Cover Page

Cite item


Influenza is a highly contagious human disease. In the course of use of antiviral drugs drug-resistant strains of the virus are formed, resulting in reduced efficiency of the chemotherapy. The review describes the biological activity of glycirrhetinic (GLA) and glycirrhizic (GA) acids in terms of their use as a therapeutic agent for viral infections. So, these compounds are against a broad spectrum of viruses, including herpes, corona-, alphaand flaviviruses, human immunodeficiency virus, vaccinia virus, poliovirus type I, vesicular stomatitis virus and influenza A virus. These data indicate that anti-viral effect of these compounds is due to several types of activity — direct antiviral effects, effects on cellular proand anti-viral and immunomodulating pathways, in particular by activation of innate immunity system. GA interferes with early steps of the viral reproductive cycle such as virus binding to its receptor, the absorption of the virus by endocytosis or virus decapsidation in the cytoplasm. This is due to the effect of GA-induced reduction of membrane fluidity. Thus, one mechanism for the antiviral activity of GA is that GA molecule increases the rigidity of cellular and viral membranes after incorporation in there. This results in increasing of energy threshold required for the formation of negative curvature at the fusion zones, as well as difficult lateral migration of the virus-receptor complexes. In addition, glycyrrhizin prevents interaction of viral nucleoprotein with cellular protein HMGB1, which is necessary for the viral life cycle. Glycyrrhizin also inhibits the induction of oxidative stress during influenza infection, exhibiting antioxidant properties, which leads to a reduction of virus-induced production of cytokines/chemokines, without affecting the replication of the virus. A wide spectrum of biological activity and effect on various aspects of the viral pathogenesis substantiate the effect of GA and GLA as a component of a complex antiviral therapy. A combination of antiviral mechanisms makes GA and GLA unique means capable of providing an antiviral effect in many types of viral pathologies that emphasizes their prospects as a component of comprehensive antiviral therapy. Further research in the field of optimization of their application may lead to the development of new antiviral drugs and effective schemes of their combined application.

About the authors

V. V. Zarubaev

Research Institute of Influenza, 197376, Russian Federation, St. Petersburg, Professor Popov str., 15/17

Author for correspondence.

PhD (Biology), Leading Researcher, Department of Pre-Clinical Trials, Research Institute of Influenza, St. Petersburg, Russian Federation

Russian Federation

V. B. Anikin

Research Institute of Influenza, 197376, Russian Federation, St. Petersburg, Professor Popov str., 15/17


Senior Researcher, Department of Pre-Clinical Trials, Research Institute of Influenza, St. Petersburg, Russian Federation

Russian Federation

V. S. Smirnov

MBRD “Cytomed”, St. Petersburg, Russian Federation


PhD, MD (Medicine), Head Researcher, MBRD “Cytomed”, St. Petersburg, Russian Federation

Russian Federation


  1. Смирнов В.С., Зарубаев В.В., Анфимов П.М., Штро А.А. Влияние комбинации глутамил-триптофана с глицирризиновой кислотой на течение острой инфекции у мышей, вызванной вирусом гриппа (H3N2). Вопросы вирусологии. 2012. Т. 57, № 3. C. 23–27. [Smirnov V.S., Zarubaev V.V., Anfimov P.M., Shtro A.A. Effect of a combination of glutamyl-tryptophan and glycyrrhizic acid on the course of acute infection caused by influenza (H3H2) virus in mice. Voprosy virusologii = Problems of Virology, 2012, vol. 57, no. 3, pp. 23–27. (In Russ.)]
  2. Смирнов В.С., Гаршинина А.В., Штро А.А., Аникин В.Б., Галочкина А.В., Беляевская С.В., Зарубаев В.В. Протективная активность комбинации глутамил-триптофана и глицирризиновой кислоты при пероральном введении на модели экспериментальной летальной гриппозной инфекции у белых мышей, вызванной осельтамивир-устойчивым штаммом вируса. Вопросы вирусологии. 2014. Т. 59, № 5. С. 31–38. [Smirnov V.S., Garshinina A.V., Shtro A.A., Anikin V.B., Galochkina A.V., Belyaevskaya S.V., Zarubaev V.V. Anti-viral activity of complex of glycirrhysic acid–alpha-glutamyltryptophan against experimental lethal influenza infection in white mice caused by oseltamivir-resistant strain of the virus. Voprosy virusologii = Problems of Virology, 2014, vol. 59, no. 5, pp. 31–38. (In Russ.)]
  3. Abe N., Ebina T., Ishida N. Interferon induction by glycyrrhizin and glycyrrhetinic acid in mice. Microbiol. Immunol., 1982, vol. 26, pp. 535–539. doi: 10.1111/j.1348 0421.1982.tb00207.x
  4. Asl M.N., Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother. Res., 2008, vol. 22, pp. 709–724. doi: 10.1002/ptr.2362
  5. Aso H., Ebina T., Ishida N., Suzuki F. Antiviral activity of Ge-132 (an organic germanium compound) in mice infected with influenza A (H2N2) virus. Chemotherapy (Tokyo), 1986, vol. 34, pp. 665–671.
  6. Cai J., Chen Y., Seth S., Furukawa S., Compans R.W. Inhibition of influenza infection by glutathione. Free Radic. Biol. Med., 2003, vol. 34, pp. 928–936. doi: 10.1016/S0891 5849(03)00023-6
  7. Chang C.Z., Wu S.C., Kwan A.L. Glycyrrhizin attenuates Toll-like receptor-2, -4 and experimental vasospasm in a rat model. J. Immunol. Res., 2014: 740549. doi: 10.1155/2014/740549
  8. 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, vol. 361 (9374), pp. 2045–2046. doi: 10.1016/S0140 6736(03)13615-X
  9. Crance J.M., Biziagos E., Passagot J., Van Cuyck-Gandre H., Deloince R. Inhibition of hepatitis A virus replication in vitro by antiviral compounds. J. Med. Virol., 1990, vol. 31, pp. 155–160. doi: 10.1002/jmv.1890310214
  10. De Flora S., Grassi C., Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur. Respir. J., 1997, vol. 10, pp. 1535–1541.
  11. Geiler J., Michaelis M., Naczk P., Leutz A., Langer K. N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus. Biochem. Pharmacol., 2010, vol. 79, pp. 413–420. doi: 10.1016/j.bcp.2009.08.025
  12. Geiss G.K., An M.C., Bumgarner R.E., Hammersmark E,. Cunningham D. Global impact of influenza virus on cellular pathways is mediated by both replication-dependent and -independent events. J. Virol., 2001, vol. 75, pp. 4321–4331. doi: 10.1128/JVI.75.9.4321 4331.200
  13. Harada S. The broad anti-viral agent glycyrrhizin directly modulates the fluidity of plasma membrane and HIV-1 envelope. Biochem. J., 2005, vol. 392, pp. 191–199. doi: 10.1042/BJ20051069
  14. Hardy M.E., Hendricks J.M., Paulson J.M., Faunce N.R. 18β-glycyrrhetinic acid inhibits rotavirus replication in culture. Virol. J., 2012, vol. 9:96. doi: 10.1186/1743-422X-9-96
  15. Hattori M., Sakamoto T., Kobashi K., Namba T. Metabolism of glycyrrhizin by human intestinal flora. Planta Med., 1983, vol. 48(1), pp. 38–42.
  16. Hattori M., Sakamoto T., Yamagishi T., Sakamoto K., Konishi K., Kobashi K., Namba T. Metabolism of glycyrrhizin by human intestinal flora. II. Isolation and characterization of human intestinal bacteria capable of metabolizing glycyrrhizin and related compounds. Chem Pharm Bull (Tokyo), 1985, vol. 33 (1), pp. 210–217.
  17. Hendricks J.M., Hoffman C., Pascual D.W., Hardy M.E. 18b-glycyrrhetinic acid delivered orally induces isolated lymphoid follicle maturation at the intestinal mucosa and attenuates rotavirus shedding. PLoS ONE, 2012, vol. 7 (11), e49491. doi: 10.1371/journal.pone.0049491
  18. Hoever G., Baltina L., Michaelis M., Kondratenko R., Baltina L., Tolstikov G.A., Doerr H.W., Cinatl J. Jr. Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. J. Med. Chem., 2005, vol. 48 (4), pp. 1256–1259.
  19. Holm C.K., Jensen S.B., Jakobsen M.R., Cheshenko N., Horan K.A., Moeller H.B., Gonzalez-Dosal R., Rasmussen S.B., Christensen M.H., Yarovinsky T.O., Rixon F.J., Herold B.C., Fitzgerald K.A., Paludan S.R. Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING. Nat. Immunol., 2012, vol. 13 (8), pp. 737–743. doi: 10.1038/ni.2350
  20. Lampi G., Deidda D., Pinza M., Pompei R. Enhancement of anti-herpetic activity of glycyrrhizic acid by physiological proteins. Antivir. Chem. Chemother., 2001, vol. 12, pp. 125–131.
  21. Lin J.C. Mechanism of action of glycyrrhizic acid in inhibition of Epstein–Barr virus replication in vitro. Antiviral Res., 2003, vol. 59, pp. 41–47.
  22. Liu S.Y., Aliyari R., Chikere K., Li G., Marsden M.D., Smith J.K., Pernet O., Guo H., Nusbaum R., Zack J.A., Freiberg A.N., Su L., Lee B., Cheng G. Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity, 2013, vol. 38 (1), pp. 92–105. doi: 10.1016/j.immuni.2012.11.005
  23. 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, vol. 6 (5):e19705. doi: 10.1371/journal.pone.0019705
  24. Moisy D., Avilov S.V., Jacob Y., Laoide B.M., Ge X., Baudin F., Naffakh N., Jestin J.L. HMGB1 protein binds to influenza virus nucleoprotein and promotes viral replication. J. Virol., 2012, vol. 86 (17), pp. 9122–9133. doi: 10.1128/JVI.00789-12
  25. Perreira J.M., Chin C.R., Feeley E.M., Brass A.L. IFITMs restrict the replication of multiple pathogenic viruses. J. Mol. Biol., 2013, vol. 425 (24), pp. 4937–4955. doi: 10.1016/j.jmb.2013.09.024
  26. Pompei R., Paghi L., Ingianni A., Uccheddu P. Glycyrrhizic acid inhibits influenza virus growth in embryonated eggs. Microbiologica, 1983, vol. 6, pp. 247–250.
  27. Pompei R., Flore O., Marccialis M.A., Pani A. Loddo B. Glycyrrhizic acid inhibits virus growth and inactivates virus particles. Nature, 1979, vol. 281, pp. 689–690.
  28. Saito N., Suzuki F., Sasaki K., Ishida N. Antiviral and interferon-inducing activity of a new glutarimide antibiotic, 9-methylstreptimidone. Antimicrob. Agents Chemother., 1976, vol. 10, pp. 14–19.
  29. Saito N., Suzuki F., Ishida N. Antiviral effect of interferon on influenza virus infection in mice. Tohoku J. Exp. Med., 1983, vol. 139, pp. 355–363.
  30. 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, 2002–2003, vol. 70, pp. 229–236.
  31. Suzuki F., Suzuki С., Shimomura E., Maeda H., Fujii T., Ishida N. Antiviral and interferon-inducing activities of a new peptidomannan, KS-2, extracted from culture mycelia Lentinus edodes. J. Antibiot., 1979, vol. 32, pp. 1336–1345.
  32. Suzuki F., Saito N., Ishida N. Antiviral effects of the interferon and interferon inducers in experimental animals. Protein, Nucleic Acid, Enzyme, 1976, vol. 21, pp. 260–270.
  33. Suzuki F., Ishida N., Suzuki M., Sato T., Suzuki S. Effect of the interferon inducer, dextran phosphate, on influenza virus infection in mice. Proc. Soc. Exp. Biol. Med., 1975, vol. 149, pp. 1069–1075.
  34. Suzuki F., Ishida N. Effective mechanisms of interferon and their inducers in vivo. Jpn. J. Clin. Med., 1977, vol. 35, pp. 136–141.
  35. Suzuki F., Koide T., Tsunoda A., Ishida N. Mushroom extract as an interferon inducer. I. Biological and physicochemical properties of spore extracts of Lentinus edodes. Mushroom Sci., 1974, vol. 9, pp. 509–519.
  36. Suzuki F., Saito N., Ishida N. The protective effects of several interferon inducers on influenza virus infection in mice. Saishin Igaku, 1975, vol. 30, pp. 1078–1084.
  37. 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, vol. 41, pp. 551–556.
  38. 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, vol. 12, no. 3, pp. 199–205.
  39. Wang X., Hinson E.R., Cresswell P. The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts. Cell Host Microbe, 2007, vol. 2, no. 2, pp. 96–105.
  40. Wolkerstorfer A., Kurz H., Bachhofner N., Szolar O.H.J. Glycyrrhizin inhibits influenza A virus uptake into the cell. Antivir. Res., 2009, vol. 83, pp. 171–178. doi: 10.1016/j.antiviral.2009.04.012

Copyright (c) 2016 Zarubaev V.V., Anikin V.B., Smirnov V.S.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies