Cellular and Molecular Life Sciences

, Volume 71, Issue 19, pp 3659–3683 | Cite as

Antiviral strategies against influenza virus: towards new therapeutic approaches

  • Arianna LoregianEmail author
  • Beatrice Mercorelli
  • Giulio Nannetti
  • Chiara Compagnin
  • Giorgio Palù


Influenza viruses are major human pathogens responsible for respiratory diseases affecting millions of people worldwide and characterized by high morbidity and significant mortality. Influenza infections can be controlled by vaccination and antiviral drugs. However, vaccines need annual updating and give limited protection. Only two classes of drugs are currently approved for the treatment of influenza: M2 ion channel blockers and neuraminidase inhibitors. However, they are often associated with limited efficacy and adverse side effects. In addition, the currently available drugs suffer from rapid and extensive emergence of drug resistance. All this highlights the urgent need for developing new antiviral strategies with novel mechanisms of action and with reduced drug resistance potential. Several new classes of antiviral agents targeting viral replication mechanisms or cellular proteins/processes are under development. This review gives an overview of novel strategies targeting the virus and/or the host cell for counteracting influenza virus infection.


Influenza virus New antivirals Drug discovery Drug targets Virus–host interaction Signaling pathways 



Work in the authors’ laboratory was supported by MURST EX60 %, Progetto di Ricerca di Ateneo 2007 (grant no. CPDA074945), and PRIN 2008 (grant no. 20085FF4J4) to A.L., by Regione Veneto and Progetto Strategico di Ateneo 2008 to G.P., by Italian Ministry of Health and Istituto Superiore Sanità, Progetto finalizzato 2009 “Studio e sviluppo di nuovi farmaci antivirali contro infezioni da virus influenzale A-H1N1” to A.L. and G.P., and by ESCMID Research Grant 2013 to B.M.


  1. 1.
    Cox NJ, Subbarao K (2000) Global epidemiology of influenza: past and present. Annu Rev Med 51:407–421PubMedGoogle Scholar
  2. 2.
    Shaw ML, Palese P (2013) Orthomyxoviruses. In: Knipe DM, Howley PM (eds) Fields virology, 6th edn. Lippincott Williams & Wilkins, Philadelphia, pp 1648–1698Google Scholar
  3. 3.
    Chen W, Calvo PA, Malide D, Gibbs J, Schubert U, Bacik I, Basta S, O’Neill R, Schickli J, Palese P, Henklein P, Bennink JR, Yewdell JW (2001) A novel influenza A virus mitochondrial protein that induces cell death. Nat Med 7(12):1306–1312PubMedGoogle Scholar
  4. 4.
    Jagger BW, Wise HM, Kash JC, Walters KA, Wills NM, Xiao YL, Dunfee RL, Schwartzman LM, Ozinsky A, Bell GL, Dalton RM, Lo A, Efstathiou S, Atkins JF, Firth AE, Taubenberger JK, Digard P (2012) An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science 337(6091):199–204PubMedPubMedCentralGoogle Scholar
  5. 5.
    Wise HM, Foeglein A, Sun J, Dalton RM, Patel S, Howard W, Anderson EC, Barclay WS, Digard P (2009) A complicated message: identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. J Virol 83(16):8021–8031PubMedPubMedCentralGoogle Scholar
  6. 6.
    Rumschlag-Booms E, Rong L (2013) Influenza a virus entry: implications in virulence and future therapeutics. Adv Virol 2013:121924PubMedPubMedCentralGoogle Scholar
  7. 7.
    Das K, Aramini JM, Ma LC, Krug RM, Arnold E (2010) Structures of influenza A proteins and insights into antiviral drug targets. Nat Struct Mol Biol 17(5):530–538PubMedPubMedCentralGoogle Scholar
  8. 8.
    Pinto LH, Lamb RA (2006) The M2 proton channels of influenza A and B viruses. J Biol Chem 281(14):8997–9000PubMedGoogle Scholar
  9. 9.
    Ito T, Gorman OT, Kawaoka Y, Bean WJ, Webster RG (1991) Evolutionary analysis of the influenza A virus M gene with comparison of the M1 and M2 proteins. J Virol 65(10):5491–5498PubMedPubMedCentralGoogle Scholar
  10. 10.
    Leonov H, Astrahan P, Krugliak M, Arkin IT (2011) How do aminoadamantanes block the influenza M2 channel, and how does resistance develop? J Am Chem Soc 133(25):9903–9911PubMedGoogle Scholar
  11. 11.
    Wang C, Takeuchi K, Pinto LH, Lamb RA (1993) Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block. J Virol 67(9):5585–5594PubMedPubMedCentralGoogle Scholar
  12. 12.
    Moss RB, Davey RT, Steigbigel RT, Fang F (2010) Targeting pandemic influenza: a primer on influenza antivirals and drug resistance. J Antimicrob Chemother 65(6):1086–1093PubMedGoogle Scholar
  13. 13.
    Bright RA, Medina MJ, Xu X, Perez-Oronoz G, Wallis TR, Davis XM, Povinelli L, Cox NJ, Klimov AI (2005) Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet 366(9492):1175–1181PubMedGoogle Scholar
  14. 14.
    Krumbholz A, Schmidtke M, Bergmann S, Motzke S, Bauer K, Stech J, Durrwald R, Wutzler P, Zell R (2009) High prevalence of amantadine resistance among circulating European porcine influenza A viruses. J Gen Virol 90(Pt 4):900–908PubMedGoogle Scholar
  15. 15.
    Wang J, Wu Y, Ma C, Fiorin G, Pinto LH, Lamb RA, Klein ML, Degrado WF (2013) Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus. Proc Natl Acad Sci USA 110(4):1315–1320PubMedPubMedCentralGoogle Scholar
  16. 16.
    Wang J, Ma C, Jo H, Canturk B, Fiorin G, Pinto LH, Lamb RA, Klein ML, DeGrado WF (2013) Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N, of the M2 proton channel from influenza A virus. J Med Chem 56(7):2804–2812PubMedPubMedCentralGoogle Scholar
  17. 17.
    Furuse Y, Suzuki A, Oshitani H (2009) Large-scale sequence analysis of M gene of influenza A viruses from different species: mechanisms for emergence and spread of amantadine resistance. Antimicrob Agents Chemother 53(10):4457–4463PubMedPubMedCentralGoogle Scholar
  18. 18.
    Wang J, Ma C, Fiorin G, Carnevale V, Wang T, Hu F, Lamb RA, Pinto LH, Hong M, Klein ML, DeGrado WF (2011) Molecular dynamics simulation directed rational design of inhibitors targeting drug-resistant mutants of influenza A virus M2. J Am Chem Soc 133(32):12834–12841PubMedPubMedCentralGoogle Scholar
  19. 19.
    Balannik V, Wang J, Ohigashi Y, Jing X, Magavern E, Lamb RA, Degrado WF, Pinto LH (2009) Design and pharmacological characterization of inhibitors of amantadine-resistant mutants of the M2 ion channel of influenza A virus. Biochemistry 48(50):11872–11882PubMedPubMedCentralGoogle Scholar
  20. 20.
    Wang J, Ma C, Wu Y, Lamb RA, Pinto LH, DeGrado WF (2011) Exploring organosilane amines as potent inhibitors and structural probes of influenza a virus M2 proton channel. J Am Chem Soc 133(35):13844–13847PubMedPubMedCentralGoogle Scholar
  21. 21.
    Wei G, Meng W, Guo H, Pan W, Liu J, Peng T, Chen L, Chen CY (2011) Potent neutralization of influenza A virus by a single-domain antibody blocking M2 ion channel protein. PLoS ONE 6(12):e28309PubMedPubMedCentralGoogle Scholar
  22. 22.
    Gamblin SJ, Skehel JJ (2010) Influenza hemagglutinin and neuraminidase membrane glycoproteins. J Biol Chem 285(37):28403–28409PubMedPubMedCentralGoogle Scholar
  23. 23.
    Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk HD (2004) Human and avian influenza viruses target different cell types in cultures of human airway epithelium. Proc Natl Acad Sci USA 101(13):4620–4624PubMedPubMedCentralGoogle Scholar
  24. 24.
    Russell RJ, Haire LF, Stevens DJ, Collins PJ, Lin YP, Blackburn GM, Hay AJ, Gamblin SJ, Skehel JJ (2006) The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. Nature 443(7107):45–49PubMedGoogle Scholar
  25. 25.
    Gubareva LV, Kaiser L, Hayden FG (2000) Influenza virus neuraminidase inhibitors. Lancet 355(9206):827–835PubMedGoogle Scholar
  26. 26.
    von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B, Van Phan T, Smythe ML, White HF, Oliver SW et al (1993) Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363(6428):418–423Google Scholar
  27. 27.
    Cass LM, Efthymiopoulos C, Bye A (1999) Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin Pharmacokinet 36(Suppl 1):1–11PubMedGoogle Scholar
  28. 28.
    Tsang KW, Eng P, Liam CK, Shim YS, Lam WK (2005) H5N1 influenza pandemic: contingency plans. Lancet 366(9485):533–534PubMedGoogle Scholar
  29. 29.
    Davies BE (2010) Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. J Antimicrob Chemother 65(Suppl 2):ii5–ii10Google Scholar
  30. 30.
    Kohno S, Kida H, Mizuguchi M, Hirotsu N, Ishida T, Kadota J, Shimada J (2011) Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients. Antimicrob Agents Chemother 55(6):2803–2812PubMedPubMedCentralGoogle Scholar
  31. 31.
    Barroso L, Treanor J, Gubareva L, Hayden FG (2005) Efficacy and tolerability of the oral neuraminidase inhibitor peramivir in experimental human influenza: randomized, controlled trials for prophylaxis and treatment. Antivir Ther 10(8):901–910PubMedGoogle Scholar
  32. 32.
    Koyama K, Takahashi M, Oitate M, Nakai N, Takakusa H, Miura S, Okazaki O (2009) CS-8958, a prodrug of the novel neuraminidase inhibitor R-125489, demonstrates a favorable long-retention profile in the mouse respiratory tract. Antimicrob Agents Chemother 53(11):4845–4851PubMedPubMedCentralGoogle Scholar
  33. 33.
    Samson M, Pizzorno A, Abed Y, Boivin G (2013) Influenza virus resistance to neuraminidase inhibitors. Antiviral Res 98(2):174–185PubMedGoogle Scholar
  34. 34.
    Pizzorno A, Bouhy X, Abed Y, Boivin G (2011) Generation and characterization of recombinant pandemic influenza A(H1N1) viruses resistant to neuraminidase inhibitors. J Infect Dis 203(1):25–31PubMedPubMedCentralGoogle Scholar
  35. 35.
    Feng E, Ye D, Li J, Zhang D, Wang J, Zhao F, Hilgenfeld R, Zheng M, Jiang H, Liu H (2012) Recent advances in neuraminidase inhibitor development as anti-influenza drugs. ChemMedChem 7(9):1527–1536PubMedGoogle Scholar
  36. 36.
    Mitrasinovic PM (2010) Advances in the structure-based design of the influenza A neuraminidase inhibitors. Curr Drug Targets 11(3):315–326PubMedGoogle Scholar
  37. 37.
    Lee CM, Weight AK, Haldar J, Wang L, Klibanov AM, Chen J (2012) Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection. Proc Natl Acad Sci USA 109(50):20385–20390PubMedPubMedCentralGoogle Scholar
  38. 38.
    Weight AK, Haldar J, Alvarez de Cienfuegos L, Gubareva LV, Tumpey TM, Chen J, Klibanov AM (2011) Attaching zanamivir to a polymer markedly enhances its activity against drug-resistant strains of influenza a virus. J Pharm Sci 100(3):831–835PubMedPubMedCentralGoogle Scholar
  39. 39.
    Honda T, Yoshida S, Arai M, Masuda T, Yamashita M (2002) Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives. Bioorg Med Chem Lett 12(15):1929–1932PubMedGoogle Scholar
  40. 40.
    Macdonald SJ, Cameron R, Demaine DA, Fenton RJ, Foster G, Gower D, Hamblin JN, Hamilton S, Hart GJ, Hill AP, Inglis GG, Jin B, Jones HT, McConnell DB, McKimm-Breschkin J, Mills G, Nguyen V, Owens IJ, Parry N, Shanahan SE, Smith D, Watson KG, Wu WY, Tucker SP (2005) Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza. J Med Chem 48(8):2964–2971PubMedGoogle Scholar
  41. 41.
    Este JA, Telenti A (2007) HIV entry inhibitors. Lancet 370(9581):81–88PubMedGoogle Scholar
  42. 42.
    Hu J, Robinson JL (2010) Treatment of respiratory syncytial virus with palivizumab: a systematic review. World J Pediatr 6(4):296–300PubMedGoogle Scholar
  43. 43.
    Matthews T, Salgo M, Greenberg M, Chung J, DeMasi R, Bolognesi D (2004) Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes. Nat Rev Drug Discov 3(3):215–225PubMedGoogle Scholar
  44. 44.
    Fleury D, Barrere B, Bizebard T, Daniels RS, Skehel JJ, Knossow M (1999) A complex of influenza hemagglutinin with a neutralizing antibody that binds outside the virus receptor binding site. Nat Struct Biol 6(6):530–534PubMedGoogle Scholar
  45. 45.
    Whittle JR, Zhang R, Khurana S, King LR, Manischewitz J, Golding H, Dormitzer PR, Haynes BF, Walter EB, Moody MA, Kepler TB, Liao HX, Harrison SC (2011) Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc Natl Acad Sci USA 108(34):14216–14221PubMedPubMedCentralGoogle Scholar
  46. 46.
    Ekiert DC, Kashyap AK, Steel J, Rubrum A, Bhabha G, Khayat R, Lee JH, Dillon MA, O’Neil RE, Faynboym AM, Horowitz M, Horowitz L, Ward AB, Palese P, Webby R, Lerner RA, Bhatt RR, Wilson IA (2012) Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489(7417):526–532PubMedPubMedCentralGoogle Scholar
  47. 47.
    Yoshida R, Igarashi M, Ozaki H, Kishida N, Tomabechi D, Kida H, Ito K, Takada A (2009) Cross-protective potential of a novel monoclonal antibody directed against antigenic site B of the hemagglutinin of influenza A viruses. PLoS Pathog 5(3):e1000350PubMedPubMedCentralGoogle Scholar
  48. 48.
    Sun XL (2007) Recent anti-influenza strategies in multivalent sialyloligosaccharides and sialylmimetics approaches. Curr Med Chem 14(21):2304–2313PubMedGoogle Scholar
  49. 49.
    Gambaryan AS, Tuzikov AB, Chinarev AA, Juneja LR, Bovin NV, Matrosovich MN (2002) Polymeric inhibitor of influenza virus attachment protects mice from experimental influenza infection. Antiviral Res 55(1):201–205PubMedGoogle Scholar
  50. 50.
    Gambaryan AS, Boravleva EY, Matrosovich TY, Matrosovich MN, Klenk HD, Moiseeva EV, Tuzikov AB, Chinarev AA, Pazynina GV, Bovin NV (2005) Polymer-bound 6′sialyl-N-acetyllactosamine protects mice infected by influenza virus. Antiviral Res 68(3):116–123PubMedGoogle Scholar
  51. 51.
    Hendricks GL, Weirich KL, Viswanathan K, Li J, Shriver ZH, Ashour J, Ploegh HL, Kurt-Jones EA, Fygenson DK, Finberg RW, Comolli JC, Wang JP (2013) Sialylneolacto-N-tetraose c (LSTc)-bearing liposomal decoys capture influenza A virus. J Biol Chem 288(12):8061–8073PubMedPubMedCentralGoogle Scholar
  52. 52.
    Spevak W, Nagy JO, Charych DH, Schaefer ME, Gilbert JH, Bednarski MD (1993) Polymerized liposomes containing C-glycosides of sialic acid: potent inhibitors of influenza virus in vitro infectivity. J Am Chem Soc 115(3):1146–1147Google Scholar
  53. 53.
    Job ER, Bottazzi B, Gilbertson B, Edenborough KM, Brown LE, Mantovani A, Brooks AG, Reading PC (2013) Serum amyloid P is a sialylated glycoprotein inhibitor of influenza A viruses. PLoS ONE 8(3):e59623PubMedPubMedCentralGoogle Scholar
  54. 54.
    Jones JC, Turpin EA, Bultmann H, Brandt CR, Schultz-Cherry S (2006) Inhibition of influenza virus infection by a novel antiviral peptide that targets viral attachment to cells. J Virol 80(24):11960–11967PubMedPubMedCentralGoogle Scholar
  55. 55.
    Nicol MQ, Ligertwood Y, Bacon MN, Dutia BM, Nash AA (2012) A novel family of peptides with potent activity against influenza A viruses. J Gen Virol 93(Pt 5):980–986PubMedGoogle Scholar
  56. 56.
    Smee DF, Bailey KW, Wong MH, O’Keefe BR, Gustafson KR, Mishin VP, Gubareva LV (2008) Treatment of influenza A (H1N1) virus infections in mice and ferrets with cyanovirin-N. Antiviral Res 80(3):266–271PubMedPubMedCentralGoogle Scholar
  57. 57.
    Dey B, Lerner DL, Lusso P, Boyd MR, Elder JH, Berger EA (2000) Multiple antiviral activities of cyanovirin-N: blocking of human immunodeficiency virus type 1 gp120 interaction with CD4 and coreceptor and inhibition of diverse enveloped viruses. J Virol 74(10):4562–4569PubMedPubMedCentralGoogle Scholar
  58. 58.
    Barrientos LG, O’Keefe BR, Bray M, Sanchez A, Gronenborn AM, Boyd MR (2003) Cyanovirin-N binds to the viral surface glycoprotein, GP1,2 and inhibits infectivity of Ebola virus. Antiviral Res 58(1):47–56PubMedGoogle Scholar
  59. 59.
    Helle F, Wychowski C, Vu-Dac N, Gustafson KR, Voisset C, Dubuisson J (2006) Cyanovirin-N inhibits hepatitis C virus entry by binding to envelope protein glycans. J Biol Chem 281(35):25177–25183PubMedGoogle Scholar
  60. 60.
    Sato Y, Hirayama M, Morimoto K, Yamamoto N, Okuyama S, Hori K (2011) High mannose-binding lectin with preference for the cluster of alpha1-2-mannose from the green alga Boodlea coacta is a potent entry inhibitor of HIV-1 and influenza viruses. J Biol Chem 286(22):19446–19458PubMedPubMedCentralGoogle Scholar
  61. 61.
    Anders EM, Hartley CA, Jackson DC (1990) Bovine and mouse serum beta inhibitors of influenza A viruses are mannose-binding lectins. Proc Natl Acad Sci USA 87(12):4485–4489PubMedPubMedCentralGoogle Scholar
  62. 62.
    Lakadamyali M, Rust MJ, Zhuang X (2004) Endocytosis of influenza viruses. Microbes Infect 6(10):929–936PubMedPubMedCentralGoogle Scholar
  63. 63.
    Harrison SC (2008) Viral membrane fusion. Nat Struct Mol Biol 15(7):690–698PubMedPubMedCentralGoogle Scholar
  64. 64.
    Bodian DL, Yamasaki RB, Buswell RL, Stearns JF, White JM, Kuntz ID (1993) Inhibition of the fusion-inducing conformational change of influenza hemagglutinin by benzoquinones and hydroquinones. Biochemistry 32(12):2967–2978PubMedGoogle Scholar
  65. 65.
    Hoffman LR, Kuntz ID, White JM (1997) Structure-based identification of an inducer of the low-pH conformational change in the influenza virus hemagglutinin: irreversible inhibition of infectivity. J Virol 71(11):8808–8820PubMedPubMedCentralGoogle Scholar
  66. 66.
    Luo G, Torri A, Harte WE, Danetz S, Cianci C, Tiley L, Day S, Mullaney D, Yu KL, Ouellet C, Dextraze P, Meanwell N, Colonno R, Krystal M (1997) Molecular mechanism underlying the action of a novel fusion inhibitor of influenza A virus. J Virol 71(5):4062–4070PubMedPubMedCentralGoogle Scholar
  67. 67.
    Staschke KA, Hatch SD, Tang JC, Hornback WJ, Munroe JE, Colacino JM, Muesing MA (1998) Inhibition of influenza virus hemagglutinin-mediated membrane fusion by a compound related to podocarpic acid. Virology 248(2):264–274PubMedGoogle Scholar
  68. 68.
    Yoshimoto J, Kakui M, Iwasaki H, Fujiwara T, Sugimoto H, Hattori N (1999) Identification of a novel HA conformational change inhibitor of human influenza virus. Arch Virol 144(5):865–878PubMedGoogle Scholar
  69. 69.
    Yu KL, Torri AF, Luo G, Cianci C, Grant-Young K, Danetz S, Tiley L, Krystal M, Meanwell NA (2002) Structure-activity relationships for a series of thiobenzamide influenza fusion inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine. Bioorg Med Chem Lett 12(23):3379–3382PubMedGoogle Scholar
  70. 70.
    Zhu L, Li Y, Li S, Li H, Qiu Z, Lee C, Lu H, Lin X, Zhao R, Chen L, Wu JZ, Tang G, Yang W (2011) Inhibition of influenza A virus (H1N1) fusion by benzenesulfonamide derivatives targeting viral hemagglutinin. PLoS ONE 6(12):e29120PubMedPubMedCentralGoogle Scholar
  71. 71.
    Boriskin YS, Leneva IA, Pecheur EI, Polyak SJ (2008) Arbidol: a broad-spectrum antiviral compound that blocks viral fusion. Curr Med Chem 15(10):997–1005PubMedGoogle Scholar
  72. 72.
    Pecheur EI, Lavillette D, Alcaras F, Molle J, Boriskin YS, Roberts M, Cosset FL, Polyak SJ (2007) Biochemical mechanism of hepatitis C virus inhibition by the broad-spectrum antiviral arbidol. Biochemistry 46(20):6050–6059PubMedPubMedCentralGoogle Scholar
  73. 73.
    Leneva IA, Russell RJ, Boriskin YS, Hay AJ (2009) Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol. Antiviral Res 81(2):132–140PubMedGoogle Scholar
  74. 74.
    Teissier E, Zandomeneghi G, Loquet A, Lavillette D, Lavergne JP, Montserret R, Cosset FL, Bockmann A, Meier BH, Penin F, Pecheur EI (2011) Mechanism of inhibition of enveloped virus membrane fusion by the antiviral drug arbidol. PLoS ONE 6(1):e15874PubMedPubMedCentralGoogle Scholar
  75. 75.
    Corti D, Voss J, Gamblin SJ, Codoni G, Macagno A, Jarrossay D, Vachieri SG, Pinna D, Minola A, Vanzetta F, Silacci C, Fernandez-Rodriguez BM, Agatic G, Bianchi S, Giacchetto-Sasselli I, Calder L, Sallusto F, Collins P, Haire LF, Temperton N, Langedijk JP, Skehel JJ, Lanzavecchia A (2011) A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 333(6044):850–856PubMedGoogle Scholar
  76. 76.
    Dreyfus C, Laursen NS, Kwaks T, Zuijdgeest D, Khayat R, Ekiert DC, Lee JH, Metlagel Z, Bujny MV, Jongeneelen M, van der Vlugt R, Lamrani M, Korse HJ, Geelen E, Sahin O, Sieuwerts M, Brakenhoff JP, Vogels R, Li OT, Poon LL, Peiris M, Koudstaal W, Ward AB, Wilson IA, Goudsmit J, Friesen RH (2012) Highly conserved protective epitopes on influenza B viruses. Science 337(6100):1343–1348PubMedPubMedCentralGoogle Scholar
  77. 77.
    Ekiert DC, Bhabha G, Elsliger MA, Friesen RH, Jongeneelen M, Throsby M, Goudsmit J, Wilson IA (2009) Antibody recognition of a highly conserved influenza virus epitope. Science 324(5924):246–251PubMedPubMedCentralGoogle Scholar
  78. 78.
    Ekiert DC, Friesen RH, Bhabha G, Kwaks T, Jongeneelen M, Yu W, Ophorst C, Cox F, Korse HJ, Brandenburg B, Vogels R, Brakenhoff JP, Kompier R, Koldijk MH, Cornelissen LA, Poon LL, Peiris M, Koudstaal W, Wilson IA, Goudsmit J (2011) A highly conserved neutralizing epitope on group 2 influenza A viruses. Science 333(6044):843–850PubMedPubMedCentralGoogle Scholar
  79. 79.
    Kashyap AK, Steel J, Rubrum A, Estelles A, Briante R, Ilyushina NA, Xu L, Swale RE, Faynboym AM, Foreman PK, Horowitz M, Horowitz L, Webby R, Palese P, Lerner RA, Bhatt RR (2010) Protection from the 2009 H1N1 pandemic influenza by an antibody from combinatorial survivor-based libraries. PLoS Pathog 6(7):e1000990PubMedPubMedCentralGoogle Scholar
  80. 80.
    Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM, Santelli E, Stec B, Cadwell G, Ali M, Wan H, Murakami A, Yammanuru A, Han T, Cox NJ, Bankston LA, Donis RO, Liddington RC, Marasco WA (2009) Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol 16(3):265–273PubMedPubMedCentralGoogle Scholar
  81. 81.
    Throsby M, van den Brink E, Jongeneelen M, Poon LL, Alard P, Cornelissen L, Bakker A, Cox F, van Deventer E, Guan Y, Cinatl J, ter Meulen J, Lasters I, Carsetti R, Peiris M, de Kruif J, Goudsmit J (2008) Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM + memory B cells. PLoS ONE 3(12):e3942PubMedPubMedCentralGoogle Scholar
  82. 82.
    Fodor E (2013) The RNA polymerase of influenza a virus: mechanisms of viral transcription and replication. Acta Virol 57(2):113–122PubMedGoogle Scholar
  83. 83.
    Gonzalez S, Zurcher T, Ortin J (1996) Identification of two separate domains in the influenza virus PB1 protein involved in the interaction with the PB2 and PA subunits: a model for the viral RNA polymerase structure. Nucleic Acids Res 24(22):4456–4463PubMedPubMedCentralGoogle Scholar
  84. 84.
    Ohtsu Y, Honda Y, Sakata Y, Kato H, Toyoda T (2002) Fine mapping of the subunit binding sites of influenza virus RNA polymerase. Microbiol Immunol 46(3):167–175PubMedGoogle Scholar
  85. 85.
    Perez DR, Donis RO (1995) A 48-amino-acid region of influenza A virus PB1 protein is sufficient for complex formation with PA. J Virol 69(11):6932–6939PubMedPubMedCentralGoogle Scholar
  86. 86.
    Poole EL, Medcalf L, Elton D, Digard P (2007) Evidence that the C-terminal PB2-binding region of the influenza A virus PB1 protein is a discrete alpha-helical domain. FEBS Lett 581(27):5300–5306PubMedGoogle Scholar
  87. 87.
    Hemerka JN, Wang D, Weng Y, Lu W, Kaushik RS, Jin J, Harmon AF, Li F (2009) Detection and characterization of influenza A virus PA-PB2 interaction through a bimolecular fluorescence complementation assay. J Virol 83(8):3944–3955PubMedPubMedCentralGoogle Scholar
  88. 88.
    Furuta Y, Takahashi K, Fukuda Y, Kuno M, Kamiyama T, Kozaki K, Nomura N, Egawa H, Minami S, Watanabe Y, Narita H, Shiraki K (2002) In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother 46(4):977–981PubMedPubMedCentralGoogle Scholar
  89. 89.
    Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H, Uehara S, Kozaki K, Nomura N, Egawa H, Shiraki K (2005) Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother 49(3):981–986PubMedPubMedCentralGoogle Scholar
  90. 90.
    Furuta Y, Takahashi K, Shiraki K, Sakamoto K, Smee DF, Barnard DL, Gowen BB, Julander JG, Morrey JD (2009) T-705 (favipiravir) and related compounds: novel broad-spectrum inhibitors of RNA viral infections. Antiviral Res 82(3):95–102PubMedGoogle Scholar
  91. 91.
    Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL (2013) Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res 100(2):446–454PubMedGoogle Scholar
  92. 92.
    Dias A, Bouvier D, Crepin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW (2009) The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 458(7240):914–918PubMedGoogle Scholar
  93. 93.
    Yuan P, Bartlam M, Lou Z, Chen S, Zhou J, He X, Lv Z, Ge R, Li X, Deng T, Fodor E, Rao Z, Liu Y (2009) Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site. Nature 458(7240):909–913PubMedGoogle Scholar
  94. 94.
    Parkes KE, Ermert P, Fassler J, Ives J, Martin JA, Merrett JH, Obrecht D, Williams G, Klumpp K (2003) Use of a pharmacophore model to discover a new class of influenza endonuclease inhibitors. J Med Chem 46(7):1153–1164PubMedGoogle Scholar
  95. 95.
    Tomassini J, Selnick H, Davies ME, Armstrong ME, Baldwin J, Bourgeois M, Hastings J, Hazuda D, Lewis J, McClements W et al (1994) Inhibition of cap (m7G pppXm)-dependent endonuclease of influenza virus by 4-substituted 2,4-dioxobutanoic acid compounds. Antimicrob Agents Chemother 38(12):2827–2837PubMedPubMedCentralGoogle Scholar
  96. 96.
    Tomassini JE, Davies ME, Hastings JC, Lingham R, Mojena M, Raghoobar SL, Singh SB, Tkacz JS, Goetz MA (1996) A novel antiviral agent which inhibits the endonuclease of influenza viruses. Antimicrob Agents Chemother 40(5):1189–1193PubMedPubMedCentralGoogle Scholar
  97. 97.
    DuBois RM, Slavish PJ, Baughman BM, Yun MK, Bao J, Webby RJ, Webb TR, White SW (2012) Structural and biochemical basis for development of influenza virus inhibitors targeting the PA endonuclease. PLoS Pathog 8(8):e1002830PubMedPubMedCentralGoogle Scholar
  98. 98.
    Kowalinski E, Zubieta C, Wolkerstorfer A, Szolar OH, Ruigrok RW, Cusack S (2012) Structural analysis of specific metal chelating inhibitor binding to the endonuclease domain of influenza pH1N1 (2009) polymerase. PLoS Pathog 8(8):e1002831PubMedPubMedCentralGoogle Scholar
  99. 99.
    Bauman JD, Patel D, Baker SF, Vijayan RS, Xiang A, Parhi AK, Martinez-Sobrido L, Lavoie EJ, Das K, Arnold E (2013) Crystallographic fragment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors. ACS Chem Biol 8(11):2501–2508PubMedGoogle Scholar
  100. 100.
    Iwai Y, Murakami K, Gomi Y, Hashimoto T, Asakawa Y, Okuno Y, Ishikawa T, Hatakeyama D, Echigo N, Kuzuhara T (2011) Anti-influenza activity of marchantins, macrocyclic bisbibenzyls contained in liverworts. PLoS ONE 6(5):e19825PubMedPubMedCentralGoogle Scholar
  101. 101.
    Perez DR, Donis RO (2001) Functional analysis of PA binding by influenza a virus PB1: effects on polymerase activity and viral infectivity. J Virol 75(17):8127–8136PubMedPubMedCentralGoogle Scholar
  102. 102.
    Sugiyama K, Obayashi E, Kawaguchi A, Suzuki Y, Tame JR, Nagata K, Park SY (2009) Structural insight into the essential PB1-PB2 subunit contact of the influenza virus RNA polymerase. EMBO J 28(12):1803–1811PubMedPubMedCentralGoogle Scholar
  103. 103.
    Loregian A, Palu G (2005) Disruption of protein–protein interactions: towards new targets for chemotherapy. J Cell Physiol 204(3):750–762. doi: 10.1002/jcp.20356 PubMedGoogle Scholar
  104. 104.
    Palu G, Loregian A (2013) Inhibition of herpesvirus and influenza virus replication by blocking polymerase subunit interactions. Antiviral Res 99(3):318–327PubMedGoogle Scholar
  105. 105.
    Ghanem A, Mayer D, Chase G, Tegge W, Frank R, Kochs G, Garcia-Sastre A, Schwemmle M (2007) Peptide-mediated interference with influenza A virus polymerase. J Virol 81(14):7801–7804PubMedPubMedCentralGoogle Scholar
  106. 106.
    Wunderlich K, Mayer D, Ranadheera C, Holler AS, Manz B, Martin A, Chase G, Tegge W, Frank R, Kessler U, Schwemmle M (2009) Identification of a PA-binding peptide with inhibitory activity against influenza A and B virus replication. PLoS ONE 4(10):e7517PubMedPubMedCentralGoogle Scholar
  107. 107.
    He X, Zhou J, Bartlam M, Zhang R, Ma J, Lou Z, Li X, Li J, Joachimiak A, Zeng Z, Ge R, Rao Z, Liu Y (2008) Crystal structure of the polymerase PA(C)-PB1(N) complex from an avian influenza H5N1 virus. Nature 454(7208):1123–1126PubMedGoogle Scholar
  108. 108.
    Obayashi E, Yoshida H, Kawai F, Shibayama N, Kawaguchi A, Nagata K, Tame JR, Park SY (2008) The structural basis for an essential subunit interaction in influenza virus RNA polymerase. Nature 454(7208):1127–1131PubMedGoogle Scholar
  109. 109.
    Muratore G, Goracci L, Mercorelli B, Foeglein A, Digard P, Cruciani G, Palu G, Loregian A (2012) Small molecule inhibitors of influenza A and B viruses that act by disrupting subunit interactions of the viral polymerase. Proc Natl Acad Sci USA 109(16):6247–6252PubMedPubMedCentralGoogle Scholar
  110. 110.
    Massari S, Nannetti G, Goracci L, Sancineto L, Muratore G, Sabatini S, Manfroni G, Mercorelli B, Cecchetti V, Facchini M, Palu G, Cruciani G, Loregian A, Tabarrini O (2013) Structural investigation of cycloheptathiophene-3-carboxamide derivatives targeting influenza virus polymerase assembly. J Med Chem 56(24):10118–10131PubMedGoogle Scholar
  111. 111.
    Loregian A, Coen DM (2006) Selective anti-cytomegalovirus compounds discovered by screening for inhibitors of subunit interactions of the viral polymerase. Chem Biol 13(2):191–200PubMedGoogle Scholar
  112. 112.
    Muratore G, Mercorelli B, Goracci L, Cruciani G, Digard P, Palu G, Loregian A (2012) Human cytomegalovirus inhibitor AL18 also possesses activity against influenza A and B viruses. Antimicrob Agents Chemother 56(11):6009–6013PubMedPubMedCentralGoogle Scholar
  113. 113.
    Fukuoka M, Minakuchi M, Kawaguchi A, Nagata K, Kamatari YO, Kuwata K (2012) Structure-based discovery of anti-influenza virus A compounds among medicines. Biochimica et Biophysica Acta 1820(2):90–95PubMedGoogle Scholar
  114. 114.
    Kessler U, Castagnolo D, Pagano M, Deodato D, Bernardini M, Pilger B, Ranadheera C, Botta M (2013) Discovery and synthesis of novel benzofurazan derivatives as inhibitors of influenza A virus. Bioorg Med Chem Lett 23(20):5575–5577PubMedGoogle Scholar
  115. 115.
    Chase G, Wunderlich K, Reuther P, Schwemmle M (2011) Identification of influenza virus inhibitors which disrupt of viral polymerase protein–protein interactions. Methods 55(2):188–191PubMedGoogle Scholar
  116. 116.
    Li C, Ba Q, Wu A, Zhang H, Deng T, Jiang T (2013) A peptide derived from the C-terminus of PB1 inhibits influenza virus replication by interfering with viral polymerase assembly. FEBS J 280(4):1139–1149PubMedGoogle Scholar
  117. 117.
    Portela A, Digard P (2002) The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication. J Gen Virol 83(Pt 4):723–734PubMedGoogle Scholar
  118. 118.
    Amorim MJ, Read EK, Dalton RM, Medcalf L, Digard P (2007) Nuclear export of influenza A virus mRNAs requires ongoing RNA polymerase II activity. Traffic 8(1):1–11PubMedGoogle Scholar
  119. 119.
    Ye Q, Krug RM, Tao YJ (2006) The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature 444(7122):1078–1082. doi: 10.1038/nature05379 PubMedGoogle Scholar
  120. 120.
    Ye Q, Guu TS, Mata DA, Kuo RL, Smith B, Krug RM, Tao YJ (2012) Biochemical and structural evidence in support of a coherent model for the formation of the double-helical influenza A virus ribonucleoprotein. MBio 4(1):e00467PubMedPubMedCentralGoogle Scholar
  121. 121.
    Moeller A, Kirchdoerfer RN, Potter CS, Carragher B, Wilson IA (2012) Organization of the influenza virus replication machinery. Science 338(6114):1631–1634PubMedPubMedCentralGoogle Scholar
  122. 122.
    Zheng W, Tao YJ (2013) Structure and assembly of the influenza A virus ribonucleoprotein complex. FEBS Lett 587(8):1206–1214PubMedGoogle Scholar
  123. 123.
    Cheng H, Wan J, Lin MI, Liu Y, Lu X, Liu J, Xu Y, Chen J, Tu Z, Cheng YS, Ding K (2012) Design, synthesis, and in vitro biological evaluation of 1H-1,2,3-triazole-4-carboxamide derivatives as new anti-influenza A agents targeting virus nucleoprotein. J Med Chem 55(5):2144–2153PubMedGoogle Scholar
  124. 124.
    Hung HC, Liu CL, Hsu JT, Horng JT, Fang MY, Wu SY, Ueng SH, Wang MY, Yaw CW, Hou MH (2012) Development of an anti-influenza drug screening assay targeting nucleoproteins with tryptophan fluorescence quenching. Anal Chem 84(15):6391–6399PubMedGoogle Scholar
  125. 125.
    Kao RY, Yang D, Lau LS, Tsui WH, Hu L, Dai J, Chan MP, Chan CM, Wang P, Zheng BJ, Sun J, Huang JD, Madar J, Chen G, Chen H, Guan Y, Yuen KY (2010) Identification of influenza A nucleoprotein as an antiviral target. Nat Biotechnol 28(6):600–605PubMedGoogle Scholar
  126. 126.
    Shen YF, Chen YH, Chu SY, Lin MI, Hsu HT, Wu PY, Wu CJ, Liu HW, Lin FY, Lin G, Hsu PH, Yang AS, Cheng YS, Wu YT, Wong CH, Tsai MD (2011) E339…R416 salt bridge of nucleoprotein as a feasible target for influenza virus inhibitors. Proc Natl Acad Sci USA 108(40):16515–16520PubMedPubMedCentralGoogle Scholar
  127. 127.
    Su CY, Cheng TJ, Lin MI, Wang SY, Huang WI, Lin-Chu SY, Chen YH, Wu CY, Lai MM, Cheng WC, Wu YT, Tsai MD, Cheng YS, Wong CH (2010) High-throughput identification of compounds targeting influenza RNA-dependent RNA polymerase activity. Proc Natl Acad Sci USA 107(45):19151–19156PubMedPubMedCentralGoogle Scholar
  128. 128.
    Lejal N, Tarus B, Bouguyon E, Chenavas S, Bertho N, Delmas B, Ruigrok RW, Di Primo C, Slama-Schwok A (2013) Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus. Antimicrob Agents Chemother 57(5):2231–2242PubMedPubMedCentralGoogle Scholar
  129. 129.
    Lin L, Liu Q, Berube N, Detmer S, Zhou Y (2012) 5′-Triphosphate-short interfering RNA: potent inhibition of influenza A virus infection by gene silencing and RIG-I activation. J Virol 86(19):10359–10369PubMedPubMedCentralGoogle Scholar
  130. 130.
    Tompkins SM, Lo CY, Tumpey TM, Epstein SL (2004) Protection against lethal influenza virus challenge by RNA interference in vivo. Proc Natl Acad Sci USA 101(23):8682–8686PubMedPubMedCentralGoogle Scholar
  131. 131.
    Chenavas S, Estrozi LF, Slama-Schwok A, Delmas B, Di Primo C, Baudin F, Li X, Crepin T, Ruigrok RW (2013) Monomeric nucleoprotein of influenza A virus. PLoS Pathog 9(3):e1003275PubMedPubMedCentralGoogle Scholar
  132. 132.
    Ruigrok RW, Baudin F (1995) Structure of influenza virus ribonucleoprotein particles. II. Purified RNA-free influenza virus ribonucleoprotein forms structures that are indistinguishable from the intact influenza virus ribonucleoprotein particles. J Gen Virol 76(Pt 4):1009–1014Google Scholar
  133. 133.
    Amorim MJ, Kao RY, Digard P (2013) Nucleozin targets cytoplasmic trafficking of viral ribonucleoprotein-Rab11 complexes in influenza A virus infection. J Virol 87(8):4694–4703PubMedPubMedCentralGoogle Scholar
  134. 134.
    Hale BG, Randall RE, Ortin J, Jackson D (2008) The multifunctional NS1 protein of influenza A viruses. J Gen Virol 89(Pt 10):2359–2376PubMedGoogle Scholar
  135. 135.
    Ayllon J, Hale BG, Garcia-Sastre A (2012) Strain-specific contribution of NS1-activated phosphoinositide 3-kinase signaling to influenza A virus replication and virulence. J Virol 86(9):5366–5370PubMedPubMedCentralGoogle Scholar
  136. 136.
    Marc D, Barbachou S, Soubieux D (2013) The RNA-binding domain of influenzavirus non-structural protein-1 cooperatively binds to virus-specific RNA sequences in a structure-dependent manner. Nucleic Acids Res 41(1):434–449PubMedPubMedCentralGoogle Scholar
  137. 137.
    Bergmann M, Garcia-Sastre A, Carnero E, Pehamberger H, Wolff K, Palese P, Muster T (2000) Influenza virus NS1 protein counteracts PKR-mediated inhibition of replication. J Virol 74(13):6203–6206PubMedPubMedCentralGoogle Scholar
  138. 138.
    Min JY, Krug RM (2006) The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: inhibiting the 2′-5′ oligo (A) synthetase/RNase L pathway. Proc Natl Acad Sci USA 103(18):7100–7105PubMedPubMedCentralGoogle Scholar
  139. 139.
    Ramos I, Carnero E, Bernal-Rubio D, Seibert CW, Westera L, Garcia-Sastre A, Fernandez-Sesma A (2013) Contribution of double-stranded RNA and CPSF30 binding domains of influenza virus NS1 to the inhibition of type I interferon production and activation of human dendritic cells. J Virol 87(5):2430–2440PubMedPubMedCentralGoogle Scholar
  140. 140.
    Gack MU, Albrecht RA, Urano T, Inn KS, Huang IC, Carnero E, Farzan M, Inoue S, Jung JU, Garcia-Sastre A (2009) Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe 5(5):439–449PubMedPubMedCentralGoogle Scholar
  141. 141.
    Zhu Z, Shi Z, Yan W, Wei J, Shao D, Deng X, Wang S, Li B, Tong G, Ma Z (2013) Nonstructural protein 1 of influenza A virus interacts with human guanylate-binding protein 1 to antagonize antiviral activity. PLoS ONE 8(2):e55920PubMedPubMedCentralGoogle Scholar
  142. 142.
    Gao S, Song L, Li J, Zhang Z, Peng H, Jiang W, Wang Q, Kang T, Chen S, Huang W (2012) Influenza A virus-encoded NS1 virulence factor protein inhibits innate immune response by targeting IKK. Cell Microbiol 14(12):1849–1866PubMedGoogle Scholar
  143. 143.
    Santos A, Pal S, Chacon J, Meraz K, Gonzalez J, Prieto K, Rosas-Acosta G (2013) SUMOylation affects the interferon blocking activity of the influenza A nonstructural protein NS1 without affecting its stability or cellular localization. J Virol 87(10):5602–5620PubMedPubMedCentralGoogle Scholar
  144. 144.
    Wang W, Riedel K, Lynch P, Chien CY, Montelione GT, Krug RM (1999) RNA binding by the novel helical domain of the influenza virus NS1 protein requires its dimer structure and a small number of specific basic amino acids. RNA 5(2):195–205PubMedPubMedCentralGoogle Scholar
  145. 145.
    Basu D, Walkiewicz MP, Frieman M, Baric RS, Auble DT, Engel DA (2009) Novel influenza virus NS1 antagonists block replication and restore innate immune function. J Virol 83(4):1881–1891PubMedPubMedCentralGoogle Scholar
  146. 146.
    Jablonski JJ, Basu D, Engel DA, Geysen HM (2012) Design, synthesis, and evaluation of novel small molecule inhibitors of the influenza virus protein NS1. Bioorg Med Chem 20(1):487–497PubMedGoogle Scholar
  147. 147.
    Walkiewicz MP, Basu D, Jablonski JJ, Geysen HM, Engel DA (2011) Novel inhibitor of influenza non-structural protein 1 blocks multi-cycle replication in an RNase L-dependent manner. J Gen Virol 92(Pt 1):60–70PubMedPubMedCentralGoogle Scholar
  148. 148.
    Ai H, Zheng F, Zhu C, Sun T, Zhang L, Liu X, Li X, Zhu G, Liu H (2010) Discovery of novel influenza inhibitors targeting the interaction of dsRNA with the NS1 protein by structure-based virtual screening. Int J Bioinform Res Appl 6(5):449–460PubMedGoogle Scholar
  149. 149.
    Maroto M, Fernandez Y, Ortin J, Pelaez F, Cabello MA (2008) Development of an HTS assay for the search of anti-influenza agents targeting the interaction of viral RNA with the NS1 protein. J Biomol Screen 13(7):581–590PubMedGoogle Scholar
  150. 150.
    Cho EJ, Xia S, Ma LC, Robertus J, Krug RM, Anslyn EV, Montelione GT, Ellington AD (2012) Identification of influenza virus inhibitors targeting NS1A utilizing fluorescence polarization-based high-throughput assay. J Biomol Screen 17(4):448–459PubMedGoogle Scholar
  151. 151.
    You L, Cho EJ, Leavitt J, Ma LC, Montelione GT, Anslyn EV, Krug RM, Ellington A, Robertus JD (2011) Synthesis and evaluation of quinoxaline derivatives as potential influenza NS1A protein inhibitors. Bioorg Med Chem Lett 21(10):3007–3011PubMedPubMedCentralGoogle Scholar
  152. 152.
    Ilyushina NA, Hoffmann E, Salomon R, Webster RG, Govorkova EA (2007) Amantadine-oseltamivir combination therapy for H5N1 influenza virus infection in mice. Antivir Ther 12(3):363–370PubMedGoogle Scholar
  153. 153.
    Smee DF, Hurst BL, Wong MH, Bailey KW, Tarbet EB, Morrey JD, Furuta Y (2010) Effects of the combination of favipiravir (T-705) and oseltamivir on influenza A virus infections in mice. Antimicrob Agents Chemother 54(1):126–133PubMedPubMedCentralGoogle Scholar
  154. 154.
    Ilyushina NA, Bovin NV, Webster RG, Govorkova EA (2006) Combination chemotherapy, a potential strategy for reducing the emergence of drug-resistant influenza A variants. Antiviral Res 70(3):121–131PubMedGoogle Scholar
  155. 155.
    Ison MG, Gnann JW Jr, Nagy-Agren S, Treannor J, Paya C, Steigbigel R, Elliott M, Weiss HL, Hayden FG (2003) Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza. Antivir Ther 8(3):183–190PubMedGoogle Scholar
  156. 156.
    Karlas A, Machuy N, Shin Y, Pleissner KP, Artarini A, Heuer D, Becker D, Khalil H, Ogilvie LA, Hess S, Maurer AP, Muller E, Wolff T, Rudel T, Meyer TF (2010) Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 463(7282):818–822PubMedGoogle Scholar
  157. 157.
    Konig R, Stertz S, Zhou Y, Inoue A, Hoffmann HH, Bhattacharyya S, Alamares JG, Tscherne DM, Ortigoza MB, Liang Y, Gao Q, Andrews SE, Bandyopadhyay S, De Jesus P, Tu BP, Pache L, Shih C, Orth A, Bonamy G, Miraglia L, Ideker T, Garcia-Sastre A, Young JA, Palese P, Shaw ML, Chanda SK (2010) Human host factors required for influenza virus replication. Nature 463(7282):813–817PubMedPubMedCentralGoogle Scholar
  158. 158.
    Muller KH, Kakkola L, Nagaraj AS, Cheltsov AV, Anastasina M, Kainov DE (2012) Emerging cellular targets for influenza antiviral agents. Trends Pharmacol Sci 33(2):89–99PubMedGoogle Scholar
  159. 159.
    Shapira SD, Gat-Viks I, Shum BO, Dricot A, de Grace MM, Wu L, Gupta PB, Hao T, Silver SJ, Root DE, Hill DE, Regev A, Hacohen N (2009) A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell 139(7):1255–1267PubMedPubMedCentralGoogle Scholar
  160. 160.
    Hao L, Sakurai A, Watanabe T, Sorensen E, Nidom CA, Newton MA, Ahlquist P, Kawaoka Y (2008) Drosophila RNAi screen identifies host genes important for influenza virus replication. Nature 454(7206):890–893PubMedPubMedCentralGoogle Scholar
  161. 161.
    Shaw ML (2011) The host interactome of influenza virus presents new potential targets for antiviral drugs. Rev Med Virol 21(6):358–369PubMedPubMedCentralGoogle Scholar
  162. 162.
    Jorba N, Juarez S, Torreira E, Gastaminza P, Zamarreno N, Albar JP, Ortin J (2008) Analysis of the interaction of influenza virus polymerase complex with human cell factors. Proteomics 8(10):2077–2088PubMedGoogle Scholar
  163. 163.
    Tafforeau L, Chantier T, Pradezynski F, Pellet J, Mangeot PE, Vidalain PO, Andre P, Rabourdin-Combe C, Lotteau V (2011) Generation and comprehensive analysis of an influenza virus polymerase cellular interaction network. J Virol 85(24):13010–13018PubMedPubMedCentralGoogle Scholar
  164. 164.
    Bottcher E, Matrosovich T, Beyerle M, Klenk HD, Garten W, Matrosovich M (2006) Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol 80(19):9896–9898PubMedPubMedCentralGoogle Scholar
  165. 165.
    Bottcher E, Freuer C, Steinmetzer T, Klenk HD, Garten W (2009) MDCK cells that express proteases TMPRSS2 and HAT provide a cell system to propagate influenza viruses in the absence of trypsin and to study cleavage of HA and its inhibition. Vaccine 27(45):6324–6329PubMedGoogle Scholar
  166. 166.
    Hatesuer B, Bertram S, Mehnert N, Bahgat MM, Nelson PS, Pohlman S, Schughart K (2013) Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice. PLoS Pathog 9(12):e1003774PubMedPubMedCentralGoogle Scholar
  167. 167.
    Horimoto T, Nakayama K, Smeekens SP, Kawaoka Y (1994) Proprotein-processing endoproteases PC6 and furin both activate hemagglutinin of virulent avian influenza viruses. J Virol 68(9):6074–6078PubMedPubMedCentralGoogle Scholar
  168. 168.
    Okumura Y, Takahashi E, Yano M, Ohuchi M, Daidoji T, Nakaya T, Bottcher E, Garten W, Klenk HD, Kido H (2010) Novel type II transmembrane serine proteases, MSPL and TMPRSS13, Proteolytically activate membrane fusion activity of the hemagglutinin of highly pathogenic avian influenza viruses and induce their multicycle replication. J Virol 84(10):5089–5096PubMedPubMedCentralGoogle Scholar
  169. 169.
    Kido H, Okumura Y, Yamada H, Le TQ, Yano M (2007) Proteases essential for human influenza virus entry into cells and their inhibitors as potential therapeutic agents. Curr Pharm Des 13(4):405–414PubMedGoogle Scholar
  170. 170.
    Zhirnov OP, Ikizler MR, Wright PF (2002) Cleavage of influenza a virus hemagglutinin in human respiratory epithelium is cell associated and sensitive to exogenous antiproteases. J Virol 76(17):8682–8689PubMedPubMedCentralGoogle Scholar
  171. 171.
    Zhirnov OP, Ovcharenko AV, Bukrinskaya AG (1984) Suppression of influenza virus replication in infected mice by protease inhibitors. J Gen Virol 65(Pt 1):191–196PubMedGoogle Scholar
  172. 172.
    Zhirnov OP, Kirzhner LS, Ovcharenko AV, Malyshev NA (1996) Clinical effectiveness of aprotinin aerosol in influenza and parainfluenza. Vestn Ross Akad Med Nauk 5:26–31PubMedGoogle Scholar
  173. 173.
    Zhirnov OP, Matrosovich TY, Matrosovich MN, Klenk HD (2011) Aprotinin, a protease inhibitor, suppresses proteolytic activation of pandemic H1N1v influenza virus. Antivir Chem Chemother 21(4):169–174PubMedGoogle Scholar
  174. 174.
    Meyer D, Sielaff F, Hammami M, Bottcher-Friebertshauser E, Garten W, Steinmetzer T (2013) Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation. Biochem J 452(2):331–343PubMedGoogle Scholar
  175. 175.
    Stieneke-Grober A, Vey M, Angliker H, Shaw E, Thomas G, Roberts C, Klenk HD, Garten W (1992) Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. EMBO J 11(7):2407–2414PubMedPubMedCentralGoogle Scholar
  176. 176.
    Becker GL, Lu Y, Hardes K, Strehlow B, Levesque C, Lindberg I, Sandvig K, Bakowsky U, Day R, Garten W, Steinmetzer T (2012) Highly potent inhibitors of proprotein convertase furin as potential drugs for treatment of infectious diseases. J Biol Chem 287(26):21992–22003PubMedPubMedCentralGoogle Scholar
  177. 177.
    Becker GL, Sielaff F, Than ME, Lindberg I, Routhier S, Day R, Lu Y, Garten W, Steinmetzer T (2010) Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics. J Med Chem 53(3):1067–1075PubMedPubMedCentralGoogle Scholar
  178. 178.
    Malakhov MP, Aschenbrenner LM, Smee DF, Wandersee MK, Sidwell RW, Gubareva LV, Mishin VP, Hayden FG, Kim DH, Ing A, Campbell ER, Yu M, Fang F (2006) Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection. Antimicrob Agents Chemother 50(4):1470–1479PubMedPubMedCentralGoogle Scholar
  179. 179.
    Nicholls JM, Moss RB, Haslam SM (2013) The use of sialidase therapy for respiratory viral infections. Antiviral Res 98(3):401–409PubMedGoogle Scholar
  180. 180.
    Triana-Baltzer GB, Sanders RL, Hedlund M, Jensen KA, Aschenbrenner LM, Larson JL, Fang F (2011) Phenotypic and genotypic characterization of influenza virus mutants selected with the sialidase fusion protein DAS181. J Antimicrob Chemother 66(1):15–28PubMedPubMedCentralGoogle Scholar
  181. 181.
    Triana-Baltzer GB, Gubareva LV, Klimov AI, Wurtman DF, Moss RB, Hedlund M, Larson JL, Belshe RB, Fang F (2009) Inhibition of neuraminidase inhibitor-resistant influenza virus by DAS181, a novel sialidase fusion protein. PLoS ONE 4(11):e7838PubMedPubMedCentralGoogle Scholar
  182. 182.
    Nicholls JM, Aschenbrenner LM, Paulson JC, Campbell ER, Malakhov MP, Wurtman DF, Yu M, Fang F (2008) Comment on: concerns of using sialidase fusion protein as an experimental drug to combat seasonal and pandemic influenza. J Antimicrob Chemother 62(2):426–428 (author reply 428–429)PubMedGoogle Scholar
  183. 183.
    Moss RB, Hansen C, Sanders RL, Hawley S, Li T, Steigbigel RT (2012) A phase II study of DAS181, a novel host directed antiviral for the treatment of influenza infection. J Infect Dis 206(12):1844–1851PubMedPubMedCentralGoogle Scholar
  184. 184.
    Takeda M, Leser GP, Russell CJ, Lamb RA (2003) Influenza virus hemagglutinin concentrates in lipid raft microdomains for efficient viral fusion. Proc Natl Acad Sci USA 100(25):14610–14617PubMedPubMedCentralGoogle Scholar
  185. 185.
    Barman S, Nayak DP (2007) Lipid raft disruption by cholesterol depletion enhances influenza A virus budding from MDCK cells. J Virol 81(22):12169–12178PubMedPubMedCentralGoogle Scholar
  186. 186.
    Wang X, Hinson ER, Cresswell P (2007) The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts. Cell Host Microbe 2(2):96–105PubMedGoogle Scholar
  187. 187.
    Tan KS, Ng WC, Seet JE, Olfat F, Engelward BP, Chow VT (2014) Investigating the efficacy of pamidronate, a chemical inhibitor of farnesyl pyrophosphate synthase, in the inhibition of influenza virus infection in vitro and in vivo. Mol Med Rep 9(1):51–56PubMedGoogle Scholar
  188. 188.
    Nagata K, Kawaguchi A, Naito T (2008) Host factors for replication and transcription of the influenza virus genome. Rev Med Virol 18(4):247–260PubMedGoogle Scholar
  189. 189.
    Naito T, Momose F, Kawaguchi A, Nagata K (2007) Involvement of Hsp90 in assembly and nuclear import of influenza virus RNA polymerase subunits. J Virol 81(3):1339–1349PubMedPubMedCentralGoogle Scholar
  190. 190.
    Chase G, Deng T, Fodor E, Leung BW, Mayer D, Schwemmle M, Brownlee G (2008) Hsp90 inhibitors reduce influenza virus replication in cell culture. Virology 377(2):431–439PubMedGoogle Scholar
  191. 191.
    Pleschka S, Wolff T, Ehrhardt C, Hobom G, Planz O, Rapp UR, Ludwig S (2001) Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Nat Cell Biol 3(3):301–305PubMedGoogle Scholar
  192. 192.
    Kujime K, Hashimoto S, Gon Y, Shimizu K, Horie T (2000) p38 mitogen-activated protein kinase and c-jun-NH2-terminal kinase regulate RANTES production by influenza virus-infected human bronchial epithelial cells. J Immunol 164(6):3222–3228PubMedGoogle Scholar
  193. 193.
    Marjuki H, Alam MI, Ehrhardt C, Wagner R, Planz O, Klenk HD, Ludwig S, Pleschka S (2006) Membrane accumulation of influenza A virus hemagglutinin triggers nuclear export of the viral genome via protein kinase Calpha-mediated activation of ERK signaling. J Biol Chem 281(24):16707–16715PubMedGoogle Scholar
  194. 194.
    Nencioni L, Iuvara A, Aquilano K, Ciriolo MR, Cozzolino F, Rotilio G, Garaci E, Palamara AT (2003) Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl-2. FASEB J 17(6):758–760PubMedGoogle Scholar
  195. 195.
    Nencioni L, De Chiara G, Sgarbanti R, Amatore D, Aquilano K, Marcocci ME, Serafino A, Torcia M, Cozzolino F, Ciriolo MR, Garaci E, Palamara AT (2009) Bcl-2 expression and p38MAPK activity in cells infected with influenza A virus: impact on virally induced apoptosis and viral replication. J Biol Chem 284(23):16004–16015PubMedPubMedCentralGoogle Scholar
  196. 196.
    Go YM, Kang SM, Roede JR, Orr M, Jones DP (2011) Increased inflammatory signaling and lethality of influenza H1N1 by nuclear thioredoxin-1. PLoS ONE 6(4):e18918PubMedPubMedCentralGoogle Scholar
  197. 197.
    Nencioni L, Sgarbanti R, De Chiara G, Garaci E, Palamara AT (2007) Influenza virus and redox mediated cell signaling: a complex network of virus/host interaction. New Microbiol 30(4):367–375PubMedGoogle Scholar
  198. 198.
    Shin YK, Liu Q, Tikoo SK, Babiuk LA, Zhou Y (2007) Influenza A virus NS1 protein activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway by direct interaction with the p85 subunit of PI3K. J Gen Virol 88(Pt 1):13–18PubMedGoogle Scholar
  199. 199.
    Kumar N, Liang Y, Parslow TG (2011) Receptor tyrosine kinase inhibitors block multiple steps of influenza a virus replication. J Virol 85(6):2818–2827PubMedPubMedCentralGoogle Scholar
  200. 200.
    Droebner K, Pleschka S, Ludwig S, Planz O (2011) Antiviral activity of the MEK-inhibitor U0126 against pandemic H1N1v and highly pathogenic avian influenza virus in vitro and in vivo. Antiviral Res 92(2):195–203PubMedGoogle Scholar
  201. 201.
    Ludwig S, Wolff T, Ehrhardt C, Wurzer WJ, Reinhardt J, Planz O, Pleschka S (2004) MEK inhibition impairs influenza B virus propagation without emergence of resistant variants. FEBS Lett 561(1–3):37–43PubMedGoogle Scholar
  202. 202.
    De Flora S, Grassi C, Carati L (1997) Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 10(7):1535–1541PubMedGoogle Scholar
  203. 203.
    Geiler J, Michaelis M, Naczk P, Leutz A, Langer K, Doerr HW, Cinatl J Jr (2010) 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 79(3):413–420PubMedGoogle Scholar
  204. 204.
    Michaelis M, Geiler J, Naczk P, Sithisarn P, Leutz A, Doerr HW, Cinatl J Jr (2011) Glycyrrhizin exerts antioxidative effects in H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory gene expression. PLoS ONE 6(5):e19705PubMedPubMedCentralGoogle Scholar
  205. 205.
    Cai J, Chen Y, Seth S, Furukawa S, Compans RW, Jones DP (2003) Inhibition of influenza infection by glutathione. Free Radic Biol Med 34(7):928–936PubMedGoogle Scholar
  206. 206.
    Sgarbanti R, Nencioni L, Amatore D, Coluccio P, Fraternale A, Sale P, Mammola CL, Carpino G, Gaudio E, Magnani M, Ciriolo MR, Garaci E, Palamara AT (2011) Redox regulation of the influenza hemagglutinin maturation process: a new cell-mediated strategy for anti-influenza therapy. Antioxid Redox Signal 15(3):593–606PubMedGoogle Scholar
  207. 207.
    Fioravanti R, Celestino I, Costi R, Cuzzucoli Crucitti G, Pescatori L, Mattiello L, Novellino E, Checconi P, Palamara AT, Nencioni L, Di Santo R (2012) Effects of polyphenol compounds on influenza A virus replication and definition of their mechanism of action. Bioorg Med Chem 20(16):5046–5052PubMedGoogle Scholar
  208. 208.
    Haasbach E, Hartmayer C, Planz O (2013) Combination of MEK inhibitors and oseltamivir leads to synergistic antiviral effects after influenza A virus infection in vitro. Antiviral Res 98(2):319–324PubMedGoogle Scholar
  209. 209.
    Rossignol JF, La Frazia S, Chiappa L, Ciucci A, Santoro MG (2009) Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J Biol Chem 284(43):29798–29808PubMedPubMedCentralGoogle Scholar
  210. 210.
    Zhou Z, Jiang X, Liu D, Fan Z, Hu X, Yan J, Wang M, Gao GF (2009) Autophagy is involved in influenza A virus replication. Autophagy 5(3):321–328PubMedGoogle Scholar
  211. 211.
    Shin YK, Liu Q, Tikoo SK, Babiuk LA, Zhou Y (2007) Effect of the phosphatidylinositol 3-kinase/Akt pathway on influenza A virus propagation. J Gen Virol 88(Pt 3):942–950PubMedGoogle Scholar
  212. 212.
    Murray JL, McDonald NJ, Sheng J, Shaw MW, Hodge TW, Rubin DH, O’Brien WA, Smee DF (2012) Inhibition of influenza A virus replication by antagonism of a PI3K-AKT-mTOR pathway member identified by gene-trap insertional mutagenesis. Antivir Chem Chemother 22(5):205–215PubMedGoogle Scholar
  213. 213.
    Kurtz JE, Ray-Coquard I (2012) PI3 kinase inhibitors in the clinic: an update. Anticancer Res 32(7):2463–2470PubMedGoogle Scholar
  214. 214.
    Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25(6):280–288PubMedGoogle Scholar
  215. 215.
    Mazur I, Wurzer WJ, Ehrhardt C, Pleschka S, Puthavathana P, Silberzahn T, Wolff T, Planz O, Ludwig S (2007) Acetylsalicylic acid (ASA) blocks influenza virus propagation via its NF-kappaB-inhibiting activity. Cell Microbiol 9(7):1683–1694PubMedGoogle Scholar
  216. 216.
    Nimmerjahn F, Dudziak D, Dirmeier U, Hobom G, Riedel A, Schlee M, Staudt LM, Rosenwald A, Behrends U, Bornkamm GW, Mautner J (2004) Active NF-kappaB signalling is a prerequisite for influenza virus infection. J Gen Virol 85(Pt 8):2347–2356PubMedGoogle Scholar
  217. 217.
    Wurzer WJ, Ehrhardt C, Pleschka S, Berberich-Siebelt F, Wolff T, Walczak H, Planz O, Ludwig S (2004) NF-kappaB-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas/FasL is crucial for efficient influenza virus propagation. J Biol Chem 279(30):30931–30937PubMedGoogle Scholar
  218. 218.
    Flory E, Kunz M, Scheller C, Jassoy C, Stauber R, Rapp UR, Ludwig S (2000) Influenza virus-induced NF-kappaB-dependent gene expression is mediated by overexpression of viral proteins and involves oxidative radicals and activation of IkappaB kinase. J Biol Chem 275(12):8307–8314PubMedGoogle Scholar
  219. 219.
    Uchide N, Ohyama K, Bessho T, Yuan B, Yamakawa T (2002) Effect of antioxidants on apoptosis induced by influenza virus infection: inhibition of viral gene replication and transcription with pyrrolidine dithiocarbamate. Antiviral Res 56(3):207–217PubMedGoogle Scholar
  220. 220.
    Uchide N, Toyoda H (2011) Antioxidant therapy as a potential approach to severe influenza-associated complications. Molecules 16(3):2032–2052PubMedGoogle Scholar
  221. 221.
    Ehrhardt C, Ruckle A, Hrincius ER, Haasbach E, Anhlan D, Ahmann K, Banning C, Reiling SJ, Kuhn J, Strobl S, Vitt D, Leban J, Planz O, Ludwig S (2013) The NF-kappaB inhibitor SC75741 efficiently blocks influenza virus propagation and confers a high barrier for development of viral resistance. Cell Microbiol 15(7):1198–1211PubMedGoogle Scholar
  222. 222.
    Leban J, Baierl M, Mies J, Trentinaglia V, Rath S, Kronthaler K, Wolf K, Gotschlich A, Seifert MH (2007) A novel class of potent NF-kappaB signaling inhibitors. Bioorg Med Chem Lett 17(21):5858–5862PubMedGoogle Scholar
  223. 223.
    Lee SM, Cheung CY, Nicholls JM, Hui KP, Leung CY, Uiprasertkul M, Tipoe GL, Lau YL, Poon LL, Ip NY, Guan Y, Peiris JS (2008) Hyperinduction of cyclooxygenase-2-mediated proinflammatory cascade: a mechanism for the pathogenesis of avian influenza H5N1 infection. J Infect Dis 198(4):525–535PubMedGoogle Scholar
  224. 224.
    Lee SM, Gai WW, Cheung TK, Peiris JS (2011) Antiviral effect of a selective COX-2 inhibitor on H5N1 infection in vitro. Antiviral Res 91(3):330–334PubMedGoogle Scholar
  225. 225.
    Beloso A, Martinez C, Valcarcel J, Santaren JF, Ortin J (1992) Degradation of cellular mRNA during influenza virus infection: its possible role in protein synthesis shutoff. J Gen Virol 73(Pt 3):575–581PubMedGoogle Scholar
  226. 226.
    Hoffmann HH, Kunz A, Simon VA, Palese P, Shaw ML (2011) Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis. Proc Natl Acad Sci USA 108(14):5777–5782PubMedPubMedCentralGoogle Scholar
  227. 227.
    Zhang L, Das P, Schmolke M, Manicassamy B, Wang Y, Deng X, Cai L, Tu BP, Forst CV, Roth MG, Levy DE, Garcia-Sastre A, de Brabander J, Phillips MA, Fontoura BM (2012) Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export. J Cell Biol 196(3):315–326PubMedPubMedCentralGoogle Scholar
  228. 228.
    Smee DF, Hurst BL, Day CW (2012) D282, a non-nucleoside inhibitor of influenza virus infection that interferes with de novo pyrimidine biosynthesis. Antivir Chem Chemother 22(6):263–272PubMedGoogle Scholar
  229. 229.
    Garcia-Sastre A (2013) Lessons from lipids in the fight against influenza. Cell 154(1):22–23PubMedGoogle Scholar
  230. 230.
    Tam VC, Quehenberger O, Oshansky CM, Suen R, Armando AM, Treuting PM, Thomas PG, Dennis EA, Aderem A (2013) Lipidomic profiling of influenza infection identifies mediators that induce and resolve inflammation. Cell 154(1):213–227PubMedPubMedCentralGoogle Scholar
  231. 231.
    Morita M, Kuba K, Ichikawa A, Nakayama M, Katahira J, Iwamoto R, Watanebe T, Sakabe S, Daidoji T, Nakamura S, Kadowaki A, Ohto T, Nakanishi H, Taguchi R, Nakaya T, Murakami M, Yoneda Y, Arai H, Kawaoka Y, Penninger JM, Arita M, Imai Y (2013) The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell 153(1):112–125PubMedGoogle Scholar
  232. 232.
    Levy BD, Kohli P, Gotlinger K, Haworth O, Hong S, Kazani S, Israel E, Haley KJ, Serhan CN (2007) Protectin D1 is generated in asthma and dampens airway inflammation and hyperresponsiveness. J Immunol 178(1):496–502PubMedPubMedCentralGoogle Scholar
  233. 233.
    Serhan CN (2007) Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol 25:101–137PubMedGoogle Scholar
  234. 234.
    Garcia-Sastre A (2011) Induction and evasion of type I interferon responses by influenza viruses. Virus Res 162(1–2):12–18PubMedPubMedCentralGoogle Scholar
  235. 235.
    Martinez-Gil L, Ayllon J, Ortigoza MB, Garcia-Sastre A, Shaw ML, Palese P (2012) Identification of small molecules with type I interferon inducing properties by high-throughput screening. PLoS ONE 7(11):e49049PubMedPubMedCentralGoogle Scholar
  236. 236.
    Ortigoza MB, Dibben O, Maamary J, Martinez-Gil L, Leyva-Grado VH, Abreu P Jr, Ayllon J, Palese P, Shaw ML (2012) A novel small molecule inhibitor of influenza A viruses that targets polymerase function and indirectly induces interferon. PLoS Pathog 8(4):e1002668PubMedPubMedCentralGoogle Scholar
  237. 237.
    Ranjan P, Jayashankar L, Deyde V, Zeng H, Davis WG, Pearce MB, Bowzard JB, Hoelscher MA, Jeisy-Scott V, Wiens ME, Gangappa S, Gubareva L, Garcia-Sastre A, Katz JM, Tumpey TM, Fujita T, Sambhara S (2010) 5′PPP-RNA induced RIG-I activation inhibits drug-resistant avian H5N1 as well as 1918 and 2009 pandemic influenza virus replication. Virol J 7:102PubMedPubMedCentralGoogle Scholar
  238. 238.
    Goulet ML, Olagnier D, Xu Z, Paz S, Belgnaoui SM, Lafferty EI, Janelle V, Arguello M, Paquet M, Ghneim K, Richards S, Smith A, Wilkinson P, Cameron M, Kalinke U, Qureshi S, Lamarre A, Haddad EK, Sekaly RP, Peri S, Balachandran S, Lin R, Hiscott J (2013) Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity. PLoS Pathog 9(4):e1003298PubMedPubMedCentralGoogle Scholar
  239. 239.
    Tamm I, Folkers K, Horsfall FL Jr (1953) Inhibition of influenza virus multiplication by alkyl derivatives of benzimidazole. II. Measurement of inhibitory activity by hemagglutination titrations. J Exp Med 98(3):229–243PubMedPubMedCentralGoogle Scholar
  240. 240.
    Wang S, Zhang J, Ye X (2012) Protein kinase inhibitor flavopiridol inhibits the replication of influenza virus in vitro. Wei Sheng Wu Xue Bao 52(9):1137–1142PubMedGoogle Scholar
  241. 241.
    Watanabe K, Takizawa N, Katoh M, Hoshida K, Kobayashi N, Nagata K (2001) Inhibition of nuclear export of ribonucleoprotein complexes of influenza virus by leptomycin B. Virus Res 77(1):31–42PubMedGoogle Scholar
  242. 242.
    Alamares-Sapuay JG, Martinez-Gil L, Stertz S, Miller MS, Shaw ML, Palese P (2013) Serum- and glucocorticoid-regulated kinase 1 is required for nuclear export of the ribonucleoprotein of influenza A virus. J Virol 87(10):6020–6026PubMedPubMedCentralGoogle Scholar
  243. 243.
    Martinez-Gil L, Alamares-Sapuay JG, Ramana Reddy MV, Goff PH, Premkumar Reddy E, Palese P (2013) A small molecule multi-kinase inhibitor reduces influenza A virus replication by restricting viral RNA synthesis. Antiviral Res 100(1):29–37PubMedGoogle Scholar
  244. 244.
    Loregian A, Palù G (2013) How academic labs can approach the drug discovery process as a way to synergize with big pharma. Trends Microbiol 21(6):261–264Google Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  • Arianna Loregian
    • 1
    Email author
  • Beatrice Mercorelli
    • 1
  • Giulio Nannetti
    • 1
  • Chiara Compagnin
    • 1
  • Giorgio Palù
    • 1
  1. 1.Department of Molecular MedicineUniversity of PaduaPaduaItaly

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