Glycyrrhizic Acid for COVID-19: Findings of Targeting Pivotal Inflammatory Pathways Triggered by SARS-CoV-2

Abstract

Background: Coronavirus disease 2019 (COVID-19) is now a worldwide public health crisis. The causative pathogen is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Novel therapeutic agents are desperately needed. Because of the frequent mutations in the virus and its ability to cause cytokine storms, targeting the viral proteins has some drawbacks. Targeting cellular factors or pivotal inflammatory pathways triggered by SARS-CoV-2 may produce a broader range of therapies. Glycyrrhizic acid (GA) might be beneficial against SARS-CoV-2 because of its anti-inflammatory and antiviral characteristics and possible ability to regulate crucial host factors. However, the mechanism underlying how GA regulates host factors remains to be determined.Methods: In our report, we conducted a bioinformatics analysis to identify possible GA targets, biological functions, protein-protein interactions, transcription-factor-gene interactions, transcription-factor-miRNA coregulatory networks, and the signaling pathways of GA against COVID-19.Results: Protein-protein interactions and network analysis showed that ICAM1, MMP9, TLR2, and SOCS3 had higher degree values, which may be key targets of GA for COVID-19. GO analysis indicated that the response to reactive oxygen species was significantly enriched. Pathway enrichment analysis showed that the IL-17, IL-6, TNF-α, IFN signals, complement system, and growth factor receptor signaling are the main pathways. The interactions of TF genes and miRNA with common targets and the activity of TFs were also recognized.Conclusions: GA may inhibit COVID-19 through its anti-oxidant, anti-viral, and anti-inflammatory effects, and its ability to activate the immune system, and targeted therapy for those pathways is a predominant strategy to inhibit the cytokine storms triggered by SARS-CoV-2 infection.

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Additionally, increased expression of ICAM1 in COVID-19 patients contributes to replication of SARS-CoV-2 and provides a favorable environment for its survival in humans ( 135 ). Therefore, ICAM1 protein can be considered a key target for treatment of COVID-19 patients ( 169 , 170 ).…”

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

“…Gowda and colleagues reported that GA could inhibit SARS-CoV-2-protein-induced high-mobility group box 1 (HMGB1) release and inhibits viral replication [ 28 ]. GA also targets SARS-CoV-2 main protease [ 29 ] and blocks proinflammatory response [ 30 ]. It is likely that GA can utilize multiple mechanisms against SARS-CoV-2 infection and disease [ 29 , 30 ].…”

“…GA also targets SARS-CoV-2 main protease [ 29 ] and blocks proinflammatory response [ 30 ]. It is likely that GA can utilize multiple mechanisms against SARS-CoV-2 infection and disease [ 29 , 30 ]. To initiate a productive cycle of infection, a virus first attaches to a host cell, followed by a cell entry and replication process.…”

Advancing combination treatment with glycyrrhizin and boswellic acids for hospitalized patients with moderate COVID-19 infection: a randomized clinical trial

“…Therefore, anti-inflammatory drugs and immunomodulatory drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm (Rabaan et al 2021 ; Reyes et al 2021 ). The antioxidant, anti-inflammatory and immunomodulatory effects of GR and BA have been confirmed in several articles (Baram et al 2019 ; Eltahir et al 2020 ; Efferth and Oesch 2020 ; Murck 2020 ; Gomaa and Abdel-Wadood 2021 , Gomaa et al 2021 ; Sun et al 2021 ; Renda et al 2021 ; Zheng et al 2021 , Zhang et al 2021b ). Moreover, GR and BA have strong inhibitory effect against NLRP3 inflammasome and NF-κB3 (Beghelli et al 2017 ; Roy et al 2019 ; Ding et al 2020 ; Majeed et al 2021 ).…”

“…GR has a high affinity for S protein-mediated cell binding and thus blocks binding of recombinant S protein to host cells (Li et al 2021 ). In addition, several reviews and in silico docking studies have provided evidence for the potent effects of GR against SARS-CoV-2 replication and virus S protein binding to host cells (Gomaa and Abdel-Wadood 2021 ; Diomede et al 2021 ; Ahmad et al 2021 ; Zheng et al 2021 ; Zhang et al 2021a ; Huan et al 2021 ). Although there are no experimental studies to date investigating the effect of BA against SARS-CoV-2, several studies have shown the antiviral effect of BA against many other viruses (Badria et al 2003 ; Von Rhein et al 2016 ; Goswami et al 2018 ; Si et al 2018 ; Xiao et al 2018 ).…”