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1.
Comput Biol Med ; 144: 105367, 2022 05.
Article in English | MEDLINE | ID: covidwho-1712540

ABSTRACT

On November 24, 2021, the SARS-CoV-2 Omicron variant (B.1.1.529) was first identified in South Africa. The World Health Organization (WHO) declared the Omicron as a variant of concern (VoC) because of the unexpected and large numbers of mutations occurred in the genome, higher viral transmission and immune evasions. The present study was performed to explore the interactions of SARS-CoV-2 spike glycoprotein receptor-binding domain (SGp RBD) of the three variants (Omicron, Delta, and WT) with the receptor hACE2. The structural changes occurred in Omicron due to the mutations at key positions improved the ability to mediate SARS-CoV-2 viral infection compared to other VoCs. The phytochemicals limonin and glycyrrhizic acid were docked with the SGp RBD of the variants WT, Delta and Omicron. The computed dock score revealed that limonin and glycyrrhizic acid binds effectively at the SGp RBD of all three variants, and showed almost similar binding affinity at the binding interface of ACE2. Therefore, despite the multiple mutations occurred in Omicron and its viral transmission is comparatively high, the computed binding affinity of the phytochemicals limonin and glycyrrhizic acid supported that the traditional medicines can be useful in formulating adjuvant therapies to fight against the SARS-CoV-2 Omicron.


Subject(s)
COVID-19 , Glycyrrhizic Acid , Angiotensin-Converting Enzyme 2 , COVID-19/drug therapy , Glycyrrhizic Acid/pharmacology , Humans , Limonins , Mutation , SARS-CoV-2
2.
Pharmacol Res ; 178: 106138, 2022 04.
Article in English | MEDLINE | ID: covidwho-1693034

ABSTRACT

Licorice (Glycyrrhiza glabra) is a well-known natural herb used to treat different ailments since ancient times. Glycyrrhizin (GL), which is the primary triterpenoid compound of licorice extract, has been known to have broad-spectrum pharmacological effects. GL is cleaved into glucuronide and the aglycone, glycyrrhetinic acid (GA), which exists in two stereoisomeric forms: 18α- and 18ß-GA. It is well documented that GL and GA have great potential as anti-inflammatory, anticancer, antiviral, anti-diabetic, antioxidant, and hepatoprotective agents. Studies undertaken during the coronavirus disease 2019 pandemic suggest that GL is effective at inhibiting the viral replication of severe acute respiratory syndrome coronavirus 2. The anticancer effects of GL and GA involve modulating various signaling pathways, such as the phosphatase and tensin homolog/phosphatidylinositol 3-kinase/protein kinase B pathway, the mitogen-activated protein kinase, and the mammalian target of rapamycin/signal transducer and activator of transcription 3, which are mainly involved in regulating cancer cell death, oxidative stress, and inflammation. The potential of GL and GA in preventing cancer development and suppressing the growth and invasion of different cancer types has been reviewed in this paper. This review also provides molecular insights on the mechanism of action for the oncopreventive and oncotherapeutic effects of GL and its derivative, GA, which could help develop more specific forms of these agents for clinical use.


Subject(s)
Antineoplastic Agents , COVID-19 , Glycyrrhiza , Triterpenes , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , Humans , Phytochemicals , Plant Extracts , Triterpenes/pharmacology , Triterpenes/therapeutic use
3.
Acta Biomed ; 92(S6): e2021455, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1503761

ABSTRACT

The COVID-19 pandemic era is causing a relevant issue for the health. There is no specific drug able to antagonize the SARS-CoV-2 infection. As a consequence, there is growing interest about potential molecules able to contrast infection. In this regard, HMGB, an alarmin, may play a relevant role in pathogenic mechanisms induced by SARS-CoV-2.  As HMGB1 is antagonized by glycyrrhizin, this substance could be potentially useful as ancillary treatment in COVID-19.


Subject(s)
COVID-19 , HMGB1 Protein , Glycyrrhizic Acid/pharmacology , Humans , Pandemics , SARS-CoV-2
4.
Molecules ; 26(20)2021 Oct 09.
Article in English | MEDLINE | ID: covidwho-1463773

ABSTRACT

Glycyrrhizic acid (GA), also known as glycyrrhizin, is a triterpene glycoside isolated from plants of Glycyrrhiza species (licorice). GA possesses a wide range of pharmacological and antiviral activities against enveloped viruses including severe acute respiratory syndrome (SARS) virus. Since the S protein (S) mediates SARS coronavirus 2 (SARS-CoV-2) cell attachment and cell entry, we assayed the GA effect on SARS-CoV-2 infection using an S protein-pseudotyped lentivirus (Lenti-S). GA treatment dose-dependently blocked Lenti-S infection. We showed that incubation of Lenti-S virus, but not the host cells with GA prior to the infection, reduced Lenti-S infection, indicating that GA targeted the virus for infection. Surface plasmon resonance measurement showed that GA interacted with a recombinant S protein and blocked S protein binding to host cells. Autodocking analysis revealed that the S protein has several GA-binding pockets including one at the interaction interface to the receptor angiotensin-converting enzyme 2 (ACE2) and another at the inner side of the receptor-binding domain (RBD) which might impact the close-to-open conformation change of the S protein required for ACE2 interaction. In addition to identifying GA antiviral activity against SARS-CoV-2, the study linked GA antiviral activity to its effect on virus cell binding.


Subject(s)
Glycyrrhizic Acid/chemistry , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Glycyrrhizic Acid/metabolism , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , Humans , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Virus Internalization/drug effects
5.
J Mol Model ; 27(7): 206, 2021 Jun 24.
Article in English | MEDLINE | ID: covidwho-1384472

ABSTRACT

The interaction between SARS-CoV-2 Spike protein and angiotensin-converting enzyme 2 (ACE2) is essential to viral attachment and the subsequent fusion process. Interfering with this event represents an attractive avenue for the development of therapeutics and vaccine development. Here, a hybrid approach of ligand- and structure-based virtual screening techniques were employed to disclose similar analogues of a reported antiviral phytochemical, glycyrrhizin, targeting the blockade of ACE2 interaction with the SARS-CoV-2 Spike. A ligand-based similarity search using a stringent cut-off revealed 40 FDA-approved compounds in DrugBank. These filtered hits were screened against ACE2 using a blind docking approach to determine the natural binding tendency of the compounds with ACE2. Three compounds, deslanoside, digitoxin, and digoxin, were reported to show strong binding with ACE2. These compounds bind at the H1-H2 binding pocket, in a manner similar to that of glycyrrhizin which was used as a control. To achieve consistency in the docking results, docking calculations were performed via two sets of docking software that predicted binding energy as ACE2-Deslanoside (AutoDock, -10.3 kcal/mol and DockThor, -9.53 kcal/mol), ACE2-Digitoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.84 kcal/mol), and ACE2-Digoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.81 kcal/mol). The docking results were validated by running molecular simulations in aqueous solution that demonstrated the stability of ACE2 with no major conformational changes in the ligand original binding mode (~ 2 Å average RMSD). Binding interactions remained quite stable with an increased potential for getting stronger as the simulation proceeded. MMGB/PBSA binding free energies were also estimated and these supported the high stability of the complexes compared to the control (~ -50 kcal/mol net MMGB/PBSA binding energy versus ~ -30 kcal/mol). Collectively, the data demonstrated that the compounds shortlisted in this study might be subjected to experimental evaluation to uncover their real blockade capacity of SARS-CoV-2 host ACE2 receptor.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Glycyrrhizic Acid/pharmacology , Receptors, Virus/antagonists & inhibitors , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/chemistry , Animals , Antiviral Agents/chemistry , Binding Sites , COVID-19/enzymology , COVID-19/virology , Drug Discovery , Drug Repositioning , Glycyrrhizic Acid/analogs & derivatives , Glycyrrhizic Acid/chemistry , Host-Pathogen Interactions , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Conformation , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Structure-Activity Relationship
6.
Pharmacol Res ; 157: 104820, 2020 07.
Article in English | MEDLINE | ID: covidwho-1318923

ABSTRACT

The Coronavirus Disease 2019 (COVID-19) pandemic has become a huge threaten to global health, which raise urgent demand of developing efficient therapeutic strategy. The aim of the present study is to dissect the chemical composition and the pharmacological mechanism of Qingfei Paidu Decoction (QFPD), a clinically used Chinese medicine for treating COVID-19 patients in China. Through comprehensive analysis by liquid chromatography coupled with high resolution mass spectrometry (MS), a total of 129 compounds of QFPD were putatively identified. We also constructed molecular networking of mass spectrometry data to classify these compounds into 14 main clusters, in which exhibited specific patterns of flavonoids (45 %), glycosides (15 %), carboxylic acids (10 %), and saponins (5 %). The target network model of QFPD, established by predicting and collecting the targets of identified compounds, indicated a pivotal role of Ma Xing Shi Gan Decoction (MXSG) in the therapeutic efficacy of QFPD. Supportively, through transcriptomic analysis of gene expression after MXSG administration in rat model of LPS-induced pneumonia, the thrombin and Toll-like receptor (TLR) signaling pathway were suggested to be essential pathways for MXSG mediated anti-inflammatory effects. Besides, changes in content of major compounds in MXSG during decoction were found by the chemical analysis. We also validate that one major compound in MXSG, i.e. glycyrrhizic acid, inhibited TLR agonists induced IL-6 production in macrophage. In conclusion, the integration of in silico and experimental results indicated that the therapeutic effects of QFPD against COVID-19 may be attributed to the anti-inflammatory effects of MXSG, which supports the rationality of the compatibility of TCM.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/analysis , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Pneumonia, Viral/drug therapy , Animals , Anti-Inflammatory Agents/analysis , Anti-Inflammatory Agents/pharmacology , COVID-19 , Cells, Cultured , Computer Simulation , Coronavirus Infections/genetics , Gene Expression/drug effects , Glycyrrhizic Acid/pharmacology , Humans , Interleukin-6/metabolism , Lipopeptides/antagonists & inhibitors , Lipopeptides/pharmacology , Lipopolysaccharides , Male , Pandemics , Pneumonia/chemically induced , Pneumonia/metabolism , Pneumonia, Viral/genetics , Rats , SARS-CoV-2 , Signal Transduction/drug effects , Thrombin/metabolism , Toll-Like Receptors/metabolism
7.
Biomolecules ; 11(6)2021 06 08.
Article in English | MEDLINE | ID: covidwho-1264413

ABSTRACT

The phytotherapeutic properties of Glycyrrhiza glabra (licorice) extract are mainly attributed to glycyrrhizin (GR) and glycyrrhetinic acid (GA). Among their possible pharmacological actions, the ability to act against viruses belonging to different families, including SARS coronavirus, is particularly important. With the COVID-19 emergency and the urgent need for compounds to counteract the pandemic, the antiviral properties of GR and GA, as pure substances or as components of licorice extract, attracted attention in the last year and supported the launch of two clinical trials. In silico docking studies reported that GR and GA may directly interact with the key players in viral internalization and replication such as angiotensin-converting enzyme 2 (ACE2), spike protein, the host transmembrane serine protease 2, and 3-chymotrypsin-like cysteine protease. In vitro data indicated that GR can interfere with virus entry by directly interacting with ACE2 and spike, with a nonspecific effect on cell and viral membranes. Additional anti-inflammatory and antioxidant effects of GR cannot be excluded. These multiple activities of GR and licorice extract are critically re-assessed in this review, and their possible role against the spread of the SARS-CoV-2 and the features of COVID-19 disease is discussed.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Glycyrrhetinic Acid/pharmacology , Glycyrrhizic Acid/pharmacology , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Animals , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/metabolism , Glycyrrhetinic Acid/therapeutic use , Glycyrrhiza/chemistry , Glycyrrhizic Acid/therapeutic use , Humans , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
8.
J Biol Regul Homeost Agents ; 35(1 Suppl. 2): 15-19, 2021.
Article in English | MEDLINE | ID: covidwho-1227259

ABSTRACT

COVID-19, the disease caused by the SARS - CoV - 2 pathogen, is currently a pandemic. At the moment there is not an available vaccine, so, scientific community is looking for strategies and drugs to implement prevention and prophylaxis. Several compounds are examined for this purpose. Glycyrrhizin, an alkaloid extracted from licorice plant (glycyrriza glabra), is one of the most studied molecules, both for its peculiar biological functions and for its pharmacological effects. This brief review aims to highlight the characteristics of glycyrrhizin for topical use on the nasal and ocular surfaces. The anti-inflammatory activity, the ability to inhibit the accumulation of ROS, the antiviral property, but, above all, the ability to bind the ACE receptor and the SARS - CoV-2 protein S in the extracellular environment make Glycyrrhizzin for topical use a compound with a high prophylactic potential for SARS - CoV - 2 infection, also due to its low cost and the absence of significant side effects.


Subject(s)
COVID-19 , Glycyrrhizic Acid , Antiviral Agents/therapeutic use , Glycyrrhizic Acid/pharmacology , Humans , Pandemics , SARS-CoV-2
9.
Viruses ; 13(4)2021 04 02.
Article in English | MEDLINE | ID: covidwho-1167761

ABSTRACT

The outbreak of SARS-CoV-2 developed into a global pandemic affecting millions of people worldwide. Despite one year of intensive research, the current treatment options for SARS-CoV-2 infected people are still limited. Clearly, novel antiviral compounds for the treatment of SARS-CoV-2 infected patients are still urgently needed. Complementary medicine is used along with standard medical treatment and accessible to a vast majority of people worldwide. Natural products with antiviral activity may contribute to improve the overall condition of SARS-CoV-2 infected individuals. In the present study, we investigated the antiviral activity of glycyrrhizin, the primary active ingredient of the licorice root, against SARS-CoV-2. We demonstrated that glycyrrhizin potently inhibits SARS-CoV-2 replication in vitro. Furthermore, we uncovered the underlying mechanism and showed that glycyrrhizin blocks the viral replication by inhibiting the viral main protease Mpro that is essential for viral replication. Our data indicate that the consumption of glycyrrhizin-containing products such as licorice root tea of black licorice may be of great benefit for SARS-CoV-2 infected people. Furthermore, glycyrrhizin is a good candidate for further investigation for clinical use to treat COVID-19 patients.


Subject(s)
Antiviral Agents/pharmacology , Glycyrrhizic Acid/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , COVID-19 , Cell Survival/drug effects , Chlorocebus aethiops , Coronavirus 3C Proteases/drug effects , Glycyrrhiza/chemistry , Humans , Peptide Hydrolases/drug effects , Plant Extracts/pharmacology , Plant Roots/chemistry , Vero Cells
10.
Cytokine ; 142: 155496, 2021 06.
Article in English | MEDLINE | ID: covidwho-1152317

ABSTRACT

Efforts to understand host factors critical for COVID-19 pathogenesis have identified high mobility group box 1 (HMGB1) to be crucial for regulating susceptibility to SARS-CoV-2. COVID-19 disease severity is correlated with heightened inflammatory responses, and HMGB1 is an important extracellular mediator in inflammation processes.In this study, we evaluated the effect of HMGB1 inhibitor Glycyrrhizin on the cellular perturbations in lung cells expressing SARS-CoV-2 viral proteins. Pyroptosis in lung cells transfected with SARS-CoV-2 S-RBD and Orf3a, was accompanied by elevation of IL-1ß and extracellular HMGB1 levels. Glycyrrhizin mitigated viral proteins-induced lung cell pyroptosis and activation of macrophages. Heightened release of proinflammatory cytokines IL-1ß, IL-6 and IL-8, as well as ferritin from macrophages cultured in conditioned media from lung cells expressing SARS-CoV-2 S-RBD and Orf3a was attenuated by glycyrrhizin. Importantly, Glycyrrhizin inhibited SARS-CoV-2 replication in Vero E6 cells without exhibiting cytotoxicity at high doses. The dual ability of Glycyrrhizin to concomitantly halt virus replication and dampen proinflammatory mediators might constitute a viable therapeutic option in patients with SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , Glycyrrhizic Acid/pharmacology , HMGB1 Protein/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Viroporin Proteins/metabolism , Virus Replication/drug effects , A549 Cells , COVID-19/drug therapy , COVID-19/genetics , HMGB1 Protein/genetics , Humans , Spike Glycoprotein, Coronavirus/genetics , U937 Cells , Viroporin Proteins/genetics
11.
Mini Rev Med Chem ; 21(16): 2204-2208, 2021.
Article in English | MEDLINE | ID: covidwho-1079425

ABSTRACT

COVID-19 is an emerging viral infection of zoonotic origin that is closely related to the severe acute respiratory syndrome coronavirus (SARS-CoV) that caused an outbreak in 2003. Therefore, scientists named the new virus SARS-CoV-2. On March 11, 2020, The World Health Organization (WHO) recognized COVID-19 as a global pandemic. At present, three vaccines have been approved or are being considered for approval by national regulatory agencies to immunize against COVID- 19. However, the vaccines do not remain widely available, and no specific treatment against the virus is available. The pathogenesis and proliferation pathways of SARS-CoV-2 are still not well known. Thus, in this article, the saponin glycyrrhizin is discussed as a new potential therapeutic agent of natural origin (licorice root, Glycyrrhiza glabra) for the potential treatment of COVID-19 infections.


Subject(s)
COVID-19/drug therapy , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , SARS-CoV-2/drug effects , COVID-19/virology , Humans , SARS-CoV-2/pathogenicity
12.
Curr Med Chem ; 27(36): 6219-6243, 2020.
Article in English | MEDLINE | ID: covidwho-945503

ABSTRACT

Licorice (Glycyrrhiza glabra L.) is widely regarded as an important medicinal plant and has been used for centuries in traditional medicine because of its therapeutic properties. Studies have shown that metabolites isolated from licorice have many pharmacological activities, such as antiinflammatory, anti-viral, participation in immune regulation, anti-tumor and other activities. This article gives an overview of the pharmacological activities and mechanisms of licorice metabolites and the adverse reactions that need attention. This review helps to further investigate the possibility of licorice as a potential drug for various diseases. It is hoped that this review can provide a relevant theoretical basis for relevant scholars' research and their own learning.


Subject(s)
Glycyrrhiza , Glycyrrhizic Acid/pharmacology , Plants, Medicinal , Drugs, Chinese Herbal , Plant Extracts
13.
Int J Mol Sci ; 21(8)2020 Apr 23.
Article in English | MEDLINE | ID: covidwho-825269

ABSTRACT

Our previous study showed that glycyrrhizin (GLY) inhibited porcine epidemic diarrhea virus (PEDV) infection, but the mechanisms of GLY anti-PEDV action remain unclear. In this study, we focused on the anti-PEDV and anti-proinflammatory cytokine secretion mechanisms of GLY. We found that PEDV infection had no effect on toll-like receptor 4 (TLR4) protein and mRNA levels, but that TLR4 regulated PEDV infection and the mRNA levels of proinflammatory cytokines. In addition, we demonstrated that TLR4 regulated p38 phosphorylation but not extracellular regulated protein kinases1/2 (Erk1/2) and c-Jun N-terminal kinases (JNK) phosphorylation, and that GLY inhibited p38 phosphorylation but not Erk1/2 and JNK phosphorylation. Therefore, we further explored the relationship between high mobility group box-1 (HMGB1) and p38. We demonstrated that inhibition of HMGB1 using an antibody, mutation, or knockdown decreased p38 phosphorylation. Thus, HMGB1 participated in activation of p38 through TLR4. Collectively, our data indicated that GLY inhibited PEDV infection and decreased proinflammatory cytokine secretion via the HMGB1/TLR4-mitogen-activated protein kinase (MAPK) p38 pathway.


Subject(s)
Glycyrrhizic Acid/pharmacology , HMGB1 Protein/metabolism , Porcine epidemic diarrhea virus/drug effects , Porcine epidemic diarrhea virus/physiology , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Cells, Cultured , Chlorocebus aethiops , Coronavirus Infections/veterinary , Swine , Swine Diseases/metabolism , Swine Diseases/virology , Vero Cells
14.
Phytomedicine ; 85: 153364, 2021 May.
Article in English | MEDLINE | ID: covidwho-813823

ABSTRACT

Coronavirus causes a disease with high infectivity and pathogenicity, especially SARS in 2003, MERS in 2012, and COVID-2019 currently. The spike proteins of these coronaviruses are critical for host cell entry by receptors. Thus, searching for broad-spectrum anti-coronavirus candidates, such as spike protein inhibitors, is vital and desirable due to the mutations in the spike protein. In this study, a combination of computer-aided drug design and biological verification was used to discover active monomers from traditional Chinese medicine. Surface plasmon resonance (SPR) assays and NanoBit assays were used to verify the predicated compounds with their binding activities to spike proteins and inhibitory activities on the SARS-CoV-2 RBD/ACE2 interaction, respectively. Furthermore, an MTT assay was used to evaluate the cell toxicities of active compounds. As a result, glycyrrhizic acid (ZZY-44) was found to be the most efficient and nontoxic broad-spectrum anti-coronavirus molecule in vitro, especially, the significant effect on SARS-CoV-2, which provided a theoretical basis for the study of the pharmacodynamic material basis of traditional Chinese medicine against SARS-CoV-2 and offered a lead compound for further structural modification in order to obtain more effective candidate drugs against SARS-CoV-2.


Subject(s)
Drug Design , Glycyrrhizic Acid/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Animals , HEK293 Cells , Humans , Medicine, Chinese Traditional , Mice , Molecular Docking Simulation , Plants, Medicinal/chemistry , Protein Binding , Surface Plasmon Resonance
15.
Phytomedicine ; 85: 153315, 2021 May.
Article in English | MEDLINE | ID: covidwho-752997

ABSTRACT

BACKGROUND: The traditional Chinese medicine (TCM) formula Qing-Fei-Pai-Du decoction (QFPDD) was the most widely used prescription in China's campaign to contain COVID-19, which has exhibited positive effects. However, the underlying mode of action is largely unknown. PURPOSE: A systems pharmacology strategy was proposed to investigate the mechanisms of QFPDD against COVID-19 from molecule, pathway and network levels. STUDY DESIGN AND METHODS: The systems pharmacological approach consisted of text mining, target prediction, data integration, network study, bioinformatics analysis, molecular docking, and pharmacological validation. Especially, we proposed a scoring method to measure the confidence of targets identified by prediction and text mining, while a novel scheme was used to identify important targets from 4 aspects. RESULTS: 623 high-confidence targets of QFPDD's 12 active compounds were identified, 88 of which were overlapped with genes affected by SARS-CoV-2 infection. These targets were found to be involved in biological processes related with the development of COVID-19, such as pattern recognition receptor signaling, interleukin signaling, cell growth and death, hemostasis, and injuries of the nervous, sensory, circulatory, and digestive systems. Comprehensive network and pathway analysis were used to identify 55 important targets, which regulated 5 functional modules corresponding to QFPDD's effects in immune regulation, anti-infection, anti-inflammation, and multi-organ protection, respectively. Four compounds (baicalin, glycyrrhizic acid, hesperidin, and hyperoside) and 7 targets (AKT1, TNF-α, IL6, PTGS2, HMOX1, IL10, and TP53) were key molecules related to QFPDD's effects. Molecular docking verified that QFPDD's compounds may bind to 6 host proteins that interact with SARS-CoV-2 proteins, further supported the anti-virus effect of QFPDD. At last, in intro experiments validated QFPDD's important effects, including the inhibition of IL6, CCL2, TNF-α, NF-κB, PTGS1/2, CYP1A1, CYP3A4 activity, the up-regulation of IL10 expression, and repressing platelet aggregation. CONCLUSION: This work illustrated that QFPDD could exhibit immune regulation, anti-infection, anti-inflammation, and multi-organ protection. It may strengthen the understanding of QFPDD and facilitate more application of this formula in the campaign to SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Drugs, Chinese Herbal/pharmacology , SARS-CoV-2/drug effects , Animals , Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , Computational Biology , Flavonoids/pharmacology , Glycyrrhizic Acid/pharmacology , Hesperidin/pharmacology , Humans , Male , Medicine, Chinese Traditional , Mice , Molecular Docking Simulation , Quercetin/analogs & derivatives , Quercetin/pharmacology , RAW 264.7 Cells , Rabbits , Signal Transduction/drug effects
16.
Pharmacol Ther ; 214: 107618, 2020 10.
Article in English | MEDLINE | ID: covidwho-613022

ABSTRACT

Safe and efficient drugs to combat the current COVID-19 pandemic are urgently needed. In this context, we have analyzed the anti-coronavirus potential of the natural product glycyrrhizic acid (GLR), a drug used to treat liver diseases (including viral hepatitis) and specific cutaneous inflammation (such as atopic dermatitis) in some countries. The properties of GLR and its primary active metabolite glycyrrhetinic acid are presented and discussed. GLR has shown activities against different viruses, including SARS-associated Human and animal coronaviruses. GLR is a non-hemolytic saponin and a potent immuno-active anti-inflammatory agent which displays both cytoplasmic and membrane effects. At the membrane level, GLR induces cholesterol-dependent disorganization of lipid rafts which are important for the entry of coronavirus into cells. At the intracellular and circulating levels, GLR can trap the high mobility group box 1 protein and thus blocks the alarmin functions of HMGB1. We used molecular docking to characterize further and discuss both the cholesterol- and HMG box-binding functions of GLR. The membrane and cytoplasmic effects of GLR, coupled with its long-established medical use as a relatively safe drug, make GLR a good candidate to be tested against the SARS-CoV-2 coronavirus, alone and in combination with other drugs. The rational supporting combinations with (hydroxy)chloroquine and tenofovir (two drugs active against SARS-CoV-2) is also discussed. Based on this analysis, we conclude that GLR should be further considered and rapidly evaluated for the treatment of patients with COVID-19.


Subject(s)
Coronavirus Infections/drug therapy , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , Pneumonia, Viral/drug therapy , Alarmins/drug effects , Betacoronavirus , COVID-19 , Coronavirus Infections/epidemiology , Drug Therapy, Combination , Humans , Hydroxychloroquine/therapeutic use , Membrane Microdomains/drug effects , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Tenofovir/therapeutic use
17.
Nutrients ; 12(4)2020 Apr 24.
Article in English | MEDLINE | ID: covidwho-116799

ABSTRACT

Novel coronaviruses (CoV) have emerged periodically around the world in recent years. The recurrent spreading of CoVs imposes an ongoing threat to global health and the economy. Since no specific therapy for these CoVs is available, any beneficial approach (including nutritional and dietary approach) is worth investigation. Based on recent advances in nutrients and phytonutrients research, a novel combination of vitamin C, curcumin and glycyrrhizic acid (VCG Plus) was developed that has potential against CoV infection. System biology tools were applied to explore the potential of VCG Plus in modulating targets and pathways relevant to immune and inflammation responses. Gene target acquisition, gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment were conducted consecutively along with network analysis. The results show that VCG Plus can act on 88 hub targets which are closely connected and associated with immune and inflammatory responses. Specifically, VCG Plus has the potential to regulate innate immune response by acting on NOD-like and Toll-like signaling pathways to promote interferons production, activate and balance T-cells, and regulate the inflammatory response by inhibiting PI3K/AKT, NF-κB and MAPK signaling pathways. All these biological processes and pathways have been well documented in CoV infections studies. Therefore, our findings suggest that VCG Plus may be helpful in regulating immune response to combat CoV infections and inhibit excessive inflammatory responses to prevent the onset of cytokine storm. However, further in vitro and in vivo experiments are warranted to validate the current findings with system biology tools. Our current approach provides a new strategy in predicting formulation rationale when developing new dietary supplements.


Subject(s)
Ascorbic Acid/therapeutic use , Coronavirus Infections/drug therapy , Curcumin/therapeutic use , Glycyrrhizic Acid/therapeutic use , Immunity, Innate/drug effects , Inflammation/drug therapy , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Ascorbic Acid/pharmacology , Coronavirus , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Curcuma/chemistry , Curcumin/pharmacology , Cytokines/metabolism , Drug Combinations , Drug Delivery Systems , Gene Ontology , Glycyrrhiza/chemistry , Glycyrrhizic Acid/pharmacology , Humans , Interferons/metabolism , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Signal Transduction , Systems Biology , T-Lymphocytes/metabolism , Vitamins/pharmacology , Vitamins/therapeutic use
18.
Small ; 16(13): e1906206, 2020 04.
Article in English | MEDLINE | ID: covidwho-1479

ABSTRACT

With the gradual usage of carbon dots (CDs) in the area of antiviral research, attempts have been stepped up to develop new antiviral CDs with high biocompatibility and antiviral effects. In this study, a kind of highly biocompatible CDs (Gly-CDs) is synthesized from active ingredient (glycyrrhizic acid) of Chinese herbal medicine by a hydrothermal method. Using the porcine reproductive and respiratory syndrome virus (PRRSV) as a model, it is found that the Gly-CDs inhibit PRRSV proliferation by up to 5 orders of viral titers. Detailed investigations reveal that Gly-CDs can inhibit PRRSV invasion and replication, stimulate antiviral innate immune responses, and inhibit the accumulation of intracellular reactive oxygen species (ROS) caused by PRRSV infection. Proteomics analysis demonstrates that Gly-CDs can stimulate cells to regulate the expression of some host restriction factors, including DDX53 and NOS3, which are directly related to PRRSV proliferation. Moreover, it is found that Gly-CDs also remarkably suppress the propagation of other viruses, such as pseudorabies virus (PRV) and porcine epidemic diarrhea virus (PEDV), suggesting the broad antiviral activity of Gly-CDs. The integrated results demonstrate that Gly-CDs possess extraordinary antiviral activity with multisite inhibition mechanisms, providing a promising candidate for alternative therapy for PRRSV infection.


Subject(s)
Carbon/pharmacology , Glycyrrhizic Acid/pharmacology , Microbial Viability , Porcine Reproductive and Respiratory Syndrome , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Immunity, Innate/drug effects , Microbial Viability/drug effects , Porcine respiratory and reproductive syndrome virus/drug effects , Swine , Virus Replication/drug effects
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