Glycyrrhizic Acid Derivatives as New Antiviral and Immune Modulating Agents

Lidia       Baltina; Rimma       Kondratenko
doi:10.2174/1573407216666200210122751
Abstract

The search for new drugs to treat viral infections and immune deficiencies of various etiologies is still one of the most important tasks of medicinal chemistry, pharmacy, and medicine due to the widespread prevalence of a number of socially dangerous viral infections. This review focuses on the chemical modification of Glycyrrhizic acid (Gl), the main component of licorice root, which is currently a leading natural glycoside that is considered to be promising for the development of new antiviral agents. The review presents the results of studies conducted over the past 15 years to obtain a library of Gl acid derivatives for biological studies and to search for leader compounds. The synthesis of new biologically active derivatives and analogues (conjugates with amino acids and dipeptides, amino sugars, licorice triterpene acids conjugates with amino sugars, saponins and mono glycosides, and heterocyclic amides) was conducted, and their antiviral and immune modulating properties were studied. Potent inhibitors of HIV, SARS CoV, Epstein-Barr, and influenza A/H1N1 viruses and the stimulators of primary immune response were found among the Gl derivatives and analogues that were produced.
Keywords: Glycyrrhizic acid, derivatives, analogues, synthesis, immune modulators, antivirals.
Graphical Abstract

[1] 
WHO. available at:  2014.http://www.who.int/mediacentre/ factsheets/fs286/en/
[2] 
De Clercq, E. Antivirals: Past, present and future. Biochem. Pharmacol.,  2013, 85(6), 727-744.
[http://dx.doi.org/10.1016/j.bcp.2012.12.011] [PMID:  23270991] 
[3] 
Martinez, J.P.; Sasse, F.; Brönstrup, M.; Diez, J.; Meyerhans, A. Antiviral drug discovery: Broad-spectrum drugs from nature. Nat. Prod. Rep.,  2015, 32(1), 29-48.
[http://dx.doi.org/10.1039/C4NP00085D] [PMID:  25315648] 
[4] 
De Clercq, E. Recent highlights in the development of new antiviral drugs. Curr. Opin. Microbiol.,  2005, 8(5), 552-560.
[http://dx.doi.org/10.1016/j.mib.2005.08.010] [PMID:  16125443] 
[5] 
Mishra, B.B.; Tiwari, V.K. Natural products: An evolving role in future drug discovery. Eur. J. Med. Chem.,  2011, 46(10), 4769-4807.
[http://dx.doi.org/10.1016/j.ejmech.2011.07.057] [PMID:  21889825] 
[6] 
Cragg, G.M.; Newman, D.J. Natural products: A continuing source of novel drug leads. Biochim. Biophys. Acta,  2013, 1830(6), 3670-3695.
[http://dx.doi.org/10.1016/j.bbagen.2013.02.008] [PMID:  23428572] 
[7] 
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod.,  2016, 79(3), 629-661.
[http://dx.doi.org/10.1021/acs.jnatprod.5b01055] [PMID:  26852623] 
[8] 
Chattopadhyay, D.; Sarkar, M.C.; Chatterjee, T.; Sharma Dey, R.; Bag, P.; Chakraborti, S.; Khan, M.T. Recent advancements for the evaluation of anti-viral activities of natural products. N. Biotechnol.,  2009, 25(5), 347-368.
[http://dx.doi.org/10.1016/j.nbt.2009.03.007] [PMID:  19464980] 
[9] 
Butler, M.S.; Robertson, A.A.B.; Cooper, M.A. Natural product and natural product derived drugs in clinical trials. Nat. Prod. Rep.,  2014, 31(11), 1612-1661.
[http://dx.doi.org/10.1039/C4NP00064A] [PMID:  25204227] 
[10] 
Barnes, E.C.; Kumar, R.; Davis, R.A. The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery. Nat. Prod. Rep.,  2016, 33(3), 372-381.
[http://dx.doi.org/10.1039/C5NP00121H] [PMID:  26739749] 
[11] 
Asl, M.N.; Hosseinzadeh, H. 
            Review of pharmacological effects of 
            Glycyrrhiza sp
            . and its bioactive compounds.
           Phytother. Res.,  2008, 22(6), 709-724.
[http://dx.doi.org/10.1002/ptr.2362] [PMID:  18446848] 
[12] 
Wang, X.; Zhang, H.; Chen, L.; Shan, L.; Fan, G.; Gao, X. Liquorice, a unique “guide drug” of traditional Chinese medicine: A review of its role in drug interactions. J. Ethnopharmacol.,  2013, 150(3), 781-790.
[http://dx.doi.org/10.1016/j.jep.2013.09.055] [PMID:  24201019] 
[13] 
Saxena, S. Glycyrrhiza glabra: Medicine over the millennium. Nat. Prod. Radiance,  2005, 4, 358-367.
[14] 
Sharma, F.; Ohtsuki, K.; Hasanzadeh, E.; Rezazadeh, Sh. The anti-inflammatory and anti-viral effects of an ethnic medicine: Glycyrrhizin. Faslnamah-i Giyahan-i Daruyi,  2010, 9, 1-28.
[15] 
Niu, T.; Yang, J.; Zhang, L.; Cheng, X.; Li, K.; Zhou, G. Research advances on anticancer effect of licorice. Curr. Bioact. Compd.,  2009, 5, 234-242.
[http://dx.doi.org/10.2174/157340709789054803] 
[16] 
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.
[http://dx.doi.org/10.1002/ptr.2295] [PMID:  17886224] 
[17] 
Pompei, R.; Laconi, S.; Ingianni, A. Antiviral properties of glycyrrhizic acid and its semisynthetic derivatives. Mini Rev. Med. Chem.,  2009, 9(8), 996-1001.
[http://dx.doi.org/10.2174/138955709788681636] [PMID:  19601894] 
[18] 
Baltina, L.A.; Kondratenko, R.M.; Baltina, L.A., Jr; Plyasunova, O.A.; Pokrovskyi, A.G.; Tolstikov, G.A. Prospects for the creation of new antiviral drugs based on Glycyrrhizic acid and its derivatives. Pharm. Chem. J.,  2009, 43, 539-548.
[http://dx.doi.org/10.1007/s11094-010-0348-2] 
[19] 
Graebin, C.S.; Verli, H.; Guimaraes, J.A. Glycyrrhizin and Glycyrrhetinic acid: Scaffolds to promising new pharmacologically active compounds. J. Braz. Chem. Soc.,  2010, 21, 1595-1615.
[http://dx.doi.org/10.1590/S0103-50532010000900002] 
[20] 
Sun, Z-G.; Zhao, T-T.; Lu, N.; Yang, Y-A.; Zhu, H-L. Research progress of Glycyrrhizic acid on antiviral activity. Mini Rev. Med. Chem.,  2019, 19(10), 826-832.
[http://dx.doi.org/10.2174/1389557519666190119111125] [PMID:  30659537] 
[21] 
Chen, K.; Yang, R.; Shen, F.; Zhu, H-L. Advances in pharmacological activities and mechanisms of glycyrrhizic acid. Curr. Med. Chem.,  2020, 27(36), 6219-6243.
[http://dx.doi.org/10.2174/0929867325666191011115407] [PMID:  31612817] 
[22] 
Tolstikov, G.A.; Baltina, L.A.; Grankina, V.P.; Kondratenko, R.M.; Tolstikova, T.G. Licorice: Biodiversity, chemistry, and application in medicine. Novosibirsk; Academic Publishing House: Geo, 2007. 
[23] 
Baltina, L.A.; Serdyuk, N.G.; Flekhter, O.B.; Krasnova, L.V.; Davydova, V.A.; Ismagilova, A.F.; Zarudii, F.S.; Tolstikov, G.A. Isomerization of glycyrrhizic acid. Antiulcer activity. Pharm. Chem. J.,  1996, 30, 613-616.
[http://dx.doi.org/10.1007/BF02333885] 
[24] 
Iwama, H.; Amagaya, S.; Ogihara, Y. 
            Effects of kampohozai (Chinese traditional medicines) on the immune responses; I. 
            
              In vivo
            
             studies of hochuekkito, juzendaihoto and tokishakuyakusan using sheep red blood cell as antigen in mice.
           Planta Med.,  1986, (4), 247-250.
[http://dx.doi.org/10.1055/s-2007-969143] [PMID:  3763710] 
[25] 
Kondratenko, R.M.; Baltina, L.A.; Mustafina, S.R.; Makarova, N.V.; Nasyrov, K.M.; Tolstikov, G.A. Crystalline Glycyrrhizic acid synthesized from commercial glycyrrham. Immune modulate property of high-purity Glycyrrhizic acid. Pharm. Chem. J.,  2001, 35, 101-104.
[http://dx.doi.org/10.1023/A:1010481123359] 
[26] 
Liang, Z.; Zhu, T.; Hang, W. 
            A preliminary study of immunoregulatory effect of glycyrrhizin. 
            Zhongguo Yike Daxue Xuebao
            , 
            1991
            ,20
            , 257-259.
           
[27] 
Utsunomiya, T.; Kobayashi, M.; Ito, M.; Herndon, D.N.; Pollard, R.B.; Suzuki, F. Glycyrrhizin restores the impaired IL-12 production in thermally injured mice. Cytokine,  2001, 14(1), 49-55.
[http://dx.doi.org/10.1006/cyto.2001.0847] [PMID:  11298492] 
[28] 
Sui, X.; Yin, J.; Ren, X. Antiviral effect of diammonium glycyrrhizinate and lithium chloride on cell infection by pseudorabies herpesvirus. Antiviral Res.,  2009, 9, 996-1001.
[29] 
Wang, W.; Zhao, Y-L.; Zhao, Z-H.; Zu, Y-G. fu Y.-J. Anti-HSV-1 activity of Glycyrrhizic acid nanoparticles prepared by supercritical antisolvent process. Curr. Nanosci.,  2015, 11, 366-370.
[http://dx.doi.org/10.2174/1573413711666150123230335] 
[30] 
Baba, M.; Shigeta, S. 
            Antiviral activity of glycyrrhizin against varicella-zoster virus 
            in vitro. Antiviral Res.,  1987, 7(2), 99-107.
[http://dx.doi.org/10.1016/0166-3542(87)90025-8] [PMID:  3034150] 
[31] 
Crance, J-M.; Lévêque, F.; Biziagos, E.; van Cuyck-Gandré, H.; Jouan, A.; Deloince, R. 
            Studies on mechanism of action of glycyrrhizin against hepatitis A virus replication 
            in vitro. Antiviral Res.,  1994, 23(1), 63-76.
[http://dx.doi.org/10.1016/0166-3542(94)90033-7] [PMID:  8141593] 
[32] 
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.
[http://dx.doi.org/10.1016/0166-3542(96)00942-4] [PMID:  8783808] 
[33] 
Matsumoto, Y.; Matsuura, T.; Aoyagi, H.; Matsuda, M.; Hmwe, S.S.; Date, T.; Watanabe, N.; Watashi, K.; Suzuki, R.; Ichinose, S.; Wake, K.; Suzuki, T.; Miyamura, T.; Wakita, T.; Aizaki, H. 
            Antiviral activity of glycyrrhizin against hepatitis C virus 
            in vitro. PLoS One,  2013, 8(7), e68992.
[http://dx.doi.org/10.1371/journal.pone.0068992] [PMID:  23874843] 
[34] 
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.
[http://dx.doi.org/10.1002/(SICI)1097-0142(19970415)79:8<1494:AID-CNCR8>3.0.CO;2-B] [PMID:  9118029] 
[35] 
Iino, S.; Tango, T.; Matsushima, T.; Toda, G.; Miyake, K.; Hino, K.; Kumada, H.; Yasuda, K.; Kuroki, T.; Hirayama, C.; Suzuki, H. Therapeutic effects of stronger neo-minophagen C at different doses on chronic hepatitis and liver cirrhosis. Hepatol. Res.,  2001, 19(1), 31-40.
[http://dx.doi.org/10.1016/S1386-6346(00)00079-6] [PMID:  11137478] 
[36] 
Kumada, H. Long-term treatment of chronic hepatitis C with glycyrrhizin [Stronger Neo-Minophagen C (SNMC)] for preventing liver cirrhosis and hepatocellular carcinoma. Oncology,  2002, 62(Suppl. 1), 94-100.
[http://dx.doi.org/10.1159/000048283] [PMID:  11868794] 
[37] 
Zhang, C.; Li, Q-J.; Wang, Y-L.; Chen, J.; Lv, C-Y.; Liu, W.W.; Chen, L.; He, J-Y.; Jiang, D-Y.; Xia, X-W.; Ding, W-J. The in vitro antiviral mechanisms of Stronger Neo-Minophagen C, an established formulation of compound Glycyrrhizin. Antiinfect. Agents,  2018, 16, 136-143.
[http://dx.doi.org/10.2174/2211352516666180619142745] 
[38] 
Okuno, T.; Arai, K.; Shindo, M. Efficacy of interferon combined glycyrrhizin therapy in patients with interferon-resistant chronic hepatitis C. Nihon Rinsho,  1995, 53(Pt 1)(Suppl), 1022-1025.
[PMID: 7563661] 
[39] 
Matsuo, K.; Takenaka, K.; Shimomura, H.; Fujii, N.; Shinagawa, K.; Kiura, K.; Harada, M. Lamivudine and glycyrrhizin for treatment of chemotherapy-induced Hepatitis B Virus (HBV) hepatitis in a chronic HBV carrier with non-Hodgkin lymphoma. Leuk. Lymphoma,  2001, 41(1-2), 191-195.
[http://dx.doi.org/10.3109/10428190109057970] [PMID:  11342373] 
[40] 
Ito, M.; Nakashima, H.; Baba, M.; Pauwels, R.; De Clercq, E.; Shigeta, S.; Yamamoto, N. Inhibitory effect of glycyrrhizin on the in vitro infectivity and cytopathic activity of the human immunodeficiency virus HIV (HTLV-III/LAV). Antiviral Res.,  1987, 7(3), 127-137.
[http://dx.doi.org/10.1016/0166-3542(87)90001-5] [PMID:  3475037] 
[41] 
Hattori, T.; Ikematsu, S.; Koito, A.; Matsushita, S.; Maeda, Y.; Hada, M.; Fujimaki, M.; Takatsuki, K. Preliminary evidence for inhibitory effect of glycyrrhizin on HIV replication in patients with AIDS. Antiviral Res.,  1989, 11(5-6), 255-261.
[http://dx.doi.org/10.1016/0166-3542(89)90035-1] [PMID:  2572198] 
[42] 
Ikegami, N.; Kinoshita, S.; Kanesaki, T.; Uno, K.; Akatani, K.; Kisida, T. Evaluation of long term treatment with glycyrrhizin and of combination therapy with glycyrrhizin and AZT or DDI on HIV-1 carries. Antiviral Res.,  1996, 30, A33.
[http://dx.doi.org/10.1016/0166-3542(96)80279-8] 
[43] 
Plyasunova, O.A.; Mamaev, O.A.; Gashnikova, N.M.; Fedyuk, N.V.; Pokrovsky, A.G. 
            Evaluation of the effectiveness of anti-HIV drugs using chronically infected HIV-1 culture of human monocytes. 
            Russ. Zhur. HIV/AIDS kinship. Problems,  1999, 3, 58.
[44] 
Plyasunova, O.A.; Egoricheva, I.N.; Fedyuk, N.B.; Pokrovskii, A.G.; Baltina, L.A.; Murinov, Y.I.; Tolstikov, G.A. Study of anti-HIV activity of β-Glycyrrhizic acid. Vopr. Virusol.,  1992, (5-6), 235-238.
[45] 
De Clercq, E. Current lead natural products for the chemotherapy of Human Immunodeficiency Virus (HIV) infection. Med. Res. Rev.,  2000, 20(5), 323-349.
[http://dx.doi.org/10.1002/1098-1128(200009)20:5<323:AID-MED1>3.0.CO;2-A] [PMID:  10934347] 
[46] 
Vlietinck, A.J.; De Bruyne, T.; Apers, S.; Pieters, L.A. Plant-derived leading compounds for chemotherapy of Human Immunodeficiency Virus (HIV) infection. Planta Med.,  1998, 64(2), 97-109.
[http://dx.doi.org/10.1055/s-2006-957384] [PMID:  9525100] 
[47] 
Ito, M.; Sato, A.; Hirabayashi, K.; Tanabe, F.; Shigeta, S.; Baba, M.; De Clercq, E.; Nakashima, H.; Yamamoto, N. Mechanism of inhibitory effect of glycyrrhizin on replication of Human Immunodeficiency Virus (HIV). Antiviral Res.,  1988, 10(6), 289-298.
[http://dx.doi.org/10.1016/0166-3542(88)90047-2] [PMID:  3250333] 
[48] 
Harada, S.; Maekawa, T.; Haneda, E.; Morikawa, Y.; Nagata, N.; Ohtsuki, K. Biochemical characterization of recombinant HIV-1 reverse Transcriptase (rRT) as a glycyrrhizin-binding protein and the CK-II-mediated stimulation of rRT activity potently inhibited by glycyrrhetinic acid derivative. Biol. Pharm. Bull.,  1998, 21(12), 1282-1285.
[http://dx.doi.org/10.1248/bpb.21.1282] [PMID:  9881639] 
[49] 
Il’ina, T.V.; Semenova, E.A.; Plyasunova, O.A.; Fedyuk, N.V.; Petrenko, N.I.; Elantseva, N.V.; Shultz, E.E.; Tolstikov, G.A.; Pokrovskii, A.G. Derivatives of plant triterpenes – inhibitors of human immunodeficiency virus reverse transcriptase inhibitors Bull. SO RAMN,  2002, (2), 20-24.
[50] 
Wolkerstorfer, A.; Kurz, H.; Bachhofner, N.; Szolar, O.H.J. Glycyrrhizin inhibits influenza A virus uptake into the cell. Antiviral Res.,  2009, 83(2), 171-178.
[http://dx.doi.org/10.1016/j.antiviral.2009.04.012] [PMID:  19416738] 
[51] 
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.
[http://dx.doi.org/10.1128/AAC.41.3.551] [PMID:  9055991] 
[52] 
Michaelis, M.; Geiler, J.; Naczk, P.; Sithisarn, P.; Leutz, A.; Doerr, H.W.; Cinatl, J. Influenza A virus-infected cells and inhibitors virus replication and pro-inflammatory gene expression. PLoS One,  2011, 6, e19705.
[http://dx.doi.org/10.1371/journal.pone.0019705] [PMID:   21611183] 
[53] 
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.
[http://dx.doi.org/10.1016/S0140-6736(03)13615-X] [PMID:  12814717] 
[54] 
Pokrovskyi, A.G.; Belanov, E.F.; Volkov, G.N.; Plyasunova, O.A.; Tolstikov, G.A. Inhibition of Marburg virus reproduction by Glycyrrhizic acid and its derivatives. Reports RAS,  1995, 344, 709-711.
[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.
[http://dx.doi.org/10.1016/S0166-3542(03)00030-5] [PMID:  12834859] 
[56] 
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.
[57] 
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.
[http://dx.doi.org/10.1016/S0166-3542(02)00185-7] [PMID:  12719009] 
[58] 
Pokrovskyi, A.G.; Plyasunova, O.A.; Il’icheva, T.N.; Borisova, O.A.; Fedyuk, N.B.; Petrenko, N.I.; Petukhova, V.Z.; Shultz, E.E.; Tolstikov, G.A. Synthesis of plants triterpene derivatives and study their antiviral and immunostimulating activity. Chem. Sustainable Developm.,  2001, 9, 485-491.
[59] 
Wang, L-J.; Geng, C-A.; Ma, Y-B.; Huang, X-Y.; Luo, J.; Chen, H.; Zhang, X-M.; Chen, J-J. Synthesis, biological evaluation and structure-activity relationships of glycyrrhetinic acid derivatives as novel anti-hepatitis B virus agents. Bioorg. Med. Chem. Lett.,  2012, 22(10), 3473-3479.
[http://dx.doi.org/10.1016/j.bmcl.2012.03.081] [PMID:  22520261] 
[60] 
Kitagawa, I. Licorice Root. A natural sweetener and an important ingredient in Chinese Medicine. Pure Appl. Chem.,  2002, 74, 1189-1198.
[http://dx.doi.org/10.1351/pac200274071189] 
[61] 
Stolyarova, O.V.; Baltina, L.A., Jr; Mikhlailova, L.R.; Gabbasov, T.M.; Baltina, L.A.; Tolstikov, G.A. 
            Optimizing the method for obtaining mono-ammonium salt of Glycyrrhizic acid from the Ural licorice (
            Glycyrrhiza uralensis Fisher
            ) roots of Siberian populations.
           Chem. Sustainable Develop.,  2008, 16, 563-568.
[62] 
Kondratenko, R.M.; Baltina, L.A.; Stolyarova, O.V.; Baltina, L.A., Jr; Mikhailova, L.R.; Gabbasov, T.M.; Galin, F.Z.; Tolstikov, G.A. The method of obtaining mono-ammonium salt of Glycyrrhizic acid (glycyram). RF Pat,  2007, 272, 299-740.
[63] 
Stolyarova, O.V.; Farrakhova, G.F.; Baltina, L.A., Jr; Gabbasov, T.M.; Bashirova, R.M.; Kondratenko, R.M.; Baltina, L.A. 
            Isolation of Glycyrrhizic acid and its mono-ammonium salt from the roots and rhizomes of 
            Glycyrrhiza Korshinskyi GRIG. Vestnik of Bashkir State University,  2008, 13, 256-258.
[64] 
Kondratenko, R.M.; Baltina, L.A.; Mikhailova, L.R.; Danilov, V.T.; Gabbasov, T.M.; Murinov, Y.I.; Tolstikov, G.A. Obtaining Glycyrrhizic acid and ist practically useful salts from a commercial licorice root extract. Pharm. Chem. J.,  2005, 39, 84-88.
[http://dx.doi.org/10.1007/s11094-005-0089-9] 
[65] 
Baltina, L.A.; Kunert, O.; Fatykhov, A.A.; Kondratenko, R.M.; Spirikhin, L.V.; Baltina, L.A., Jr; Galin, F.Z.; Tolstikov, G.A.; Haslinger, E. High-resolution 1H and 13C NMR of Glycyrrhizic acid and its esters. Chem. Nat. Compd.,  2005, 41, 432-435.
[http://dx.doi.org/10.1007/s10600-005-0171-2] 
[66] 
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.
[http://dx.doi.org/10.2174/0929867033368538] [PMID:  12570715] 
[67] 
Plyasunova, O.A.; Il’ina, T.V.; Kiseleva, Y.Y.; Fedyuk, N.B.; Baltina, L.A.; Tolstikov, G.A. Anti-HIV activity of penta-O-nicotinate of Glycyrrhizic acid. Vestnik RAMS.,  2004, (11), 42-46.
[68] 
Baltina, L.A.; Ryzhova, S.A.; Vasil’eva, E.V.; Tolstikov, G.A. Transformations of Glycyrrhizic acid. IV. Synthesis of triterpene glycopeptides. Russ. J. Bioorg. Chem.,  1994, 20, 40-46.
[69] 
Baltina, L.A.; Ryzhova, S.A.; Vasil’eva, E.V.; Tolstikov, G.A. Transformations of Glycyrrhizic acid. VI. A new method for obtaining of carboxyl protected glycopeptides. Zh. Obsh. Khim,  1993, 63, 2140-2147.
[70] 
Baltina, L.A., Jr; Fairushina, A.I.; Baltina, L.A. New method of preparation of carboxyl protected amino acid conjugates of Glycyrrhizic acid. Russ. J. Gen. Chem.,  2016, 86, 826-829.
[http://dx.doi.org/10.1134/S1070363216040113] 
[71] 
Baltina, L.A.; Fairushina, A.I.; Baltina, L.A. Method for obtaining of carboxyl protected Glycyrrhizic acid glycopeptides. RF Pat.,  2015, 152, 572-785.
[72] 
Fairushina, A.I.; Baltina, L.A., Jr; Baltina, L.A.; Konovalova, N.I.; Petrova, P.A.; Eropkin, M.Y. Synthesis and antiviral activity of novel Glycyrrhizic acid conjugates with D-amino acid esters. Russ. J. Bioorg. Chem.,  2017, 43, 456-462.
[http://dx.doi.org/10.1134/S1068162017040045] 
[73] 
Baltina, L.A., Jr; Fairushina, A.I.; Baltina, L.A. Synthesis of amino acid conjugates of Glycyrrhizic acid using N-hydroxyphtalimide and N,N′-diciclohexylcarbodiimide. Russ. J. Gen. Chem.,  2015, 85, 2735-2738.
[http://dx.doi.org/10.1134/S1070363215120129] 
[74] 
Baltina, L.A.; Fairushina, A.I.; Baltina, L.A.; Eropkin, M.Y.; Konovalova, N.I.; Petrova, P.A.; Eropkina, E.M. Synthesis and antiviral activity of Glycyrrhizic acid conjugates with aromatic amino acids. Chem. Nat. Compd.,  2017, 53, 1096-1100.
[http://dx.doi.org/10.1007/s10600-017-2209-7] 
[75] 
Kondratenko, R.M.; Baltina, L.A.; Vasil’eva, E.V.; Nasyrov, K.M.; Kireeva, R.M.; Baschenko, N.Z.; Fridman, S.M.; Baltina, L.A., Jr; Tolstikov, G.A. Synthesis and immunomodulating activity of new amino acid derivatives of Glycyrrhizic acid and its methyl ester. Russ. J. Bioorg. Chem.,  2004, 30, 148-153.
[http://dx.doi.org/10.1023/B:RUBI.0000023100.52170.6b] 
[76] 
Baltina, L.A., Jr; Kondratenko, R.M.; Baltina, L.A.; Baschenko, N.Z.; Pliasunova, O.A. Synthesis and biological activity of new glycyrrhizic acid conjugates with amino acids and dipeptides. Bioorg. Khim.,  2009, 35(4), 563-571.
[77] 
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.
[http://dx.doi.org/10.1016/j.bmcl.2015.02.074] [PMID:  25801933] 
[78] 
Kondratenko, R.M.; Baltina, L.A., Jr; Baltina, L.A.; Mufazalova, N.A.; Petrova, S.F.; Zarubaev, V.V. Immune modulating and antiviral activity of proline-containing conjugates of Glycyrrhizic acid. Eur. Union of Scientists,  2018, 4(49) part 2. , 65-70.
[79] 
Baltina, L.A., Jr; Stolyarova, O.V.; Baltina, L.A.; Kondratenko, R.M.; Fedorova, V.A.; Orshanskaya, Y.A.; Zarubaev, V.V. New amino-acid conjugates of Glycyrrhizic acid. Chem. Nat. Compd.,  2014, 50, 317-320.
[http://dx.doi.org/10.1007/s10600-014-0941-9] 
[80] 
Kondratenko, R.M.; Baltina, L.A.; Vasil’eva, E.V.; Baltina, L.A., Jr; Ismagilova, A.F.; Nasyrov, K.M.; Baschenko, N.Z.; Kireeva, R.M.; Fridman, S.M. Synthesis and immune stimulating activity of cysteine-containing derivatives of Glycyrrhizic acid. Russ. J. Bioorg. Chem.,  2004, 30, 53-59.
[http://dx.doi.org/10.1023/B:RUBI.0000015774.09619.80] 
[81] 
Baltina, L.A., Jr; Kondratenko, R.M.; Baltina, L.A.; Plyasunova, O.A.; Galin, F.Z.; Tolstikov, G.A. Synthesis of Glycyrrhizic acid conjugates containing L-lysine. Chem. Nat. Compd.,  2006, 42, 543-548.
[http://dx.doi.org/10.1007/s10600-006-0210-7] 
[82] 
Kondratenko, R.M.; Baltina, L.A., Jr; Baltina, L.A.; Baschenko, N.Z.; Tolstikov, G.A. Synthesis and immune modulating activity of new glycopeptides of Glycyrrhizic acid containing residues of L-Glutamic acid. Russ. J. Bioorg. Chem.,  2006, 32, 595-601.
[http://dx.doi.org/10.1134/S1068162006060136] 
[83] 
Baltina, L.A., Jr; Chistoedova, E.S.; Baltina, L.A.; Kondratenko, R.M.; Plyasunova, O.A. Synthesis and anti-HIV-1 activity of new conjugates of 18β- and 18α-Glycyrrhizic acids with aspartic acid esters. Chem. Nat. Compd.,  2012, 48, 262-266.
[http://dx.doi.org/10.1007/s10600-012-0217-1] 
[84] 
Baltina, L.A., Jr; Stolyarova, O.V.; Baltina, L.A.; Kondratenko, R.M.; Plysunova, O.A.; Pokrovskyi, A.G. Synthesis and antiviral activity of 18α-Glycyrrhizic acid and its esters. Pharm. Chem. J.,  2010, 44, 299-302.
[http://dx.doi.org/10.1007/s11094-010-0454-1] 
[85] 
Kondratenko, R.M.; Baltina, L.A.; Baltina, L.A., Jr; Plyasunova, O.A.; Pokrovskyi, A.G.; Tolstikov, G.A. Synthesis of new hetero- and carbocyclic aromatic amides of Glycyrrhizic acid as potential anti-HIV agents. Pharm. Chem. J.,  2009, 43, 383-388.
[http://dx.doi.org/10.1007/s11094-009-0316-x] 
[86] 
Baltina, L.A.; Baltina, L.A.; Zarubaev, V.V.; Kiselev, O.I.; Yunusov, M.S. A remedy to be an amide of glycyrrhizic acid with 5-amino uracil exhibiting antiviral activity against influenza virus A. RF Patent,   2,568,849, .2015.
[87] 
Baltina, L.A., Jr; Stolyarova, O.V.; Kondratenko, R.M.; Gabbasov, T.M.; Baltina, L.A.; Plyasunova, O.A.; Il’ina, T.V. Synthesis and anti-HIV-1 activity of olean-9(11),12(13)-dien-30-oic acid 3β-(2-O-β-D-glucuronopyranosyl-β-D-glucuronopyranoside). Pharm. Chem. J.,  2014, 8, 439-443.
[http://dx.doi.org/10.1007/s11094-014-1127-2] 
[88] 
Stolyarova, O.V.; Baltina, L.A.; Gabbasov, T.M.; Baltina, L.A.; Kondratenko, R.M.; Ilyina, T.V.; Plyasunova, O.A. The agent, which is 3-O-beta-D-glucuronopyranosyl-β-D-glucuronopyranoside olean-9 (11), 12 (13) -diene-30-oic acid, exhibiting anti-HIV-1 activity, and a method for producing it. RF Patent 2,475,246,  February 20, 2013
[89] 
Davis, B.G. Recent developments in glycoconjugates. J. Chem. Soc.,  1999, 1, 3215-3237.
[90] 
Kondratenko, R.M.; Baltina, L.A.; Mustafina, S.R.; Vasil’eva, E.V.; Pompei, R.; Deidda, D.; Plyasunova, O.A.; Pokrovskii, A.G.; Tolstikov, G.A. The synthesis and antiviral activity of Glycyrrhizic acid conjugates with α-D-glucosamine and some glycosyl amines. Russ. J. Bioorg. Chem.,  2004, 30, 275-282.
[http://dx.doi.org/10.1023/B:RUBI.0000030135.97089.37] 
[91] 
Kondratenko, R.M.; Baltina, L.A.; Mustafina, S.R.; Vasil’eva, E.V.; Ismagilova, A.F.; Vasil’eva, N.G.; Tolstikov, G.A. Transformations of Glycyrrhizic acid: XV. Synthesis of triterpene saponins with monosaccharide residues attached through ester bonds. Russ. J. Bioorg. Chem.,  2003, 29, 601-605.
[http://dx.doi.org/10.1023/B:RUBI.0000008903.65076.93] 
[92] 
Kondratenko, R.M.; Mustafina, S.R.; Baltina, L.A.; Galin, F.Z.; Tolstikov, G.A. Synthesis of triterpene derivatives of D-glucosamine – modified analogs of Glycyrrhizic acid. Chem. Nat. Compd.,  2005, 41, 7-10.
[http://dx.doi.org/10.1007/s10600-005-0061-7] 
[93] 
Baltina, L.A., Jr; Kondratenko, R.M.; Plyasunova, O.A.; Baltina, L.A.; Pokrovskii, A.G.; Khalilov, L.M.; Galin, F.Z.; Tolstikov, G.A. Synthesis and anti-HIV activity of triterpene conjugates of α-D-glucosamine. Pharm. Chem. J.,  2008, 42, 64-67.
[http://dx.doi.org/10.1007/s11094-008-0061-6] 
[94] 
Mustafina, S.R.; Baltina, L.A., Jr; Kondratenko, R.M.; Baltina, L.A.; Galin, F.Z.; Tolstikov, G.A. Synthesis of N-glycoconjugates of Glycyrrhetic acid. Chem. Nat. Compd.,  2006, 42, 67-70.
[http://dx.doi.org/10.1007/s10600-006-0037-2] 
[95] 
Kondratenko, R.M.; Mustafina, S.R.; Baltina, L.A.; Vasil’eva, N.G.; Ismagilova, A.F.; Vasil’eva, E.V.; Nasyrov, K.M.; Galin, F.Z.; Tolstikov, G.A. Synthesis and antiulcer activity of 3-O-acylated Glycyrrhetic acid methylates. Pharm. Chem. J.,  2001, 35, 243-246.
[http://dx.doi.org/10.1023/A:1011905103576] 
[96] 
Mikhailova, L.R.; Baltina, L.A., Jr; Baltina, L.A.; Kondratenko, R.M.; Nepogodiev, S.A.; Field, R.A.; Kunert, O.; Yin, M.C. 
            A simple method of synthesis of triterpene glycosides similar to glycyrrhizic acid and their hepatoprotective activity 
            in vitro
            .
           Bioorg. Khim.,  2009, 35(5), 686-695.
[97] 
Baltina, L.A., Jr; Baltina, L.A.; Kondratenko, R.M.; Plyasunova, O.A.; Nepogodiev, S.A.; Field, R.A. Synthesis and anti-HIV activity of triterpene 3-O-galactopyranosides, analogs of Glycyrrhizic acid. Chem. Nat. Compd.,  2010, 46, 576-582.
[http://dx.doi.org/10.1007/s10600-010-9679-1] 
[98] 
Kondratenko, R.M.; Baltina, L.A., Jr; Baschenko, N.J.; Baltina, L.A.; Ismagilova, A.F Glycopeptide of Glycyrrhizic acid with L-proline stimulating humoral immune response. RF Patent 2,303,601, 2007. ,July 27, 2007.
[99] 
Kondratenko, R.M.; Baltina, L.A.; Baschenko, N.Z.; Nasyrov, K.M.; Fridman, S.M.; Tolstikov, G.A. Diglycopeptide of Glycyrrhizic acid with L-valine methyl ester stimulating a primary immune response. RF Patent 2,238,944.,  October 27, 2004.
[100] 
Baltina, L.A.; Tolstikov, G.A. Muramylpeptides. Ekaterinbug; Urals Branch of Russian Academy of Sciences: Ekaterinburg, 1998. 
[101] 
Kondratenko, R.M.; Baltina, L.A.; Plyasunova, O.A.; Pokrovskii, A.G.; Tolstikov, G.A. Glycopeptide of Glycyrrhizic acid with S-benzyl-L-cysteine, exhibiting anti-HIV activity. RF Patent 2,198,177, 2003.
[102] 
Baltina, L.A.; Plysunova, O.A.; Baltina, L.A., Jr; Pokrovskii, A.G.; Tolstikov, G.A. Glycopeptide of Glycyrrhizic acid with glycyl-L-phenylalanine, exhibiting anti-HIV-1 activity. RF. Patent 2,315,058,  January 20, 2008
[103] 
Hoever, G.; Baltina, L.; Michaelis, M.; Kondratenko, R.; Baltina, L., Jr; Tolstikov, G.A.; Doerr, H.W.; Cinatl, J. Jr Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. J. Med. Chem.,  2005, 48(4), 1256-1259.
[http://dx.doi.org/10.1021/jm0493008] [PMID:  15715493] 
[104] 
Sui, J.; Li, W.; Murakami, A.; Tamin, A.; Matthews, L.J.; Wong, S.K.; Moore, M.J.; Tallarico, A.S.; Olurinde, M.; Choe, H.; Anderson, L.J.; Bellini, W.J.; Farzan, M.; Marasco, W.A. Potent neutralization of Severe Acute Respiratory Syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc. Natl. Acad. Sci. USA,  2004, 101(8), 2536-2541.
[http://dx.doi.org/10.1073/pnas.0307140101] [PMID:  14983044] 
[105] 
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.
[http://dx.doi.org/10.1016/j.antiviral.2008.01.160] [PMID:  18423902] 
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DOI https://dx.doi.org/10.2174/1573407216666200210122751	Print ISSN 1573-4072
Publisher Name Bentham Science Publisher	Online ISSN 1875-6646
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Glycyrrhizic Acid Derivatives as New Antiviral and Immune Modulating Agents

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