Table 2.

The antiviral activity and mechanism of action of glycyrrhizin (Glycyrrhizic Acid) and its various derivatives in articles published  from 1979 to 2020.

Glycyrrhizic Acid and its derivatives	Method of research	Major finding	Mechanism of actions	References
Glycyrrhizic acid Glycyrrhizic acid Glycyrrhizin Ribavirin, 6-azauridine, pyrazofurin, mycophenolic acid, and glycyrrhizin Glycyrrhizic Acid Derivatives Glycyrrhizin Glycyrrhizin Chalcones isolated by bioassay-guided fractionation of acetone extract of Glycyrrhiza ‘inflata.’ . Glycyrrhizin 18β-glycyrrhetinic acid (GRA) and Glycyrrhizin (GA) Glycyrrhizin Pentacyclic triterpenes,glycyrr. Licorice triterpene glycyrrhizic acid (GRA Glycyrrhizin Gycyrrhizic acid  derivatives Glycyrrhizic acid Triterpenoids Water-Soluble β-Cyclodextrin-glycyrrhetinic Acid Conjugates Glycyrrhizic acid (GL) derivatives Glycyrrhizin Glycyrrhizic‐Acid Based Carbon Dots Glycyrrhizin	Cell culture Cell culture Cell line MT-4 and MOLT-4 cells Two clinical isolates of coronavirus (FFM-1 and FFM-2) from patients with SARS Human Respiratory Tract Cell Lines Lung epithelial (A549) cells Porcine reproductive and respiratory syndrome virus (PRRSV). HCV infected liver cells MDCK cells A/WSN/33 (H1N1) virus using the cytopathic effect assay. Cell culture-produced HCV (HCVcc. Balb/C mice Cultured human cells MARC-145 cells infected with  porcine reproductive and respiratory syndrome virus ( PRRSV). Porcine kidney (PK‐15) cells, African green monkey kidney (Vero) cells, Sprague–Dawley Cell lines Many celllines as Human embryonic kidney (293T cells). Cell lines Infected DENV type 2 (DENV2) in Vero E6 cells. Cell line MOCK infected cells Molecular docking  study	Inhibits growth and cytopathology of several unrelated DNA and RNA viruses, while not affecting cell activity and ability to replicate. Inhibits the growth of several DNA and RNA viruses in cell cultures and inactivates Herpes simplex 1 virus irreversibly. Suppress hepatitis B virus. glycyrrhizin administered intravenously might bind to hepatocytes at the concentration at which glycyrrhizin could modify the expression of HBV-related antigens on the hepatocyte . Of all the compounds, glycyrrhizin was the most active in inhibiting replication of the SARS-associated virus. Modified glycyrrhizin has 70-fold increased activity against SARS-CoV but also increased cytotoxicity. It has antiviral effect and this inhibitory effect was abolished by treatment 1 h after virus infection. It inhibited H5N1-induced expression of the pro-inflammatory molecules CXCL10, interleukin 6, CCL2, and CCL5  and interfered with H5N1 replication. Strong inhibitory effects on influenza viral strains, H1N1, H9N2, novel H1N1 (WT), and oseltamivir-resistant novel H1N1and  synergistic effect with oseltamivir. GL inhibit HCV full length  and function in a dose dependent manner  and had synergistic effect with interferon. GRA, but not GA, has significant antiviral activity against rotavirus replication in vitro, Treatment of HCV-infected Huh7 cells caused a reduction of infectious HCV production. combination treatment with GL augmented IFN-induced reduction of virus in the HCVcc system. Exhibited good inhibitory activities against the influenza virus A/WSN/33 (H1N1) in MDCK cells and  showed anti-HIV activities. GRA demonstrated a strong antiherpes simplex virus type 1,  (HSV1) activity, resistance typewhereas rapamycin had no activity. Glycyrrhizin significantly reduced PRRSV proliferation and PRRSV-encoded protein expression in a dose-dependent manner. GL derivatives are potent as anti-influenza A/H1N1 agents. Entecavir and glycyrrhizic acid combination but not Glycyrrhizin produce synergistic  anti-HBV activity. Effective against  Ebola, Marburg, HIV, and influenza A, triterpenoids are viral fusion inhibitors. Findings suggested that GA could be used as a lead compound for the development of potential anti-influenza virus agents. GL conjugates were found as potent anti- Dengue virus. Glycyrrhizin (GLY) inhibited porcine epidemic diarrhea virus (PEDV) infection, Gly‐CDs possess extraordinary antiviral activity, providing a promising candidate for treatment of  respiratory syndrome virus infection. Has potential anti-2019-nCoV and may prevent the 2019-nCoV infection.	Unknown Unknown Inhibit RANTES secretion. Unknown The mechanism of glycyrrhizin's activity against SARS-CV may be through  Glycyrrhizin affects cellular signaling pathways such as protein kinase C; casein kinase II; and transcription factors such as activator protein 1 and nuclear factor κB. The antiviral activity is mediated by an interaction with the cell membrane which most likely results in reduced endocytotic activity and hence reduced virus uptake. Inhibition of H5N1-induced formation of reactive oxygen species and (in turn) reduced activation of NFκB, JNK, and p38, redox-sensitive signaling events known to be relevant for influenza A. Neuraminidase inhibitors GL dose dependently inhibit the expression of HCV 3a core gene both at mRNA and protein levels. Inhibitory effects on various neuraminidases. Due to its inhibitory effect on PLA2G1B( phospholipase A2 of  group 1B PLA2 Triterpenoids bind tightly to the viral envelope hemagglutinin (HA), disrupting the interaction of HA with the sialic acid receptor and thus the attachment of viruses to host cells. GRA induced a Beclin 1 production that was more than twofold higher than that produced by rapamycin, GRA is a strong inducer of the autophagy activator Beclin 1, which establishes a resistance state to HSV1 replication. Gycyrrhizin mainly inhibits the penetration stage, and has little effect on the steps of adsorption or release of PRRSV in its life cycle. With multisite inhibition mechanisms. Synergistic actions were primarily due to the inhibitory effect of glycyrrhizic acid on MRP4 and BCRP, which transport Entecavir out of hepatocytes. Triterpenoid block the entry of  many viruses by capturing the HR2 domain prevalent in viral envelopes. Unknown May through interaction with DENV2 targets like NS2B-NS3 protease, NS3 helicase, and NS5 RNA-dependent RNA polymerase. Glycyrrhizin inhibited PEDV infection and decreased proinflammatory cytokine secretion via the HMGB1/TLR4-mitogen-activated protein kinase (MAPK) p38 pathway. Host receptor for 2019-nCoV Angiotensinconverting enzyme 2 (ACE2), is the same as the host receptor for SARS-CoV. Gycyrrhizin. Unknown	Pompei et al., 1979 Pompei et al., 1980 Sato et al., 1996 Cinatl et al., 2003 Hoever et al., 2005 Wolkerstorfer et al., 2009 Michaelis et al., 2011 Dao et al., 2011 Ashfaq et al., 2017 Hardy et al., 2012 Matsumoto et al., 2013 Yu et al., 2014 Laconi et al., 2014 Duan et al., 2015 Baltina et al., 2015 Chen et al., 2017b Si et al., 2018 Liang  et al., 2019 Baltina et al., 2019 Gao et al., 2020 Tong et al.,(2020) Chen and Du, 2020