Evaluation of the Antiviral Efficacy of Subcutaneous Nafamostat Formulated with Glycyrrhizic Acid against SARS-CoV-2 in a Murine Model.

The ongoing COVID-19 pandemic highlights the urgent need for effective antiviral agents and vaccines. Drug repositioning, which involves modifying existing drugs, offers a promising approach for expediting the development of novel therapeutics. In this study, we developed a new drug, MDB-MDB-601a-NM, by modifying the existing drug nafamostat (NM) with the incorporation of glycyrrhizic acid (GA). We assessed the pharmacokinetic profiles of MDB-601a-NM and nafamostat in Sprague-Dawley rats, revealing rapid clearance of nafamostat and sustained drug concentration of MDB-601a-NM after subcutaneous administration. Single-dose toxicity studies showed potential toxicity and persistent swelling at the injection site with high-dose administration of MDB-601a-NM. Furthermore, we evaluated the efficacy of MDB-601a-NM in protecting against SARS-CoV-2 infection using the K18 hACE-2 transgenic mouse model. Mice treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM exhibited improved protectivity in terms of weight loss and survival rates compared to the nafamostat-treated group. Histopathological analysis revealed dose-dependent improvements in histopathological changes and enhanced inhibitory efficacy in MDB-601a-NM-treated groups. Notably, no viral replication was detected in the brain tissue when mice were treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM. Our developed MDB-601a-NM, a modified Nafamostat with glycyrrhizic acid, shows improved protectivity against SARS-CoV-2 infection. Its sustained drug concentration after subcutaneous administration and dose-dependent improvements makes it a promising therapeutic option.

Metabolic dysfunction associated fatty liver disease and coronavirus disease 2019: clinical relationship and current management.

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). At present, the COVID-19 has been prevalent worldwide for more than a year and caused more than four million deaths. Liver injury was frequently observed in patients with COVID-19. Recently, a new definition of metabolic dysfunction associated fatty liver disease (MAFLD) was proposed by a panel of international experts, and the relationship between MAFLD and COVID-19 has been actively investigated. Several previous studies indicated that the patients with MAFLD had a higher prevalence of COVID-19 and a tendency to develop severe type of respiratory infection, and others indicated that liver injury would be exacerbated in the patients with MAFLD once infected with COVID-19. The mechanism underlying the relationship between MAFLD and COVID-19 infection has not been thoroughly investigated, and recent studies indicated that multifactorial mechanisms, such as altered host angiotensin converting enzyme 2 (ACE2) receptor expression, direct viral attack, disruption of cholangiocyte function, systemic inflammatory reaction, drug-induced liver injury, hepatic ischemic and hypoxic injury, and MAFLD-related glucose and lipid metabolic disorders, might jointly contribute to both of the adverse hepatic and respiratory outcomes. In this review, we discussed the relationship between MAFLD and COVID-19 based on current available literature, and summarized the recommendations for clinical management of MAFLD patients during the pandemic of COVID-19.

Glycyrrhizin through liquorice intake modulates ACE2 and HMGB1 levels-A pilot study in healthy individuals with implications for COVID-19 and ARDS.

BACKGROUND: Glycyrrhizin, an active component of liquorice root extract, exhibits antiviral and immunomodulatory properties by direct inhibition of the pro-inflammatory alarmin HMGB1 (High-mobility group box 1). OBJECTIVE: The aim of this study was to explore the role of liquorice intake on the viral entry receptor ACE2 (angiotensin-converting enzyme 2) and the immunoregulatory HMGB1 in healthy individuals and to explore HMGB1 expression in coronavirus disease 2019 (COVID-19) or non-COVID-19 in ARDS (acute respiratory distress syndrome patients). MATERIAL AND METHODS: This study enrolled 43 individuals, including hospitalised patients with i) acute respiratory distress syndrome (ARDS) due to COVID-19 (n = 7) or other underlying causes (n = 12), ii) mild COVID-19 (n = 4) and iii) healthy volunteers (n = 20). Healthy individuals took 50 g of liquorice (containing 3% liquorice root extract) daily for 7 days, while blood samples were collected at baseline and on day 3 and 7. Changes in ACE2 and HMGB1 levels were determined by Western blot analysis and enzyme-linked immunosorbent assay, respectively. Additionally, HMGB1 levels were measured in hospitalised COVID-19 patients with mild disease or COVID-19 associated acute respiratory distress syndrome (ARDS) and compared with a non-COVID-19-ARDS group. RESULTS: Liquorice intake significantly reduced after 7 days both cellular membranous ACE2 expression (-51% compared to baseline levels, p = 0.008) and plasma HMGB1 levels (-17% compared to baseline levels, p<0.001) in healthy individuals. Half of the individuals had a reduction in ACE2 levels of at least 30%. HMGB1 levels in patients with mild COVID-19 and ARDS patients with and without COVID-19 were significantly higher compared with those of healthy individuals (+317%, p = 0.002), but they were not different between COVID-19 and non-COVID-19 ARDS. CONCLUSIONS: Liquorice intake modulates ACE2 and HMGB1 levels in healthy individuals. HMGB1 is enhanced in mild COVID-19 and in ARDS with and without COVID-19, warranting evaluation of HMGB1 as a potential treatment target and glycyrrhizin, which is an active component of liquorice root extract, as a potential treatment in COVID-19 and non-COVID-19 respiratory disease.

Glycyrrhizin and boswellic acids, the golden nutraceuticals: multitargeting for treatment of mild-moderate COVID-19 and prevention of post-COVID cognitive impairment.

Breakthrough infections have been reported in fully vaccinated persons. Furthermore, rebound symptoms have been reported following the new FDA granted emergency use to combat SARS-CoV-2. Glycyrrhizin (GR) and boswellic acids (BAs) combination has been shown to have highly successful actions against COVID-19 in our recent clinical trial. However, the study is limited by the small sample size, and therefore, the aim of this article is to comprehensively evaluate recent evidence on the efficacy of GR and BAs in preventing the development of COVID-19 in patients with mild and moderate infections and in preventing post-COVID-19 cognitive impairment, which is the most important symptom after recovery from Covid-19 disease. We have reviewed and discussed information published since the outbreak of the COVID-19 pandemic until July 2022 on preclinical (in vivo, in vivo and bioinformatics) and clinical studies related to the antiviral, anti-inflammatory and immunomodulatory activity of Gr and BAs. Sixteen studies were performed to determine the efficacy of GR against SARS-CoV-2. Ten studies were used primarily for in vitro and in vivo assays and six used molecular docking studies. However, the antiviral activity of BAs against SARS-CoV-2 was determined in only five studies using molecular modeling and bioinformatics. All these studies confirmed that GR n and BAs have strong antiviral activity and can be used as a therapeutic agent for COVID-19 and as a protective agent against SARS-CoV-2. They may act by inhibiting the main protease SARS-CoV-2 (Mpro) responsible for replication and blocking spike protein-mediated cell entry. Only seven rigorously designed clinical trials regarding the usefulness of GR, BAs or their combinations in the treatment of COVID-19 have been published as of July 2022. Although there is no clinical study regarding the treatment of cognitive impairment after COVID-19 that has been published so far, several preclinical and clinical studies have demonstrated the potential effect of GR and BAs in the prevention and treatment of cognitive impairment by inhibiting the activity of several molecules that activate inflammatory signaling pathway. In conclusion, the findings of our study documented the beneficial use of GR and BAs to treat SARS-CoV-2 and its variants and prevent post-COVID cognitive impairment. However, it warrants further studies with a larger randomized sample size to ensure that the studies have sufficient evidence of benefits against COVID-19 and post-COVID-19 symptoms.

Oncopreventive and oncotherapeutic potential of licorice triterpenoid compound glycyrrhizin and its derivatives: Molecular insights.

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.

Repurposing Methotrexate in Dampening SARS-CoV2-S1-Mediated IL6 Expression: Lessons Learnt from Lung Cancer.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) is associated with uncontrolled inflammatory responses. Loss of pulmonary angiotensin-converting enzyme 2 (ACE2) function has been associated with SARS-CoV-2 infection. The aberrant signalling and dysregulated inflammation characteristic of lung cancer have marked similarities with SARS-CoV-2 infection. Spearman's correlation analysis of The Cancer Genome Atlas (TCGA) datasets indicated an inverse correlation between ACE2 and IL6 in lung adenocarcinoma. qRT-PCR analysis revealed CoV-2-SRBD-mediated diminished ACE2 expression in lung cancer cells that was concomitant with increased IL6 expression. Western blot and qRT-PCR analysis suggested that treatment with methotrexate (MTx) dampened CoV-2-SRBD-mediated increase in JAK1/STAT3 phosphorylation, gp130, IL6, and folate-binding protein (FBP) expressions. MTx also rescued the diminished expression of ACE2 in CoV-2-SRBD transfected cells. As lung tissue injury in severely affected COVID-19 patients is characterised by aberrant inflammatory response, repurposing MTx as an effective therapy against critical regulators of inflammation in SARS-CoV-2 infection warrants investigation.

Glycyrrhizic Acid Inhibits SARS-CoV-2 Infection by Blocking Spike Protein-Mediated Cell Attachment.

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.

Drug repurposing for COVID-19: could vitamin C combined with glycyrrhizic acid be at play by the findings of Li et al.'s database-based network pharmacology analysis?

The outbreak and pandemic of SARS-CoV-2 in 2019 has caused a severe public health burden and will challenge global health for the future. The discovery and mechanistic investigation of drugs against Coronavirus disease 2019 (COVID-19) is in deadly demand. The paper published by Li and colleagues proposed the hypothesis that vitamin C combined with glycyrrhizic acid in treating COVID-19 and its mechanistic investigation was performed by a database-based network pharmacology. In this letter, we present critical comments on the limitations and insufficiencies involved, from both the perspective of network pharmacology and current evidence on COVID-19.

Integrative pharmacological mechanism of vitamin C combined with glycyrrhizic acid against COVID-19: findings of bioinformatics analyses.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a fatal and fast-spreading viral infection. To date, the number of COVID-19 patients worldwide has crossed over six million with over three hundred and seventy thousand deaths (according to the data from World Health Organization; updated on 2 June 2020). Although COVID-19 can be rapidly diagnosed, efficient clinical treatment of COVID-19 remains unavailable, resulting in high fatality. Some clinical trials have identified vitamin C (VC) as a potent compound pneumonia management. In addition, glycyrrhizic acid (GA) is clinically as an anti-inflammatory medicine against pneumonia-induced inflammatory stress. We hypothesized that the combination of VC and GA is a potential option for treating COVID-19. METHODS: The aim of this study was to determine pharmacological targets and molecular mechanisms of VC + GA treatment for COVID-19, using bioinformational network pharmacology. RESULTS: We uncovered optimal targets, biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of VC + GA against COVID-19. Our findings suggested that combinatorial VC and GA treatment for COVID-19 was associated with elevation of immunity and suppression of inflammatory stress, including activation of the T cell receptor signaling pathway, regulation of Fc gamma R-mediated phagocytosis, ErbB signaling pathway and vascular endothelial growth factor signaling pathway. We also identified 17 core targets of VC + GA, which suggest as antimicrobial function. CONCLUSIONS: For the first time, our study uncovered the pharmacological mechanism underlying combined VC and GA treatment for COVID-19. These results should benefit efforts to address the most pressing problem currently facing the world.

The Potential of Glycyrrhizinate in the Management of COVID-19: A Systematic Review of the Efficacy and Safety of Glycyrrhizin Preparations in the Treatment of SARS and MERS.

The SARS-CoV-2 outbreak in 2019 highlighted the fact that no specific medications providing effective treatment have been identified and approved. We explored the possibilities for COVID-19 by systematically reviewing evidence on the efficacy and safety of glycyrrhizin preparations for SARS and MERS. Electronic databases were systematically searched from inception to February 2020 for eligible studies that evaluated the efficacy and safety of glycyrrhizin preparations for SARS and MERS. A quantitative analysis or descriptive analysis was applied. Five retrospective cohort studies were included, and NOS scores ranged from 5-7 points. The clinical symptoms of dry cough, chest distress and dyspnoea improved quickly, and elevated serum levels of aminotransferase decreased after compound glycyrrhizin treatment. The SARS-CoV antibody appeared earlier in the treated group than in the control group ([Formula: see text][Formula: see text]d). Compared to that with conventional medications, the average period from peak to 50% improvement of lesions, in terms of X-ray manifestations, was shorter with compound glycyrrhizin treatment ([Formula: see text]2.1[Formula: see text]d), and treatment reduced the dosage ([Formula: see text][Formula: see text]mg/d) and duration of the corticosteroids used, without other serious adverse reactions. Based on the available evidence regarding glycyrrhizin preparations for treating SARS and MERS, we infer that compound glycyrrhizin could be an optional therapeutic strategy for SARS-CoV-2 infections, especially those complicated with liver damage. Further research using well-designed randomized clinical trials (RCTs) is warranted to determine the dosage and duration of use of compound glycyrrhizin and to monitor its specific adverse effects.

Food Enrichment with Glycyrrhiza glabra Extract Suppresses ACE2 mRNA and Protein Expression in Rats-Possible Implications for COVID-19.

Angiotensin converting enzyme 2 (ACE2) is a key entry point of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus known to induce Coronavirus disease 2019 (COVID-19). We have recently outlined a concept to reduce ACE2 expression by the administration of glycyrrhizin, a component of Glycyrrhiza glabra extract, via its inhibitory activity on 11beta hydroxysteroid dehydrogenase type 2 (11betaHSD2) and resulting activation of mineralocorticoid receptor (MR). We hypothesized that in organs such as the ileum, which co-express 11betaHSD2, MR and ACE2, the expression of ACE2 would be suppressed. We studied organ tissues from an experiment originally designed to address the effects of Glycyrrhiza glabra extract on stress response. Male Sprague Dawley rats were left undisturbed or exposed to chronic mild stress for five weeks. For the last two weeks, animals continued with a placebo diet or received a diet containing extract of Glycyrrhiza glabra root at a dose of 150 mg/kg of body weight/day. Quantitative PCR measurements showed a significant decrease in gene expression of ACE2 in the small intestine of rats fed with diet containing Glycyrrhiza glabra extract. This effect was independent of the stress condition and failed to be observed in non-target tissues, namely the heart and the brain cortex. In the small intestine we also confirmed the reduction of ACE2 at the protein level. Present findings provide evidence to support the hypothesis that Glycyrrhiza glabra extract may reduce an entry point of SARS-CoV-2. Whether this phenomenon, when confirmed in additional studies, is linked to the susceptibility of cells to the virus requires further studies.

Can Antiviral Activity of Licorice Help Fight COVID-19 Infection?

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.

Development and validation of a rapid high-performance thin-layer chromatographic method for quantification of gallic acid, cinnamic acid, piperine, eugenol, and glycyrrhizin in Divya-Swasari-Vati, an ayurvedic medicine for respiratory ailments.

Divya-Swasari-Vati is a calcium containing polyherbal ayurvedic medicine prescribed for the lung-related ailments observed in the current pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 infections. The formulation is a unique quintessential blend of nine herbs cited in Ayurvedic texts for chronic cough and lung infection. Analytical standardization of herbal medicines is the pressing need of the hour to ascertain the quality compliance. This persuaded us to develop a simple, rapid, and selective high-performance thin-layer chromatographic method for Divya-Swasari-Vati quality standardization. The developed method was validated for the quantification of marker components, gallic acid, cinnamic acid, piperine, eugenol and glycyrrhizin, against reference standards in five different batches of Divya-Swasari-Vati. The analytes were identified by visualization at 254 nm, and by matching their retention factor with authentic standards. The developed method was validated as per the guidelines recommended by the International Council for Harmonization for parameters like, linearity, limit of detection, limit of quantification, accuracy, and precision. Therefore, the developed novel high-performance thin-layer chromatographic process could be employed for rapid standardization of Divya-Swasari-Vati and other related herbal formulation, which would aid in quality manufacturing and product development.

Glycyrrhizic Acid Nanoparticles as Antiviral and Anti-inflammatory Agents for COVID-19 Treatment.

COVID-19 has been diffusely pandemic around the world, characterized by massive morbidity and mortality. One of the remarkable threats associated with mortality may be the uncontrolled inflammatory processes, which were induced by SARS-CoV-2 in infected patients. As there are no specific drugs, exploiting safe and effective treatment strategies is an instant requirement to dwindle viral damage and relieve extreme inflammation simultaneously. Here, highly biocompatible glycyrrhizic acid (GA) nanoparticles (GANPs) were synthesized based on GA. In vitro investigations revealed that GANPs inhibit the proliferation of the murine coronavirus MHV-A59 and reduce proinflammatory cytokine production caused by MHV-A59 or the N protein of SARS-CoV-2. In an MHV-A59-induced surrogate mouse model of COVID-19, GANPs specifically target areas with severe inflammation, such as the lungs, which appeared to improve the accumulation of GANPs and enhance the effectiveness of the treatment. Further, GANPs also exert antiviral and anti-inflammatory effects, relieving organ damage and conferring a significant survival advantage to infected mice. Such a novel therapeutic agent can be readily manufactured into feasible treatment for COVID-19.

A Novel Computational Approach for the Discovery of Drug Delivery System Candidates for COVID-19.

In order to treat Coronavirus Disease 2019 (COVID-19), we predicted and implemented a drug delivery system (DDS) that can provide stable drug delivery through a computational approach including a clustering algorithm and the Schrödinger software. Six carrier candidates were derived by the proposed method that could find molecules meeting the predefined conditions using the molecular structure and its functional group positional information. Then, just one compound named glycyrrhizin was selected as a candidate for drug delivery through the Schrödinger software. Using glycyrrhizin, nafamostat mesilate (NM), which is known for its efficacy, was converted into micelle nanoparticles (NPs) to improve drug stability and to effectively treat COVID-19. The spherical particle morphology was confirmed by transmission electron microscopy (TEM), and the particle size and stability of 300-400 nm were evaluated by measuring DLSand the zeta potential. The loading of NM was confirmed to be more than 90% efficient using the UV spectrum.

Glycyrrhizin: An old weapon against a novel coronavirus.

Currently, over 100 countries are fighting against a common enemy, the severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which causes COVID-19. This has created a demand for a substance whose effectiveness has already been demonstrated in a similar scenario. Glycyrrhizin (GZ) is a promising agent against SARS-CoV-2 as its antiviral activity against SARS-CoV has already been confirmed. It is worthwhile to extrapolate from its proven therapeutic effects as there is a high similarity in the structure and genome of SARS-CoV and SARS-CoV-2. There are many possible mechanisms through which GZ acts against viruses: increasing nitrous oxide production in macrophages, affecting transcription factors and cellular signalling pathways, directly altering the viral lipid-bilayer membrane, and binding to the ACE2 receptor. In this review, we discuss the possible use of GZ in the COVID-19 setting, where topical administration appears to be promising, with the nasal and oral cavity notably being the potent location in terms of viral load. The most recently published papers on the distribution of ACE2 in the human body and documented binding of GZ to this receptor, as well as its antiviral activity, suggest that GZ can be used as a therapeutic for COVID-19 and as a preventive agent against SARS-CoV-2.

Glycyrrhizin as a Potential Treatment for the Novel Coronavirus (COVID-19).

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.

Glycyrrhizin: An alternative drug for the treatment of COVID-19 infection and the associated respiratory syndrome?

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.

Symptomatic Protective Action of Glycyrrhizin (Licorice) in COVID-19 Infection?

The role of the ACE2 enzyme in the COVID-19 infection is 2-fold, with opposing implications for the disease development. 1. The membrane bound angiotensin converting enzyme 2 (ACE2) serves as the entry point of COVID-19 2. Conversely, it supports an anti-inflammatory pathway. This led to the controversy of the impact of medications, which influence its expression. ACE2 is part of the wider renin-angiotensin-aldosterone system (RAAS) and is upregulated via compounds, which inhibits the classical ACE, thereby plasma aldosterone and aldosterone receptor (MR) activation. MR activation may therefore protect organs from binding the COVID-19 by reducing ACE2 expression. Glycyrrhizin (GL) is a frequent component in traditional Chinese medicines, which have been used to control COVID-19 infections. Its systemically active metabolite glycyrrhetinic acid (GA) inhibits 11beta hydroxysteroid dehydrogenase(11betaHSD2) and activates MR in organs, which express this enzyme, including the lungs. Does this affect the protective effect of ACE2? Importantly, GL has anti-inflammatory properties by itself via toll like receptor 4 (TLR4) antagonism and therefore compensates for the reduced protection of the downregulated ACE2. Finally, a direct effect of GL or GA to reduce virus transmission exists, which may involve reduced expression of type 2 transmembrane serine protease (TMPRSS2), which is required for virus uptake. Glycyrrhizin may reduce the severity of an infection with COVID-19 at the two stages of the COVID-19 induced disease process, 1. To block the number of entry points and 2. provide an ACE2 independent anti-inflammatory mechanism.

Pharmacological perspective: glycyrrhizin may be an efficacious therapeutic agent for COVID-19.

Coronavirus disease 2019 (COVID-19) caused by the previously unknown pathogen, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) is now a global pandemic. There are no vaccines or specific treatments against this new virus; therefore, there is an urgent need to advance novel therapeutic interventions for COVID-19. Glycyrrhizin is a triterpene saponin with various biological functions and pharmacological effects. This brief article discusses the therapeutic potential of glycyrrhizin for the treatment of COVID-19 from the perspective of its pharmacological action, including binding angiotensin-converting enzyme II (ACE2), downregulating proinflammatory cytokines, inhibiting the accumulation of intracellular reactive oxygen species (ROS), inhibiting thrombin, inhibiting the hyperproduction of airway exudates, and inducing endogenous interferon.