/chemistry , Plant Extracts/pharmacology , Respiratory Tract Infections/drug therapy , Antiviral Agents/therapeutic use , Cell Line , Cytopathogenic Effect, Viral/drug effects , Flavonoids/pharmacology , Humans , Mass Spectrometry , Microbial Sensitivity Tests , Picornaviridae/drug effects , Plant Bark/chemistry , Plant Extracts/therapeutic use , Plant Leaves/chemistry
17.
Phytother Res ; 35(9): 4988-5006, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1432473

ABSTRACT

The SARS-CoV-2 virus, responsible for COVID-19, spread rapidly worldwide and became a pandemic in 2020. In some patients, the virus remains in the respiratory tract, causing pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), and sepsis, leading to death. Natural flavonoids (aglycone and glycosides) possess broad biological activities encompassing antiinflammatory, antiviral, antitumoral, antiallergic, antiplatelet, and antioxidant effects. While many studies have focused on the effects of natural flavonoids in experimental models, reports based on clinical trials are still insufficient. In this review, we highlight the effects of flavonoids in controlling pulmonary diseases, particularly the acute respiratory distress syndrome, a consequence of COVID-19, and their potential use in coronavirus-related diseases. Furthermore, we also focus on establishing a relationship between biological potential and chemical aspects of related flavonoids and discuss several possible mechanisms of action, pointing out some possible effects on COVID-19.


Subject(s)
COVID-19 , Flavonoids , Lung Injury , COVID-19/complications , Flavonoids/pharmacology , Humans , Lung Injury/drug therapy , Lung Injury/virology , Pandemics
18.
Biomed Pharmacother ; 140: 111596, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1385083

ABSTRACT

Flavonoids are natural phytochemicals known for their antiviral activity. The flavonoids acts at different stages of viral infection, such as viral entrance, replication and translation of proteins. Viruses cause various diseases such as SARS, Hepatitis, AIDS, Flu, Herpes, etc. These, and many more viral diseases, are prevalent in the world, and some (i.e. SARS-CoV-2) are causing global chaos. Despite much struggle, effective treatments for these viral diseases are not available. The flavonoid class of phytochemicals has a vast number of medicinally active compounds, many of which are studied for their potential antiviral activity against different DNA and RNA viruses. Here, we reviewed many flavonoids that showed antiviral activities in different testing environments such as in vitro, in vivo (mice model) and in silico. Some flavonoids had stronger inhibitory activities, showed no toxicity & the cell proliferation at the tested doses are not affected. Some of the flavonoids used in the in vivo studies also protected the tested mice prophylactically from lethal doses of virus, and effectively prevented viral infection. The glycosides of some of the flavonoids increased the solubility of some flavonoids, and therefore showed increased antiviral activity as compared to the non-glycoside form of that flavonoid. These phytochemicals are active against different disease-causing viruses, and inhibited the viruses by targeting the viral infections at multiple stages. Some of the flavonoids showed more potent antiviral activity than the market available drugs used to treat viral infections.


Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Flavonoids/pharmacology , Flavonoids/therapeutic use , Virus Diseases/drug therapy , Viruses/drug effects , Animals , Cell Proliferation/drug effects , Glycosides/metabolism , Humans , Virus Diseases/metabolism
19.
Sci Rep ; 11(1): 15452, 2021 07 29.
Article in English | MEDLINE | ID: covidwho-1387487

ABSTRACT

SARS-CoV-2 main protease is a common target for inhibition assays due to its high conservation among coronaviruses. Since flavonoids show antiviral activity, several in silico works have proposed them as potential SARS-CoV-2 main protease inhibitors. Nonetheless, there is reason to doubt certain results given the lack of consideration for flavonoid promiscuity or main protease plasticity, usage of short library sizes, absence of control molecules and/or the limitation of the methodology to a single target site. Here, we report a virtual screening study where dorsilurin E, euchrenone a11, sanggenol O and CHEMBL2171598 are proposed to inhibit main protease through different pathways. Remarkably, novel structural mechanisms were observed after sanggenol O and CHEMBL2171598 bound to experimentally proven allosteric sites. The former drastically affected the active site, while the latter triggered a hinge movement which has been previously reported for an inactive SARS-CoV main protease mutant. The use of a curated database of 4.8 k flavonoids, combining two well-known docking software (AutoDock Vina and AutoDock4.2), molecular dynamics and MMPBSA, guaranteed an adequate analysis and robust interpretation. These criteria can be considered for future screening campaigns against SARS-CoV-2 main protease.


Subject(s)
COVID-19/metabolism , Coronavirus 3C Proteases/antagonists & inhibitors , Flavonoids/pharmacology , Antiviral Agents/pharmacology , Binding Sites , COVID-19/drug therapy , COVID-19/immunology , Coronavirus 3C Proteases/immunology , Coronavirus 3C Proteases/metabolism , Databases, Factual , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/pharmacology , Protein Binding , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/metabolism
20.
Int J Mol Sci ; 22(16)2021 Aug 20.
Article in English | MEDLINE | ID: covidwho-1374421

ABSTRACT

Polyphenols, such as flavonoids and phenolic acids, are a group of specialized metabolites in plants that largely aid in plant defense by deterring biotic stressors and alleviating abiotic stress. Polyphenols offer a wide range of medical applications, acting as preventative and active treatments for diseases such as cancers and diabetes. Recently, researchers have proposed that polyphenols may contribute to certain applications aimed at tackling challenges related to the COVID-19 pandemic. Understanding the beneficial impacts of phytochemicals, such as polyphenols, could potentially help prepare society for future pandemics. Thus far, most reviews have focused on polyphenols in cancer prevention and treatment. This review aims to provide a comprehensive discussion on the critical roles that polyphenols play in both plant chemical defense and human health based on the most recent studies while highlighting prospective avenues for future research, as well as the implications for phytochemical-based applications in both agricultural and medical fields.


Subject(s)
Plants/metabolism , Polyphenols/pharmacology , Polyphenols/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Biological Availability , COVID-19/drug therapy , COVID-19/prevention & control , Flavonoids/pharmacology , Flavonoids/therapeutic use , Humans , Hydroxybenzoates/pharmacology , Hypoglycemic Agents/pharmacology , Neoplasms/drug therapy , Phytochemicals , Plants/chemistry , Polyphenols/metabolism , Prospective Studies , SARS-CoV-2/drug effects
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