INFLUENCE ON CELLULAR TARGETS FOR TREATING INFLUENZA INFECTION

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Abstract

Аbstract. Influenza is a highly contagious infection of humans. The use of specific antivirals leads to emergence of drug-resistant strains following by the decrease of efficacy of ethiotropic chemotherapy. In this review the data about the decrease of the level of viral replication and severity of pathological process based on the use of alternative targets of cellular instead of viral origin are presented. The medicines for decreasing the production of proinflammatory cytokines (eritoran), restricting the degranulation of mast cells (ketotifen), inhibitors of cyclooxygenases (celexocib, mesalasine, SC-560), inhibitors of sphingosine-1-phospate pathway (AAL-R) and compounds increasing the capillars stability by strengthe ning the contacts between endothelial cells (Slit protein) have been described in the review. The special attention is paid to the inhibitors of cellular pathways that are used by the virus to provide its reproduction, such as NF-κB, Raf/MEK/ERK, PI3K/AKT/mTOR. Information concerning anti-influenza activity of kinase and autophagy inhibitors is summarised as well as data about the preparations of combined mechanism of activity — glycirrhizic acid and dipeptide alpha-glutamyl-tryptophane. Further studies in the field of search and optimization of inhibitors of cellular components as remedies against influenza infection could lead to the development of novel antivirals with high efficacy, broad spectrum of activity and low probability of virus resistance.

About the authors

V. V. Zarubaev

Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg

Author for correspondence.
Email: zarubaev@influenza.spb.ru

PhD (Biology), Head of the Laboratory of Molecular Anti-Viral Chemotherapy

197376, Russian Federation, St. Petersburg, Professor Popov str., 15/17

Russian Federation

V. S. Smirnov

MBRD “Cytomed”, St. Petersburg

Email: zarubaev@influenza.spb.ru
PhD, MD (Medicine), Principal Scientist, MBRD “Cytomed”, St. Petersburg Russian Federation

References

  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. — № 3. — C. 23–27. Smirnov V.S., Zarubaev V.V., Anfimov P.M., Shtro A.A. Vliyanie kombinatsii glutamil-triptofana s glitsirrizinovoy kislotoy na techenie ostroy infektsii u myshey, vyzvannoy virusom grippa (H3N2) [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.
  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 (в печати). Smirnov V.S., Garshinina A.V., Shtro A.A., Anikin V.B., Galochkina A.V., Belyaevskaya S.V., Zarubaev V.V. Protektivnaya aktivnost` kombinatsii glutamil-triptofana i glitsirrizinovoy kisloty pri peroral`nom vvedenii na modeli eksperimental`noy letal`noy grippoznoy infektsii u belykh myshey, vyzvannoy osel`tamivir-ustoychivym shtammom virusa (v pechati) [Antiviral activity of complex of glycirrhysic acid–alpha-glutamyltryptophan against experimental lethal influenza infection in white mice caused by oseltamivir-resistant strain of the virus (in press)]. Voprosy virusologii — Problems of Virology, 2014.
  3. Черняев А.Л., Зайратьянц О.В., Полянко Н.И. Патологическая анатомия гриппа A/H1N1 // Архив патологии. — 2010. — № 3. — C. 3–6. Chernyaev A.L., Zayrat`yants O.V., Polyanko N.I. Patologicheskaya anatomiya grippa A/H1N1 [Pathological anatomy of influenza virus A(H1N1)]. Arkhiv patologii — Archive of Pathology, 2010, no. 3, pp. 3–6.
  4. Яковлев А.А., Рахманова А.Г., Цинзерлинг В.А. О пандемии гриппа А/H1N1 у иммунодепрессивных лиц в Санкт-Петербурге (апрель-декабрь 2009 г.) // ВИЧ-инфекция и иммуносупрессии. — 2010. — Т. 2, № 1. — С. 94–101. Yakovlev A.A., Rakhmanova A.G., Tsinzerling V.A. O pandemii grippa A/H1N1 u immunodepressivnykh lits v Sankt-Peterburge (aprel’-dekabr’ 2009 g.) [On the influenza pandemic A(H1N1) among immunosuppressed patients in St. Petersburg (April–December 2009)]. VICh-infektsiia i immunosupressii — HIV-infection and immunosuppression, 2010, vol. 2, no. 1, pp. 94–101.
  5. Arias C.F., Escalera-Zamudio M., de los Dolores Soto-Del Rio M., Cobián-Güemes A.G., Isa P., López S. Molecular Anatomy of 2009 Influenza Virus A (H1N1). Archives of Medical Research., 2009, vol. 40, pp. 643–654.
  6. Carey M.A., Bradbury J.A., Rebolloso Y.D., Graves J.P., Zeldin D.C., Germolec D.R. Pharmacologic inhibition of COX-1 and COX-2 in influenza A viral infection in mice. PLoS One, 2010, vol. 5(7), e11610.
  7. Dai J.P., Li W.Z., Zhao X.F., Wang G.F., Yang J.C., Zhang L., Chen X.X., Xu Y.X., Li K.S. A drug screening method based on the autophagy pathway and studies of the mechanism of evodiamine against influenza A virus. PLoS One, 2012, vol. 7(8), e42706.
  8. De Clercq E. Antiviral agents active against influenza A viruses. Nat. Rev. Drug Discov., 2006, vol. 5, pp. 1015–1025.
  9. Dixit R., Khandaker G., Ilgoutz S., Rashid H., Booy R. Emergence of oseltamivir resistance: control and management of influenza before, during and after the pandemic. Infect. Disord. Drug Targets, 2013, vol. 13, no. 1, pp. 34–45.
  10. Drake J.W., Charlesworth B., Charlesworth D., Crow J.F. Rates of spontaneous mutation. Genetics, 1998, vol. 148, no. 4, pp. 1667–1686.
  11. Droebner K., Pleschka S., Ludwig S., Planz O. Antiviral activity of the MEKinhibitor U0126 against pandemic H1N1v and highly pathogenic avian influenza virus in vitro and in vivo. Antiviral Res., 2011, vol. 92, pp. 195–203.
  12. Ehrhardt C., Ludwig S. A new player in a deadly game: influenza viruses and the PI3K/Akt signalling pathway. Cell. Microbiol., 2009, vol. 11, pp. 863–871.
  13. Ehrhardt C., Wolff T., Pleschka S., Planz O., Beermann W., Bode J.G., Schmolke M., Ludwig S. Influenza A virus NS1 protein activates the PI3K/Akt pathway to mediate antiapoptotic signaling responses. J. Virol., 2007, vol. 81, pp. 3058–3067.
  14. Fedson D.S. Treating influenza with statins and other immunomodulatory agents. Antiviral Res., 2013, vol. 99, no. 3, pp. 417–435.
  15. Fiore C., Eisenhut M., Krausse R., Ragazzi E., Pellati D., Armanini D., Bielenberg J. Antiviral effects of Glycyrrhiza species. Phytother. Res., 2008, vol. 22, no. 2, pp. 141–148.
  16. Gill J.R., Sheng Z.M., Ely S.F., Guinee D.G.Jr., Beasley M.B., Suh J., Deshpande C., Mollura D.J., Morens D.M., Bray M., Travis W.D., Taubenberger J.K. Pulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1 viral infections. Arch. Pathol. Lab. Med., 2010, vol. 134, pp. 235–243.
  17. Gilmore T.D., Garbati M.R. Inhibition of NF-kappaB signaling as a strategy in disease therapy. Curr. Top. Microbiol. Immunol., 2011, vol. 349, pp. 245–263.
  18. Gilmore T.D., Herscovitch M. Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene, 2006, vol. 25, pp. 6887–6899.
  19. Govorkova E.A., Baranovich T., Seiler P., Armstrong J., Burnham A., Guan Y., Peiris M., Webby R.J., Webster R.G. Antiviral resistance among highly pathogenic influenza A (H5N1) viruses isolated worldwide in 2002–2012 shows need for continued monitoring. Antiviral Res., 2013, vol. 98, no. 2, pp. 297–304.
  20. Haasbach E., Hartmayer C., Planz O. Combination of MEK inhibitors and oseltamivir leads to synergistic antiviral effects after influenza A virus infection in vitro. Antiviral Res., 2013, vol. 98, pp. 319–324.
  21. Harada S., Yusa K., Monde K., Akaike T., Maeda Y. Influence of membrane fluidity on human immunodeficiency virus type 1 entry. Biochem. Biophys. Res. Commun., 2005, vol. 329, pp. 480–486.
  22. Hay A.J., Hayden F.G. Oseltamivir resistance during treatment of H7N9 infection. Lancet, 2013, vol. 381, no. 9885, pp. 2230–2232.
  23. http://www.who.int/mediacentre/factsheets/2003/fs211/en.
  24. Hu Y., Jin Y., Han D., Zhang G., Cao S., Xie J., Xue J., Li Y., Meng D., Fan X., Sun L.Q., Wang M. Mast cell-induced lung injury in mice infected with H5N1 influenza virus. J. Virol., 2012, vol. 86, no. 6, pp. 3347–3356.
  25. Hui D.S., Lee N., Chan P.K. Adjunctive therapies and immunomodulatory agents in the management of severe influenza. Antiviral Res., 2013, vol. 98, no. 3, pp. 410–416.
  26. Huston D.P., Bressler R.B., Kaliner M., Sowell L.K., Baylor M.W. Prevention of mast-cell degranulation by ketotifen in patients with physical urticarias. Ann. Intern. Med., 1986, vol. 104, no. 4, pp. 507–510.
  27. Konig R., Stertz S., Zhou Y., Inoue A., Hoffmann H.H., Bhattacharyya S., Alamares J.G., Tscherne D.M., Ortigoza M.B., Liang Y., Gao Q., Andrews S.E., Bandyopadhyay S., De Jesus P., Tu B.P., Pache L., Shih C., Orth A., Bonamy G., Miraglia L., Ideker T., Garcia-Sastre A., Young J.A., Palese P., Shaw M.L., Chanda S.K. Human host factors required for influenza virus replication. Nature, 2010, vol. 463, pp. 813–817.
  28. Kuiken T., Riteau B., Fouchier R.A., Rimmelzwaan G.F. Pathogenesis of influenza virus infections: the good, the bad and the ugly. Curr. Opin. Virol., 2012, vol. 2, no. 3, pp. 276–286.
  29. Kumar A. Early versus late oseltamivir treatment in severely ill patients with 2009 pandemic influenza A (H1N1): speed is life. J. Antimicrob. Chemother., 2011, vol. 66, no. 5, pp. 959–963
  30. Kumar N., Liang Y., Parslow T.G., Liang Y. Receptor tyrosine kinase inhibitors block multiple steps of influenza a virus replication. J. Virol., 2011, vol. 85, no. 6, pp. 2818–2827.
  31. Kunkel G.T., Maceyka M., Milstien S., Spiegel S. Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat. Rev. Drug Discov., 2013, vol. 12, no. 9, pp. 688–702.
  32. London N.R., Zhu W., Bozza F.A., Smith M.C., Greif D.M., Sorensen L.K., Chen L., Kaminoh Y., Chan A.C., Passi S.F., Day C.W., Barnard D.L., Zimmerman G.A., Krasnow M.A., Li D.Y. Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci. Transl. Med., 2010, vol. 2, no. 23, 23ra19.
  33. Ludwig S., Wolff T., Ehrhardt C., Wurzer W.J., Reinhardt, J., Planz O., Pleschka S. MEK inhibition impairs influenza B virus propagation without emergence of resistant variants. FEBS Lett., 2004, vol. 561, pp. 37–43.
  34. Maira S.M., Finan P., Garcia-Echeverria C. From the bench to the bed side: PI3K pathway inhibitors in clinical development. Curr. Top. Microbiol. Immunol., 2010, vol. 347, pp. 209–239.
  35. Marjuki H., Yen H.L., Franks J., Webster R.G., Pleschka S., Hoffmann E. Higher polymerase activity of a human influenza virus enhances activation of the hemagglutinin-induced Raf/MEK/ERK signal cascade. Virol. J., 2007, vol. 4, pp. 134.
  36. Marsolais D., Hahm B., Walsh K.B., Edelmann K.H., McGavern D., Hatta Y., Kawaoka Y., Rosen H., Oldstone M.B. A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection. Proc. Natl. Acad. Sci USA, 2009, vol. 106, no. 5, pp. 1560–1565.
  37. Martinez-Gil L., Alamares-Sapuay J.G., Ramana Reddy M.V., Goff P.H., Premkumar Reddy E., Palese P. A small molecule multi-kinase inhibitor reduces influenza A virus replication by restricting viral RNA synthesis. Antiviral. Res., 2013, vol. 100, no. 1, pp. 29–37.
  38. Mazur I., Wurzer W.J., Ehrhardt C., Pleschka S., Puthavathana P., Silberzahn T., Wolff T., Planz O., Ludwig S. Acetylsalicylic acid (ASA) blocks influenza virus propagation via its NF-kappaB-inhibiting activity. Cell. Microbiol., 2007, vol. 9, pp. 1683–1694.
  39. Mei L., Song P., Tang Q., Shan K., Tobe R.G., Selotlegeng L., Ali A.H., Cheng Y., Xu L. Changes in and shortcomings of control strategies, drug stockpiles, and vaccine development during outbreaks of avian influenza A H5N1, H1N1, and H7N9 among humans. Biosci. Trends., 2013, vol. 7, no. 2, pp. 64–76.
  40. Michaelis M., Geiler J., Naczk P., Sithisarn P., Ogbomo H., Altenbrandt B., Leutz A., Doerr HW., Cinatl J Jr. Glycyrrhizin inhibits highly pathogenic H5N1 influenza A virus-induced pro-inflammatory cytokine and chemokine expression in human macrophages. Med. Microbiol. Immunol., 2010, vol. 199, no. 4, pp. 291–297.
  41. 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, no. 5, e19705.
  42. Mullarkey M., Rose J.R., Bristol J., Kawata T., Kimura A., Kobayashi S., Przetak M., Chow J., Gusovsky F., Christ W.J., Rossignol D.P. Inhibition of endotoxin response by E5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J. Pharmacol. Exp. Ther., 2003, vol. 304, pp. 1093–1102.
  43. Nacken W., Ehrhardt C., Ludwig S. Small molecule inhibitors of the c-Jun N-terminal kinase (JNK) possess antiviral activity against highly pathogenic avian and human pandemic influenza A viruses. Biol. Chem., 2012, vol. 393, no. 6, pp. 525–534.
  44. Nobusawa E., Sato K. Comparison of the mutation rates of human influenza A and B viruses. J. Virol., 2006, vol. 80, no. 7, pp. 3675–3678.
  45. Olschlager V., Pleschka S., Fischer T., Rziha H.J., Wurzer W., Stitz L., Rapp U.R., Ludwig S., Planz O. Lung-specific expression of active Raf kinase results in increased mortality of influenza A virus-infected mice. Oncogene, 2004, vol. 23, pp. 6639–6646.
  46. Pitha P.M., Kunzi M.S. Type I interferon: the ever unfolding story. Curr. Top. Microbiol. Immunol., 2007, vol. 316, pp. 41–70.
  47. Planz O. Development of cellular signaling pathway inhibitors as new antivirals against influenza. Antiviral Res., 2013, vol. 98. no. 3, pp. 457–468.
  48. Rossman J.S., Lamb R.A. Influenza virus assembly and budding. Virology, 2011, vol. 411, no. 2, pp. 229–236.
  49. Scholtissek C., Quack G., Klenk H.D., Webster R.G. How to overcome resistance of influenza A viruses against adamantane derivatives. Antiviral Res., 1998, vol. 37, pp. 83–95.
  50. Shetty A.K., Peek L.A. Peramivir for the treatment of influenza. Expert Rev. Anti Infect. Ther., 2012, vol. 10, pp. 123–143.
  51. Shin Y.K., Li Y., Liu Q., Anderson D.H., Babiuk L.A., Zhou Y. SH3 binding motif 1 in influenza A virus NS1 protein is essential for PI3K/Akt signaling pathway activation. J. Virol., 2007, vol. 81, pp. 12730–12739.
  52. Shirey K.A., Lai W., Scott A.J., Lipsky M., Mistry P., Pletneva L.M., Karp C.L., McAlees J., Gioannini T.L., Weiss J., Chen W.H., Ernst R.K., Rossignol D.P., Gusovsky F., Blanco J.C., Vogel S.N. The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature, 2013, vol. 497, no. 7450, pp. 498–502.
  53. Smee D.F., Julander J.G., Tarbet E.B., Gross M., Nguyen J. Treatment of oseltamivir-resistant influenza A (H1N1) virus infections in mice with antiviral agents. Antiviral. Res., 2012, vol. 96, no. 1, pp. 13–20.
  54. Smith D.B., Inglis S.C. The mutation rate and variability of eukaryotic viruses: an analytical review. J. Gen. Virol., 1987, vol. 68, pt 11, pp. 2729–2740.
  55. Tazulakhova E.B., Parshina O.V., Guseva T.S., Ershov F.I. Russian experience in screening, analysis, and clinical application of novel interferon inducers. J. Interferon Cytokine Res., 2001, vol. 21, no. 2, pp. 65–73.
  56. Tisoncik J.R., Korth M.J., Simmons C.P., Farrar J., Martin T.R., Katze M.G. Into the eye of the cytokine storm. Microbiol. Mol. Biol. Rev., 2012, vol. 76, no. 1, pp. 16–32
  57. 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, no. 3, pp. 551–556.
  58. Vavricka C.J., Li Q., Wu Y., Qi J., Wang M., Liu Y., Gao F., Liu J., Feng E., He J., Wang J., Liu H., Jiang H., Gao G.F. Structural and functional analysis of laninamivir and its octanoate prodrug reveals group specific mechanisms for influenza NA inhibition. PLoS Pathog., 2011, vol. 7, e1002249.
  59. Walsh K.B., Teijaro J.R., Wilker P.R., Jatzek A., Fremgen D.M., Das S.C., Watanabe T., Hatta M., Shinya K., Suresh M., Kawaoka Y., Rosen H., Oldstone M.B. Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus. Proc. Natl. Acad. Sci. USA, 2011, vol. 108, no. 29, pp. 12018–12023.
  60. Warner T.D., Mitchell J.A. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J., 2004, vol. 18, pp. 790–804.
  61. Wolkerstorfer A., Kurz H., Bachhofner N., Szolar O.H. Glycyrrhizin inhibits influenza A virus uptake into the cell. Antivir Res., 2009, vol. 83, pp. 171–178.
  62. Zheng B.J., Chan K.W., Lin Y.P., Zhao G.Y., Chan C., Zhang H.J., Chen H.L., Wong S.S., Lau S.K., Woo P.C., Chan K.H., Jin D.Y., Yuen K.Y. Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus. Proc. Natl. Acad. Sci. USA, 2008, vol. 105, no. 23, pp. 8091–8096.
  63. Zhirnov O.P., Klenk H.D. Control of apoptosis in influenza virus-infected cells by up-regulation of Akt and p53 signaling. Apoptosis, 2007, vol. 12, pp. 1419–1432.
  64. Zhou Z., Jiang X., Liu D., Fan Z., Hu X., Yan J., Wang M., Gao G.F. Autophagy is involved in influenza A virus replication. Autophagy, 2009, vol. 5, no. 3, pp. 321–328.

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