Abstract
Glycyrrhizic acid (GA), a triterpene isolated from the roots and rhizomes of licorice, named Glycyrrhiza glabra, is the principal bioactive ingredient of anti-viral, anti-inflammatory and hepatoprotective effects. GA has been used in the clinical treatment of hepatitis, bronchitis, gastric ulcer, AIDS (acquired immunodeficiency syndrome), certain cancers and skin diseases. It has a direct effect on anti-HBV (hepatitis B virus) via affecting the HBsAg (hepatitis B surface antigen) to extracellular secretion, improving liver dysfunction in patients with chronic hepatitis B, and ultimately improving the immune status of HBV. GA can significantly inhibit the proliferation of HIV, showing an immune activation. The clinical application of GA on the prevention and treatments of various diseases may derive from its numerous pharmacological properties. This review provides the summary of the antiviral effects of GA on research progress and mechanism in recent years.
Keywords: Glycyrrhizic acid, antiviral effects, hepatitis virus, HIV, influenza virus, herpes virus.
Graphical Abstract
[1]
Fiore, C.; Eisenhut, M.; Krausse, R.; Ragazzi, E.; Pellati, D.; Armanini, D.; Bielenberg, J. Antiviral effects of Glycyrrhiza species. Phytother. Res., 2008, 22(2), 141-148.
[2]
Li, Y.; Sun, F.; Jing, Z.; Wang, X.; Hua, X.; Wan, L. Glycyrrhizic acid exerts anti-inflammatory effect to improve cerebral vasospasm secondary to subarachnoid hemorrhage in a rat model. Neurol. Res., 2017, 39(8), 727-732.
[3]
Pang, H.; Huang, T.; Song, J.; Li, D.; Zhao, Y.; Ma, X. Inhibiting HMGB1 with glycyrrhizic acid protects brain injury after DAI via its anti-inflammatory effect. Mediators Inflamm., 2016, 2016(3)4569521
[4]
Akman, T.; Guven, M.; Aras, A.B.; Ozkan, A.; Sen, H.M.; Okuyucu, A.; Kalkan, Y.; Sehitoglu, I.; Silan, C.; Cosar, M. The neuroprotective effect of glycyrrhizic acid on an experimental model of focal cerebral ischemia in rats. Inflammation, 2015, 38(4), 1-8.
[5]
Orazizadeh, M.; Fakhredini, F.; Mansouri, E.; Khorsandi, L. Effect of glycyrrhizic acid on titanium dioxide nanoparticles-induced hepatotoxicity in rats. Chem. Biol. Interact., 2014, 220, 214-221.
[6]
Ojha, S.; Javed, H.; Azimullah, S.; Abul Khair, S.B.; Haque, M.E. Glycyrrhizic acid attenuates neuroinflammation and oxidative stress in rotenone model of parkinson’s disease. Neurotox. Res., 2015, 29(2), 1-13.
[7]
Ming, L.J.; Yin, A.C. Therapeutic effects of glycyrrhizic acid. Nat. Prod. Commun., 2013, 8(3), 415-418.
[8]
Su, X.; Wu, L.; Hu, M.; Dong, W.; Xu, M.; Zhang, P. Glycyrrhizic acid: A promising carrier material for anticancer therapy. Biomed. Pharmacother., 2017, 95, 670-678.
[9]
Hoever, G.; Baltina, L.; Michaelis, M.; Kondratenko, R.; Baltina, L. GAT; HWD; Cinatl, J. Antiviral activity of glycyrrhizic acid derivatives against SARS−coronavirus. J. Med. Chem., 2005, 48(4), 1256-1259.
[10]
Baltina, L.A. Chemical modification of glycyrrhizic acid as a route to new bioactive compounds for medicine. Curr. Med. Chem., 2003, 10(2), 155-171.
[11]
Lin, J.C.; Cherng, J.M.; Hung, M.S.; Baltina, L.A.; Baltina, L.; Kondratenko, R. Inhibitory effects of some derivatives of glycyrrhizic acid against Epstein-Barr virus infection: Structure-activity relationships. Antiviral Res., 2008, 79(1), 6-11.
[12]
Baba, M.; Shigeta, S. Antiviral activity of glycyrrhizin against varicella-zoster virus in vitro. Antiviral Res., 1987, 7(2), 99-107.
[13]
Fenwick, G.R.; Lutomski, J.; Nieman, C. Liquorice, Glycyrrhiza glabra L.—Composition, uses and analysis. Food Chem., 1990, 38(2), 119-143.
[14]
Hayashi, H.; Huang, P.; Kirakosyan, A.; Inoue, K.; Hiraoka, N.; Ikeshiro, Y.; Kushiro, T.; Shibuya, M.; Ebizuka, Y. Cloning and characterization of a cDNA encoding beta-amyrin synthase involved in glycyrrhizin and soyasaponin biosyntheses in licorice. Biol. Pharm. Bull., 2001, 24(8), 912-916.
[15]
Shaneyfelt, M.E.; Burke, A.D.; Graff, J.W.; Jutila, M.A.; Hardy, M.E. Natural products that reduce rotavirus infectivity identified by a cell-based moderate-throughput screening assay. Virol. J., 2006, 3(1), 68.
[16]
Mori, K.; Sakai, H.; Suzuki, S.; Sugai, K.; Akutsu, Y.; Ishikawa, M.; Seino, Y.; Ishida, N.; Uchida, T.; Kariyone, S. Effects of glycyrrhizin (SNMC: Stronger Neo-Minophagen C) in hemophilia patients with HIV infection. Tohoku J. Experiment. Med, 1989, 158(1), 25-35.
[17]
Thyagarajan, S.P.; Jayaram, S.; Gopalakrishnan, V.; Hari, R.; Jeyakumar, P.; Sripathi, M.S. Herbal medicines for liver diseases in India. J. Gastroenterol. Hepatol., 2002, 17, Suppl 3(s3), S370-S376.
[18]
Harada, S. The broad anti-viral agent glycyrrhizin directly modulates the fluidity of plasma membrane and HIV-1 envelope. Biochem. J., 2005, 392(Pt 1), 191-199.
[19]
Selyutina, O.Y.; Polyakov, N.E.; Korneev, D.V.; Zaitsev, B.N. Effect of glycyrrhizic acid on hemolysis of red blood cells and properties of cell membranes. Russ. Chem. Bull., 2014, 63(5), 1201-1204.
[20]
Selyutina, O.Y.; Apanasenko, I.E.; Polyakov, N.E. Membrane-modifying activity of glycyrrhizic acid. Russ. Chem. Bull., 2015, 64(7), 1555-1559.
[21]
Baltina, L.A.; Kondratenko, R.M.; Baltina, L.A.; Nzh, B.; Pliasunova, O.A. Synthesis and biological activity of new glycyrrhizic acid conjugates with amino acids and dipeptides. Russ. J. Bioorganic Chem., 2009, 35(4), 510-517.
[22]
Koonin, E.V.; Senkevich, T.G.; Dolja, V.V. The ancient Virus World and evolution of cells. Biol. Direct, 2006, 1(1), 29.
[23]
Estoppey, D.; Lee, C.M.; Janoschke, M.; Lee, B.H.; Wan, K.F.; Dong, H.; Mathys, P.; Filipuzzi, I.; Schuhmann, T.; Riedl, R. The natural product cavinafungin selectively interferes with zika and dengue virus replication by inhibition of the host signal peptidase. Cell Rep., 2017, 19(3), 451-460.
[24]
van Rossum, T.G.; Vulto, A.G.; de Man, R.A.; Brouwer, J.T.; Schalm, S.W. Review article: glycyrrhizin as a potential treatment for chronic hepatitis C. Aliment. Pharmacol. Ther., 1998, 12(3), 199-205.
[25]
van Rossum, T.G.; Vulto, A.G.; Hop, W.C.; Schalm, S.W. Glycyrrhizin-induced reduction of ALT in European patients with chronic hepatitis C. Am. J. Gastroenterol., 2001, 96(8), 2432-2437.
[26]
Hidaka, I.; Hino, K.; Korenaga, M.; Gondo, T.; Nishina, S.; Ando, M.; Okuda, M.; Sakaida, I. Stronger Neo-Minophagen C, a glycyrrhizin-containing preparation, protects liver against carbon tetrachloride-induced oxidative stress in transgenic mice expressing the hepatitis C virus polyprotein. Liver Int., 2007, 27(6), 845-853.
[27]
Takahara, T.; Watanabe, A.; Shiraki, K. Effects of glycyrrhizin on hepatitis B surface antigen: A biochemical and morphological study. J. Hepatol., 1994, 21(4), 601-609.
[28]
Sato, H.; Goto, W.; Yamamura, J.; Kurokawa, M.; Kageyama, S.; Takahara, T.; Watanabe, A.; Shiraki, K. Therapeutic basis of glycyrrhizin on chronic hepatitis B. Antiviral Res., 1996, 30(2-3), 171-177.
[29]
Tao, X.; Lou, L.; Xiaofei, L.I.; Chen, Y.; Weiwei, Y.E.; Shuang, W.U. Efficacy of glycyrrhizic acid monopotassium salt tablet in treatment of chronic hepatitis B. Chin. Arch. Tradit. Chin. Med, 2013, 31(6), 1437-1439.
[30]
Kiso, Y.; Tohkin, M.; Hikino, H.; Hattori, M.; Sakamoto, T.; Namba, T. Mechanism of antihepatotoxic activity of glycyrrhizin. I: Effect on free radical generation and lipid peroxidation. Planta Med., 1984, 50(4), 298-302.
[31]
Jeong, H.G.; You, H.J.; Park, S.J.; Moon, A.R.; Chung, Y.C.; Kang, S.K.; Chun, H.K. Hepatoprotective effects of 18beta-glycyrrhetinic acid on carbon tetrachloride-induced liver injury: inhibition of cytochrome P450 2E1 expression. Pharmacol. Res., 2002, 46(3), 221-227.
[32]
Tandon, A.; Tandon, B.N.; Bhujwala, R.A. Treatment of subacute hepatitis with Lamivudine and intravenous Glycyrrhizin: A pilot study. Hepatol. Res. Off. J. Japan Soc. Hepatol, 2001, 20(1), 1-8.
[33]
Kang, F.B.; Wang, L.; Sun, D.X. Hepatitis B virus infection in an HBsAb-positive lymphoma patient who received chemotherapy. A case report. Medicine., 2017, 96(44)e8518
[34]
Song-Qi, B.U.; Xia, Q.Q.; Zhong-Ping, P.U.; Wards, T. Clinical therapeutic effects on chronic viral hepatitis B in the patients treated with the compound chinese herbal formula and western medicine. World J. Integrat. Tradit. West. Med, 2018, 13(1), 77-80.
[35]
Penin, F.; Dubuisson, J.; Rey, F.A.; Moradpour, D.; Pawlotsky, J.M. Structural biology of hepatitis C virus. Hepatology, 2004, 39(1), 5-19.
[36]
Matsumoto, Y.; Matsuura, T.; Aoyagi, H.; Matsuda, M.; Hmwe, S.S.; Date, T.; Watanabe, N.; Watashi, K.; Suzuki, R.; Ichinose, S. Antiviral activity of glycyrrhizin against hepatitis C virus in vitro. PLoS One, 2013, 8(7)e68992
[37]
Ashfaq, U.A.; Masoud, M.S.; Nawaz, Z.; Riazuddin, S. Glycyrrhizin as antiviral agent against Hepatitis C Virus. J. Transl. Med., 2011, 9(1), 112.
[38]
Arase, Y.; Ikeda, K.; Murashima, N.; Chayama, K.; Tsubota, A.; Koida, I.; Suzuki, Y.; Saitoh, S.; Kobayashi, M.; Kumada, H. The long term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer, 1997, 79(8), 1494-1500.
[39]
Orlent, H.; Hansen, B.E.; Willems, M.; Brouwer, J.T.; Huber, R.; Kullak-Ublick, G.A.; Gerken, G.; Zeuzem, S.; Nevens, F.; Tielemans, W.C.M. Biochemical and histological effects of 26 weeks of glycyrrhizin treatment in chronic hepatitis C: A randomized phase II trial. J. Hepatol., 2006, 45(4), 539-546.
[40]
Cherng, J-M.; Lin, H-J.; Hsu, Y-H.; Hung, M-S.; Lin, J-C. A quantitative bioassay for HIV-1 gene expression based on UV activation: effect of glycyrrhizic acid. Antiviral Res., 2004, 62(1), 27-36.
[41]
Sasaki, H.; Takei, M.; Kobayashi, M.; Pollard, R.B.; Suzuki, F. Effect of glycyrrhizin, an active component of licorice roots, on hiv replication in cultures of peripheral blood mononuclear cells from HIV-seropositive patients. Pathobiology, 2002, 70(4), 229-236.
[42]
Wang, J.; Guo, J.; Liu, S. Inhibitory effect of glycyrrhizin on NF-kappa B binding activity in CCl4 plus ethanol induced liver cirrhosis in rats. Liver Int., 1998, 18(3), 180-185.
[43]
Wang, C.; Lu, L.; Na, H.; Li, X.; Wang, Q.; Jiang, X.; Xu, X.; Yu, F.; Zhang, T.; Li, J. Conjugation of a nonspecific antiviral sapogenin with a specific HIV fusion inhibitor: A promising strategy for discovering new antiviral therapeutics. J. Med. Chem., 2014, 57(17), 7342-7354.
[44]
Zheng, C.G.; Wu, C.Q.; Xue, M.H.; Ma, Z.H. Clinical study of thymopentin combined with glycyrrhizin in the treatment of liver damage in patients with HIV/AIDS. Heilongjiang Med. J., 2017, 30(4), 727-730.
[45]
Chen, X.X.; Zhou, H.X.; Qi, W.B.; Ning, Z.Y.; Ma, Y.J.; Li, Y.L.; Wang, G.C.; Chen, J.X. Antiviral effects of the combination of glycyrrhizin and ribavirin against influenza A H1N1 virus infection in vivo. Yao xue xue bao =. Acta pharmaceutica Sinica, 2015, 50(8), 966-972.
[46]
Utsunomiya, T.; Kobayashi, M.; Pollard, R.B.; Suzuki, F. Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus. Antimicrob. Agents Chemother., 1997, 41(3), 551-556.
[47]
Wolkerstorfer, A.; Kurz, H.; Bachhofner, N.; Szolar, O.H. Glycyrrhizin inhibits influenza A virus uptake into the cell. Antiviral Res., 2009, 83(2), 171-178.
[48]
Hsieh, C.F.; Lo, C.W.; Liu, C.H.; Lin, S.; Yen, H.R.; Lin, T.Y.; Horng, J.T. Mechanism by which ma-xing-shi-gan-tang inhibits the entry of influenza virus. J. Ethnopharmacol., 2012, 143(1), 57-67.
[49]
Michaelis, M.; Geiler, J.; Naczk, P.; Sithisarn, P.; Leutz, A.; Doerr, H.W.; Cinatl, J., Jr Glycyrrhizin exerts antioxidative effects in H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory gene expression. PLoS One, 2011, 6(5)e19705
[50]
Camberos, L.O.; Tapia, G.; Gutiérrez, L.; López, H.S.S. Effects of
glycyrrhizic acid (Viusid-Vet® powder) on the reduction of influenza
virus spread and on production parameters in pigs. 2017, 4(1), 32-44.
[51]
Baltina, L.A.; Zarubaev, V.V.; Baltina, L.A.; Orshanskaya, I.A.; Fairushina, A.I.; Kiselev, O.I.; Yunusov, M.S. Glycyrrhizic acid derivatives as influenza A/H1N1 virus inhibitors. Bioorg. Med. Chem. Lett., 2015, 25(8), 1742-1746.
[52]
Tsuji, M.; Sriwilaijaroen, N.; Inoue, H.; Miki, K.; Kinoshita, K.; Koyama, K.; Furuhata, K.; Suzuki, Y.; Takahashi, K. Synthesis and anti-influenza virus evaluation of triterpene-sialic acid conjugates. Bioorg. Med. Chem., 2018, 26(1), 17-24.
[53]
Sekizawa, T.; Yanagi, K.Y. Glycyrrhizin increases survival of mice with herpes simplex encephalitis. Acta Virol., 2001, 45(1), 51-54.
[54]
Lampi, G.; Deidda, D.; Pinza, M.; Pompei, R. Enhancement of anti-herpetic activity of glycyrrhizic acid by physiological proteins. Antivir. Chem. Chemother., 2001, 12(2), 125-131.
[55]
Lin, J.C. Mechanism of action of glycyrrhizic acid in inhibition of Epstein-Barr virus replication in vitro. Antiviral Res., 2003, 59(1), 41-47.
[56]
Curreli, F.; Friedman-Kien, A.E.; Flore, O. Glycyrrhizic acid alters Kaposi sarcoma-associated herpesvirus latency, triggering p53-mediated apoptosis in transformed B lymphocytes. J. Clin. Invest., 2005, 115(3), 642-652.
[57]
Kang, H.; Lieberman, P.M. Mechanism of glycyrrhizic acid inhibition of kaposi’s sarcoma-associated herpesvirus: Disruption of CTCF-Cohesin-Mediated RNA Polymerase II pausing and sister chromatid cohesion. J. Virol., 2011, 85(21), 11159-11169.
[58]
Wang, Y.H.; Lan, W.Y.; Chen, T. Antiviral effects of glycyrrhizic acid on human cytomegalovirus AD169 strain in vitro. Chin. Tradit. Pat. Med., 2016, 38(10), 2121-2127.
[59]
Yang, G. Clinical effects of valaciclovir combined with compound glycyrrhizin in the treatment of herpes zoster. China Modern Doctor, 2015, 53(17), 111-113.
[60]
Kai, L.I.; Tan, Y.; Liu, Z.; Department, M. The clinical curative effect of acyclovir combined with Glycyrrhizin in treatment of herpes zoster and postherpetic neuralgia. China Med. Pharm, 2015, 5(15), 109-111.
[61]
Liu, L.; Zhang, X.B. Therapeutic Efficacy Observation of Famciclovir Combined with Compound Glycyrrhizin for Recurrent Genital Herpes. Chin. J. Dermatovenereol., 2013, 27(6), 641-642.
[62]
Cinatl, J.; Morgenstern, B.; Bauer, G.; Chandra, P.; Rabenau, H.; Doerr, H.W. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet, 2003, 361(9374), 2045-2046.
[63]
Chen, F.; Chan, K.H.; Jiang, Y.; Kao, R.Y.; Lu, H.T.; Fan, K.W.; Cheng, V.C.; Tsui, W.H.; Hung, I.F.; Lee, T.S. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J. Clin. Virol., 2004, 31(1), 69-75.
[64]
Wu, Y.S.; Lin, W.H.; Hsu, J.T.; Hsieh, H.P. Antiviral drug discovery against SARS-CoV. Curr. Med. Chem., 2006, 13(17), 2003-2020.
[65]
Zhang, H.; Song, Y.; Zhang, Z. Glycyrrhizin administration ameliorates coxsackievirus B3-induced myocarditis in mice. Am. J. Med. Sci., 2012, 344(3), 206-210.
[66]
Wang, J.; Chen, X.; Wang, W.; Zhang, Y.; Yang, Z.; Jin, Y.; Ge, H.M.; Li, E.; Yang, G. Glycyrrhizic acid as the antiviral component of Glycyrrhiza uralensis Fisch. against coxsackievirus A16 and enterovirus 71 of hand foot and mouth disease. J. Ethnopharmacol., 2013, 147(1), 114-121.
[67]
Ohtsuki, K.; Iahida, N. Inhibitory effect of glycyrrhizin on polypeptide phosphorylation by polypeptide-dependent protein kinase (kinase P) in vitro. Biochem. Biophys. Res. Commun., 1988, 157(2), 597-604.
[68]
Badam, L. In vitro antiviral activity of indigenous glycyrrhizin, licorice and glycyrrhizic acid (Sigma) on Japanese encephalitis virus. J. Commun. Dis., 1997, 29(2), 91-99.
[69]
Crance, J.M.; Scaramozzino, N.; Jouan, A.; Garin, D. Interferon, ribavirin, 6-azauridine and glycyrrhizin: antiviral compounds active against pathogenic flaviviruses. Antiviral Res., 2003, 58(1), 73-79.
[70]
Wang, W.; Zhao, Y.; Zhao, X.; Zu, Y.; Fu, Y. Anti-HSV-1 Activity of Glycyrrhizic Acid Nanoparticles Prepared by Supercritical Antisolvent Process. Curr. Nanosci., 2015, 11(3), 366-370.
Related Books
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Frontiers in Natural Product Chemistry
Therapeutic Use of Plant Secondary Metabolites
Therapeutic Implications of Natural Bioactive Compounds
Frontiers in Bioactive Compounds
Frontiers in Natural Product Chemistry
Frontiers in Natural Product Chemistry
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Frontiers in Natural Product Chemistry
Frontiers in Natural Product Chemistry
Article Metrics
192
29