Chapter 11 : Influenza Virus Antiviral Targets

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Influenza viruses are classified as type A, B, or C based on antigenic reactions of their internal proteins. Type A influenza viruses are further divided into subtypes according to the antigenic properties of their surface antigens, the glycoproteins hemagglutinin (HA) and neuraminidase (NA). The genome of influenza virus consists of eight segments of single-stranded RNA, ranging in size from ~900 to 2,300 nucleotides. Each RNA segment contains the coding information for one or two proteins, but in the negative sense. The RNA segments are coated with the nucleoprotein (NP), and some are associated with the three subunits of the viral RNA-dependent RNA polymerase complex. The chapter discusses targets for antivirals against influenza. The M2 ion channel is the target of the earliest licensed antiviral drugs against influenza, amantadine and rimantadine. NA is the second most abundant glycoprotein on the virus surface. It cleaves sialic acid residues from glycoproteins and some glycolipids, thus acting as a receptordestroying activity. The cyclopentane peramivir was developed by BioCryst, again based on the crystal structure of NA and its interactions with inhibitors. The aim was to find an inhibitor that was readily synthesized and orally available and that did not induce resistance. The chapter talks about development of antiviral drugs targeted to influenza, and targeting host functions. The diversity of influenza viruses and their capacity to change present a particular challenge to the development and use of anti-influenza antivirals.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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Image of Figure 1.
Figure 1.

Structure and functions of the polymerase trimer. (A) Location of active sites on the polymerase trimer. C, cap-binding; E, endonuclease; 3’, binding site for 3’ end of template RNA; 5’, binding site for 5’ end of template RNA; pol, polymerase active site. The figure has been composed using information from references , and . No specific functions have yet been mapped to the PA subunit, which interacts with PB1 but apparently not to PB2 ( ). (B) Chimeric model using the three-dimensional reconstruction of a short RNP ( ) docked to a three-dimensional reconstruction of the polymerase trimer ( ). Reproduced from reference with permission.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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Image of Figure 2.
Figure 2.

Amantadine and rimantadine.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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Image of Figure 3.
Figure 3.

Structures of NA inhibitors.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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Figure 4.

Administration of Relenza. Instructions from GlaxoSmithKline are available at http://www.relenza.com/inhaler-step-by-step.html.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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Image of Figure 5.
Figure 5.

Inhibitors of the influenza polymerase and endonuclease activities.

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
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1. Abe, M.,, J. Smith,, A. Urae,, J. Barrett,, H. Kinoshita, and, C. R. Rayner. 2006. Pharmacokinetics of oseltamivir in young and very elderly subjects. Ann. Pharmacother. 40:17241730.
2. Abed, Y.,, N. Goyette, and, G. Boivin. 2005. Generation and characterization of recombinant influenza A (H1N1) viruses harboring amantadine resistance mutations. Antimicrob. Agents Chemother. 49:556559.
3. Air, G. M., and, M. Luo. 1997. Structure-guided therapeutic strategies: general overview, p. 411–431. In W. Chiu,, R. Burnett, and, R. Garcea (ed.), Structural Biology of Viruses. Oxford University Press, Cambridge, England.
4. Akarsu, H.,, W. P. Burmeister,, C. Petosa,, I. Petit,, C. W. Muller,, R. W. Ruigrok, and, F. Baudin. 2003. Crystal structure of the M1 protein-binding domain of the influenza A virus nuclear export protein (NEP/NS2). EMBO J. 22:46464655.
5. Amonsen, M.,, D. F. Smith,, R. D. Cummings, and, G. M. Air. 2007. Human parainfluenza viruses hPIV1 and hPIV3 bind α2-3 sialylated oligosaccharides that are distinct from those bound by avian influenza viruses. J. Virol. 81:83418345.
6. Area, E.,, J. Martin-Benito,, P. Gastaminza,, E. Torreira,, J. M. Valpuesta,, J. L. Carrascosa, and, J. Ortin. 2004. 3D structure of the influenza virus polymerase complex: localization of subunit domains. Proc. Natl. Acad. Sci. USA 101:308313.
7. Arzt, S.,, F. Baudin,, A. Barge,, P. Timmins,, W. P. Burmeister, and, R. W. Ruigrok. 2001. Combined results from solution studies on intact influenza virus M1 protein and from a new crystal form of its N-terminal domain show that M1 is an elongated monomer. Virology 279:439446.
8. Asaoka, N.,, Y. Tanaka,, T. Sakai,, Y. Fujii,, R. Ohuchi, and, M. Ohuchi. 2006. Low growth ability of recent influenza clinical isolates in MDCK cells is due to their low receptor binding affinities. Microbes Infect. 8:511519.
9. Babu, Y. S.,, P. Chand,, S. Bantia,, P. Kotian,, A. Dehghani,, Y. El-Kattan,, T. H. Lin,, T. L. Hutchison,, A. J. Elliott,, C. D. Parker,, S. L. Ananth,, L. L. Horn,, W. G. Laver, and, J. A. Montgomery. 2000. BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. J. Med. Chem. 43:34823486.
10. Baigent, S. J.,, R. C. Bethell, and, J. W. McCauley. 1999. Genetic analysis reveals that both haemagglutinin and neuraminidase determine the sensitivity of naturally occurring avian influenza viruses to zanamivir in vitro. Virology 263:323338.
11. Balzarini, J. 2007. Carbohydrate-binding agents: a potential future cornerstone for the chemotherapy of enveloped viruses? Antivir. Chem. Chemother. 18:111.
12. Bantia, S.,, A. A. Ghate,, S. L. Ananth,, Y. S. Babu,, G. M. Air, and, G. M. Walsh. 1998. Generation and characterization of a mutant of influenza A virus selected with the neuraminidase inhibitor BCX-140. Antimicrob. Agents Chemother. 42:801807.
13. Barbey-Morel, C. L.,, T. N. Oeltmann,, K. M. Edwards, and, P. F. Wright. 1987. Role of respiratory tract proteases in infectivity of influenza A virus. J. Infect. Dis. 155:667672.
14. Barinaga, M. 1989. The missing crystallography data. Sciene 245:11791181.
15. Barnett, J. M.,, A. Cadman,, F. M. Burrell,, S. H. Madar,, A. P. Lewis,, M. Tisdale, and, R. Bethell. 1999. In vitro selection and characterisation of influenza B/Beijing/1/87 isolates with altered susceptibility to zanamivir. Virology 265:286295.
16. Barr, I. G.,, A. C. Hurt,, N. Deed,, P. Iannello,, C. Tomasov, and, N. Komadino. 2007. The emergence of adamantane resistance in influenza A(H1) viruses in Australia and regionally in 2006. Anti-vir. Res. 75:173176.
17. Barroso, L.,, J. Treanor,, L. Gubareva, and, F. G. Hayden. 2005. Efficacy and tolerability of the oral neuraminidase inhibitor peramivir in experimental human influenza: randomized, controlled trials for prophylaxis and treatment. Antivir. Ther. 10:901910.
18. Bauer, C. M.,, L. H. Pinto,, T. A. Cross, and, R. A. Lamb. 1999. The influenza virus M2 ion channel protein: probing the structure of the transmembrane domain in intact cells by using engineered disulfide cross-linking. Virology 254:196209.
19. Baum, L. G., and, J. C. Paulson. 1991. The N2 neuraminidase of human influenza virus has acquired a substrate specificity complementary to the hemagglutinin receptor specificity. Virology 180:1015.
20. Baz, M.,, Y. Abed, and, G. Boivin. 2007. Characterization of drug-resistant recombinant influenza A/H1N1 viruses selected in vitro with peramivir and zanamivir. Antivir. Res. 74:159162.
21. Bhatia, A., and, R. E. Kast. 2007. How influenza’s neuraminidase promotes virulence and creates localized lung mucosa immunodeficiency. Cell. Mol. Biol. Lett. 12:111119.
22. Blick, T. J.,, T. Tiong,, A. Sahasrabudhe,, J. N. Varghese,, P. M. Colman,, G. J. Hart,, R. C. Bethell, and, J. L. McKimm-Breschkin. 1995. Generation and characterization of an influenza virus neuraminidase mutant with decreased sensitivity to the neuraminidase-specific inhibitor 4-guanidino-Neu5Ac2en. Virology 214:475484.
23. Bodian, D. L.,, R. B. Yamasaki,, R. L. Buswell,, J. F. Stearns,, J. M. White, and, I. D. Kuntz. 1993. Inhibition of the fusion-inducing conformational change of influenza hemagglutinin by benzoquinones and hydroquinones. Biochemistry 32:29672978.
24. Bornholdt, Z. A., and, B. V. Prasad. 2006. X-ray structure of influenza virus NS1 effector domain. Nat. Struct. Mol. Biol. 13:559560.
25. Bossart-Whitaker, P.,, M. Carson,, Y. S. Babu,, C. D. Smith,, W. G. Laver, and, G. M. Air. 1993. Three-dimensional structure of influenza A N9 neuraminidase and its complex with the inhibitor 2-deoxy 2,3-dehydro-N-acetyl neuraminic acid. J. Mol. Biol. 232:10691083.
26. Bottcher, E.,, T. Matrosovich,, M. Beyerle,, H. D. Klenk,, W. Garten, and, M. Matrosovich. 2006. Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J. Virol. 80:98969898.
27. Brouillette, W. J.,, V. R. Atigadda,, M. Luo,, G. M. Air,, Y. S. Babu, and, S. Bantia. 1999. Design of benzoic acid inhibitors of influenza neuraminidase containing a cyclic substitution for the N-acetyl grouping. Bioorg. Med. Chem. Lett. 9:19011906.
28. Brouillette, W. J.,, S. N. Bajpai,, S. M. Ali,, S. E. Velu,, V. R. Atigadda,, B. S. Lommer,, J. B. Finley,, M. Luo, and, G. M. Air. 2003. Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: modifications of essential pyrrolidinone ring substituents. Bioorg. Med. Chem. 11:27392749.
29. Bullough, P. A.,, F. M. Hughson,, J. J. Skehel, and, D. C. Wiley. 1994. Structure of influenza haemagglutinin at the pH of membrane fusion. Nature 371:3743.
30. Burmeister, W. P.,, B. Henrissat,, C. Bosso,, S. Cusack, and, R. W. Ruigrok. 1993. Influenza B virus neuraminidase can synthesize its own inhibitor. Structure 1:1926.
31. Burmeister, W. P.,, R. W. Ruigrok, and, S. Cusack. 1992. The 2.2 A resolution crystal structure of influenza B neuraminidase and its complex with sialic acid. EMBO J. 11:4956.
32. Burnet, F. M., and, D. R. Bull. 1943. Changes in influenza virus associated with adaptation to passage in chick embryos. Aust. J. Exp. Biol. 21:5669.
33. Centers for Disease Control and Prevention. 1998. Update: isolation of avian influenza A(H5N1) viruses from humans—Hong Kong, 1997–1998. Morb. Mortal. Wkly. Rep. 46:12451247.
34. Chand, P.,, S. Bantia,, P. L. Kotian,, Y. El-Kattan,, T. H. Lin, and, Y. S. Babu. 2005. Comparison of the anti-influenza virus activity of cyclopentane derivatives with oseltamivir and zanamivir in vivo. Bioorg. Med. Chem. 13:40714077.
35. Chen, B. J.,, G. P. Leser,, E. Morita, and, R. A. Lamb. 2007. Influenza virus hemagglutinin and neuraminidase, but not the matrix protein, are required for assembly and budding of plasmid-derived virus-like particles. J. Virol. 81:71117123.
36. Chen, H.,, R. A. Bright,, K. Subbarao,, C. Smith,, N. J. Cox,, J. M. Katz, and, Y. Matsuoka. 2007. Polygenic virulence factors involved in pathogenesis of 1997 Hong Kong H5N1 influenza viruses in mice. Virus Res. 128:159163.
37. Chen, J.,, J. J. Skehel, and, D. C. Wiley. 1999. N- and C-terminal residues combine in the fusion-pH influenza hemagglutinin HA(2) subunit to form an N cap that terminates the triple-stranded coiled coil. Proc. Natl. Acad. Sci. USA 96:89678972.
38. Chen, W.,, P. A. Calvo,, D. Malide,, J. Gibbs,, U. Schubert,, I. Bacik,, S. Basta,, R. O’Neill,, J. Schickli,, P. Palese,, P. Henklein,, J. R. Bennink, and, J. W. Yewdell. 2001. A novel influenza A virus mitochondrial protein that induces cell death. Nat. Med. 7:13061312.
39. Chen, X.,, T. Wu, and, G. Liu. 2006. Chinese medicinal herbs for influenza: a systematic review. J. Altern. Complement. Med. 12:171180.
40. Choppin, P. W.,, C. D. Richardson,, D. C. Merz, and, A. Scheid. 1981. Functions of surface glycoproteins of myxoviruses and paramyxoviruses and their inhibition. Ciba Found. Symp. 80:252269.
41. Choppin, P. W., and, I. Tamm. 1959. Two kinds of particles with contrasting properties in influenza A virus strains from the 1957 pandemic. Virology 8:539542.
42. Cole, J. L.,, L. C. Kuo, and, D. B. Olsen. 1995. Assay for influenza virus endonuclease using DNA polymerase extension of a specific cleavage product. Anal. Biochem. 231:309314.
43. Compans, R. W.,, J. Content, and, P. H. Duesberg. 1972. Structure of the ribonucleoprotein of influenza virus. J. Virol. 10:795800.
44. Crusat, M., and, M. D. de Jong. 2007. Neuraminidase inhibitors and their role in avian and pandemic influenza. Antivir. Ther. 12:593602.
45. Davies, W. L.,, R. R. Grunert,, R. F. Haff,, J. W. McGahen,, E. M. Neumayer,, M. Paulshock,, J. C. Watts,, T. R. Wood,, E. C. Hermann, and, C. E. Hoffmann. 1964. Antiviral activity of 1-adamantanamine (amantadine). Science 144:862863.
46. De Clercq, E. 2006. Antiviral agents active against influenza A viruses. Nat. Rev. Drug Discov. 5:10151025.
47. de Jong, M. D.,, T. T. Tran,, H. K. Truong,, M. H. Vo,, G. J. Smith,, V. C. Nguyen,, V. C. Bach,, T. Q. Phan,, Q. H. Do,, Y. Guan,, J. S. Peiris,, T. H. Tran, and, J. Farrar. 2005. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N. Engl. J. Med. 353:26672672.
48. Deshpande, K. L.,, V. A. Fried,, M. Ando, and, R. G. Webster. 1987. Glycosylation affects cleavage of an H5N2 influenza virus hemag-glutinin and regulates virulence. Proc. Natl. Acad. Sci. USA 84:3640.
49. Deyde, V. M.,, X. Xu,, R. A. Bright,, M. Shaw,, C. B. Smith,, Y. Zhang,, Y. Shu,, L. V. Gubareva,, N. J. Cox, and, A. I. Klimov. 2007. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J. Infect. Dis. 196:249257.
50. Eisen, M. B.,, S. Sabesan,, J. J. Skehel, and, D. C. Wiley. 1997. Binding of the influenza A virus to cell-surface receptors: structures of five hemagglutinin-sialyloligosaccharide complexes determined by X-ray crystallography. Virology 232:1931.
51. Els, M. C.,, W. G. Laver, and, G. M. Air. 1989. Sialic acid is cleaved from glycoconjugates at the cell surface when influenza virus neuraminidases are expressed from recombinant vaccinia virus vectors. Virology 170:346351.
52. Englund, J. A.,, R. E. Champlin,, P. R. Wyde,, H. Kantarjian,, R. L. Atmar,, J. Tarrand,, H. Yousuf,, H. Regnery,, A. I. Klimov,, N. J. Cox, and, E. Whimbey. 1998. Common emergence of amantadine-and rimantadine-resistant influenza A viruses in symptomatic immunocompromised adults. Clin. Infect. Dis. 26:14181424.
53. Ferraris, O., and, B. Lina. 2008. Mutations of neuraminidase implicated in neuraminidase inhibitors resistance. J. Clin. Virol. 41:1319.
54. Furuta, Y.,, K. Takahashi,, Y. Fukuda,, M. Kuno,, T. Kamiyama,, K. Kozaki,, N. Nomura,, H. Egawa,, S. Minami,, Y. Watanabe,, H. Narita, and, K. Shiraki. 2002. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob. Agents Che-mother. 46:977981.
55. Furuta, Y.,, K. Takahashi,, M. Kuno-Maekawa,, H. Sangawa,, S. Uehara,, K. Kozaki,, N. Nomura,, H. Egawa, and, K. Shiraki. 2005. Mechanism of action of T-705 against influenza virus. Antimicrob. Agents Chemother. 49:981986.
56. Gambaryan, A. S.,, A. B. Tuzikov,, A. A. Chinarev,, L. R. Juneja,, N. V. Bovin, and, M. N. Matrosovich. 2002. Polymeric inhibitor of influenza virus attachment protects mice from experimental influenza infection. Antivir. Res. 55:201205.
57. Gamblin, S. J.,, L. F. Haire,, R. J. Russell,, D. J. Stevens,, B. Xiao,, Y. Ha,, N. Vasisht,, D. A. Steinhauer,, R. S. Daniels,, A. Elliot,, D. C. Wiley, and, J. J. Skehel. 2004. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303:18381842.
58. Garten, W.,, S. Hallenberger,, D. Ortmann,, W. Schafer,, M. Vey,, H. Angliker,, E. Shaw, and, H. D. Klenk. 1994. Processing of viral glycoproteins by the subtilisin-like endoprotease furin and its inhibition by specific peptidylchloroalkylketones. Biochimie 76:217225.
59. Ge, Q.,, M. Pastey,, D. Kobasa,, P. Puthavathana,, C. Lupfer,, R. K. Bestwick,, P. L. Iversen,, J. Chen, and, D. A. Stein. 2006. Inhibition of multiple subtypes of influenza A virus in cell cultures with morpholino oligomers. Antimicrob. Agents Chemother. 50:37243733.
60. Ghate, A. A., and, G. M. Air. 1998. Mechanism of enzyme activity of influenza virus neuraminidase tested by site-directed mutagenesis. Eur. J. Biochem. 258:320331.
61. Gilbert, B. E., and, V. Knight. 1986. Biochemistry and clinical applications of ribavirin. Antimicrob. Agents Chemother. 30:201205.
62. Govorkova, E. A.,, N. A. Ilyushina,, D. A. Boltz,, A. Douglas,, N. Yilmaz, and, R. G. Webster. 2007. Efficacy of oseltamivir therapy in ferrets inoculated with different clades of H5N1 influenza virus. Antimicrob. Agents Chemother. 51:14141424.
63. Gubareva, L. V. 2004. Molecular mechanisms of influenza virus resistance to neuraminidase inhibitors. Virus Res. 103:199203.
64. Gubareva, L. V.,, R. Bethell,, G. J. Hart,, K. G. Murti,, C. R. Penn, and, R. G. Webster. 1996. Characterization of mutants of influenza A virus selected with the neuraminidase inhibitor 4-guanidino-Neu5Ac2en. J. Virol. 70:18181827.
65. Gubareva, L. V.,, M. N. Matrosovich,, M. K. Brenner,, R. C. Bethell, and, R. G. Webster. 1998. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J. Infect. Dis. 178:12571262.
66. Gubareva, L. V.,, M. J. Robinson,, R. C. Bethell, and, R. G. Webster. 1997. Catalytic and framework mutations in the neuraminidase active site of influenza viruses that are resistant to 4-guanidino-Neu5Ac2en. J. Virol. 71:33853390.
67. Gulati, U.,, W. Wu,, S. Gulati,, K. Kumari,, J. Waner, and, G. Air. 2005. Mismatched hemagglutinin and neuraminidase activities in recent human H3N2 influenza viruses. Virology 339:1220.
68. Ha, Y.,, D. J. Stevens,, J. J. Skehel, and, D. C. Wiley. 2001. X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs. Proc. Natl. Acad. Sci.US. 98:1118111186.
69. Hara, K.,, M. Shiota,, H. Kido,, Y. Ohtsu,, T. Kashiwagi,, J. Iwahashi,, N. Hamada,, K. Mizoue,, N. Tsumura,, H. Kato, and, T. Toyoda. 2001. Influenza virus RNA polymerase PA subunit is a novel serine protease with Ser624 at the active site. Genes Cells 6:8797.
70. Harris, A.,, G. Cardone,, D. C. Winkler,, J. B. Heymann,, M. Brecher,, J. M. White, and, A. C. Steven. 2006. Influenza virus pleiomorphy characterized by cryoelectron tomography. Proc. Natl. Acad. Sci. USA 103:1912319127.
71. Harris, A.,, F. Forouhar,, S. Qiu,, B. Sha, and, M. Luo. 2001. The crystal structure of the influenza matrix protein M1 at neutral pH: M1-M1 protein interfaces can rotate in the oligomeric structures of M1. Virology 289:3444.
72. Hastings, J. C.,, H. Selnick,, B. Wolanski, and, J. E. Tomassini. 1996. Anti-influenza virus activities of 4-substituted 2,4-dioxobutanoic acid inhibitors. Antimicrob. Agents Chemother. 40:13041307.
73. Hatakeyama, S.,, N. Sugaya,, M. Ito,, M. Yamazaki,, M. Ichikawa,, K. Kimura,, M. Kiso,, H. Shimizu,, C. Kawakami,, K. Koike,, K. Mitamura, and, Y. Kawaoka. 2007. Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. JAMA 297:14351442.
74. Hayden, F. G.,, R. B. Belshe,, R. D. Clover,, A. J. Hay,, M. G. Oakes, and, W. Soo. 1989. Emergence and apparent transmission of rimantidine-resistant influenza A virus in families. N. Engl. J. Med. 321:16961702.
75. Herlocher, M. L.,, R. Truscon,, S. Elias,, H. L. Yen,, N. A. Roberts,, S. E. Ohmit, and, A. S. Monto. 2004. Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. J. Infect. Dis. 190:16271630.
76. Hoffman, L. R.,, I. D. Kuntz, and, J. M. White. 1997. Structure-based identification of an inducer of the low-pH conformational change in the influenza virus hemagglutinin: irreversible inhibition of infectivity. J. Virol. 71:88088820.
77. Holsinger, L. J.,, D. Nichani,, L. H. Pinto, and, R. A. Lamb. 1994. Influenza A virus M2 ion channel protein: a structure-function analysis. J. Virol. 68:15511563.
78. Honda, A.,, K. Mizumoto, and, A. Ishihama. 2002. Minimum molecular architectures for transcription and replication of the influenza virus. Proc. Natl. Acad. Sci.US. 99:1316613171.
79. Hsieh, H. P., and, J. T. Hsu. 2007. Strategies of development of antiviral agents directed against influenza virus replication. Curr. Pharm. Des. 13:35313542.
80. Hulse, D. J.,, R. G. Webster,, R. J. Russell, and, D. R. Perez. 2004. Molecular determinants within the surface proteins involved in the pathogenicity of H5N1 influenza viruses in chickens. J. Virol. 78:99549964.
81. Hurt, A. C.,, P. Selleck,, N. Komadina,, R. Shaw,, L. Brown, and, I. G. Barr. 2007. Susceptibility of highly pathogenic A(H5N1) avian influenza viruses to the neuraminidase inhibitors and adamantanes. Antivir. Res. 73:228231.
82. Ison, M. G.,, L. V. Gubareva,, R. L. Atmar,, J. Treanor, and, F. G. Hayden. 2006. Recovery of drug-resistant influenza virus from immunocompromised patients: a case series. J. Infect. Dis. 193:760764.
83. Ives, J. A.,, J. A. Carr,, D. B. Mendel,, C. Y. Tai,, R. Lambkin,, L. Kelly,, J. S. Oxford,, F. G. Hayden, and, N. A. Roberts. 2002. The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antivir. Res. 55:307317.
84. Jefferson, T. O.,, V. Demicheli,, C. Di Pietrantonj,, M. Jones, and, D. Rivetti. 2006. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst. Rev. 2003:CD002744.
85. Jing, X.,, C. Ma,, Y. Ohigashi,, F. A. Oliveira,, T. S. Jardetzky,, L. H. Pinto, and, R. A. Lamb. 2008. Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton, selective ion channel. Proc. Natl. Acad. Sci. USA 105:1096710972.
86. Kati, W. M.,, D. Montgomery,, R. Carrick,, L. Gubareva,, C. Maring,, K. McDaniel,, K. Steffy,, A. Molla,, F. Hayden,, D. Kempf, and, W. Kohlbrenner. 2002. In vitro characterization of A-315675, a highly potent inhibitor of A and B strain influenza virus neuraminidases and influenza virus replication. Antimicrob. Agents Chemother. 46:10141021.
87. Kido, H.,, Y. Okumura,, H. Yamada,, T. Q. Le, and, M. Yano. 2007. Proteases essential for human influenza virus entry into cells and their inhibitors as potential therapeutic agents. Curr. Pharm. Des. 13:405414.
88. Kido, H.,, Y. Yokogoshi,, K. Sakai,, M. Tashiro,, Y. Kishino,, A. Fukutomi, and, N. Katunuma. 1992. Isolation and characterization of a novel trypsin-like protease found in rat bronchiolar epithelial Clara cells. A possible activator of the viral fusion glycoprotein. J. Biol. Chem. 267:1357313579.
89. Kilby, J. M.,, S. Hopkins,, T. M. Venetta,, B. DiMassimo,, G. A. Cloud,, J. Y. Lee,, L. Alldredge,, E. Hunter,, D. Lambert,, D. Bolognesi,, T. Matthews,, M. R. Johnson,, M. A. Nowak,, G. M. Shaw, and, M. S. Saag. 1998. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat. Med. 4:13021307.
90. Kim, C. U.,, W. Lew,, M. A. Williams,, H. Liu,, L. Zhang,, S. Swam-inathan,, N. Bischofberger,, M. S. Chen,, D. B. Mendel,, C. Y. Tai,, W. G. Laver, and, R. C. Stevens. 1997. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J. Am. Chem. Soc. 119:681690.
91. Kiso, M.,, K. Mitamura,, Y. Sakai-Tagawa,, K. Shiraishi,, C. Kawakami,, K. Kimura,, F. G. Hayden,, N. Sugaya, and, Y. Kawaoka. 2004. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 364:759765.
92. Kobasa, D.,, S. Kodihalli,, M. Luo,, M. R. Castrucci,, I. Donatelli,, Y. Suzuki,, T. Suzuki, and, Y. Kawaoka. 1999. Amino acid residues contributing to the substrate specificity of the influenza A virus neuraminidase. J. Virol. 73:67436751.
93. Kochs, G.,, A. Garcia-Sastre, and, L. Martinez-Sobrido. 2007. Multiple anti-interferon actions of the influenza A virus NS1 protein. J. Virol. 81:70117021.
94. Kolocouris, A.,, R. K. Hansen, and, R. W. Broadhurst. 2004. Interaction between an amantadine analogue and the transmembrane portion of the influenza A M2 protein in liposomes probed by 1H NMR spectroscopy of the ligand. J. Med. Chem. 47:49754978.
95. Kolpashchikov, D. M.,, A. Honda, and, A. Ishihama. 2004. Structure-function relationship of the influenza virus RNA polymerase: primer-binding site on the PB1 subunit. Biochemistry 43:58825887.
96. Krueger, A. C.,, Y. Xu,, W. M. Kati,, D. J. Kempf,, C. J. Maring,, K. F. McDaniel,, A. Molla,, D. Montgomery, and, W. E. Kohlbrenner. 2008. Synthesis of potent pyrrolidine influenza neuraminidase inhibitors. Bioorg. Med. Chem. Lett. 18:16921695.
97. Krug, R. M.,, W. Yuan,, D. L. Noah, and, A. G. Latham. 2003. Intracellular warfare between human influenza viruses and human cells: the roles of the viral NS1 protein. Virology 309:181189.
98. Kumari, K.,, S. Gulati,, D. F. Smith,, U. Gulati,, R. D. Cummings, and, G. M. Air. 2007. Receptor binding specificity of recent human H3N2 influenza viruses. Virol. J. 4:42.
99. Lagoja, I. M., and, E. De Clercq. 2008. Anti-influenza virus agents: synthesis and mode of action. Med. Res. Rev. 28:138.
100. Le, Q. M.,, M. Kiso,, K. Someya,, Y. T. Sakai,, T. H. Nguyen,, K. H. Nguyen,, N. D. Pham,, H. H. Ngyen,, S. Yamada,, Y. Muramoto,, T. Horimoto,, A. Takada,, H. Goto,, T. Suzuki,, Y. Suzuki, and, Y. Kawaoka. 2005. Avian flu: isolation of drug-resistant H5N1 virus. Nature 437:1108.
101. Lee, M. T.,, K. Klumpp,, P. Digard, and, L. Tiley. 2003. Activation of influenza virus RNA polymerase by the 5’ and 3’ terminal duplex of genomic RNA. Nucleic Acids Res. 31:16241632.
102. Lees, W. J.,, A. Spaltenstein,, J. E. Kingery-Wood, and, G. M. Whitesides. 1994. Polyacrylamides bearing pendant alpha-sialoside groups strongly inhibit agglutination of erythrocytes by influenza A virus: multivalency and steric stabilization of particulate biological systems. J. Med. Chem. 37:34193433.
103. Li, M. L.,, P. Rao, and, R. M. Krug. 2001. The active sites of the influenza cap-dependent endonuclease are on different polymerase subunits. EMBO J. 20:20782086.
104. Liu, C.,, M. C. Eichelberger,, R. W. Compans, and, G. M. Air. 1995. Influenza type A virus neuraminidase does not play a role in viral entry, replication, assembly, or budding. J. Virol. 69:10991106.
105. Lommer, B. S., and, M. Luo. 2002. Structural plasticity in influenza virus protein NS2 (NEP). J. Biol. Chem. 277:71087117.
106. Luo, G.,, A. Torri,, W. E. Harte,, S. Danetz,, C. Cianci,, L. Tiley,, S. Day,, D. Mullaney,, K. L. Yu,, C. Ouellet,, P. Dextraze,, N. Mean-well,, R. Colonno, and, M. Krystal. 1997. Molecular mechanism underlying the action of a novel fusion inhibitor of influenza A virus. J. Virol. 71:40624070.
107. Macdonald, S. J.,, R. Cameron,, D. A. Demaine,, R. J. Fenton,, G. Foster,, D. Gower,, J. N. Hamblin,, S. Hamilton,, G. J. Hart,, A. P. Hill,, G. G. Inglis,, B. Jin,, H. T. Jones,, D. B. McConnell,, J. McKimm-Breschkin,, G. Mills,, V. Nguyen,, I. J. Owens,, N. Parry,, S. E. Shanahan,, D. Smith,, K. G. Watson,, W. Y. Wu, and, S. P. Tucker. 2005. Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza. J. Med. Chem. 48:29642971.
108. Macdonald, S. J.,, K. G. Watson,, R. Cameron,, D. K. Chalmers,, D. A. Demaine,, R. J. Fenton,, D. Gower,, J. N. Hamblin,, S. Hamilton,, G. J. Hart,, G. G. Inglis,, B. Jin,, H. T. Jones,, D. B. McConnell,, A. M. Mason,, V. Nguyen,, I. J. Owens,, N. Parry,, P. A. Reece,, S. E. Shanahan,, D. Smith,, W. Y. Wu, and, S. P. Tucker. 2004. Potent and long-acting dimeric inhibitors of influenza virus neuraminidase are effective at a once-weekly dosing regimen. Antimicrob. Agents Chemother. 48:45424549.
109. Malaisree, M.,, T. Rungrotmongkol,, P. Decha,, P. Intharathep,, O. Aruksakunwong, and, S. Hannongbua. 2008. Understanding of known drug-target interactions in the catalytic pocket of neuraminidase subtype N1. Proteins 71:19081918.
110. Malakhov, M. P.,, L. M. Aschenbrenner,, D. F. Smee,, M. K. Wander-see,, R. W. Sidwell,, L. V. Gubareva,, V. P. Mishin,, F. G. Hayden,, D. H. Kim,, A. Ing,, E. R. Campbell,, M. Yu, and, F. Fang. 2006. Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection. Antimicrob. Agents Chemother. 50:14701479.
111. Mammen, M.,, G. Dahmann, and, G. M. Whitesides. 1995. Effective inhibitors of hemagglutination by influenza virus synthesized from polymers having active ester groups. Insight into mechanism of inhibition. J. Med. Chem. 38:41794190.
112. Maring, C. J.,, V. S. Stoll,, C. Zhao,, M. Sun,, A. C. Krueger,, K. D. Stewart,, D. L. Madigan,, W. M. Kati,, Y. Xu,, R. J. Carrick,, D. A. Montgomery,, A. Kempf-Grote,, K. C. Marsh,, A. Molla,, K. R. Steffy,, H. L. Sham,, W. G. Laver,, Y. G. Gu,, D. J. Kempf, and, W. E. Kohlbrenner. 2005. Structure-based characterization and optimization of novel hydrophobic binding interactions in a series of pyrrolidine influenza neuraminidase inhibitors. J. Med. Chem. 48:39803990.
113. Martin-Benito, J.,, E. Area,, J. Ortega,, O. Llorca,, J. M. Valpuesta,, J. L. Carrascosa, and, J. Ortin. 2001. Three-dimensional reconstruction of a recombinant influenza virus ribonucleoprotein particle. EMBO Rep. 2:313317.
114. Matheson, N. J.,, A. R. Harnden,, R. Perera,, A. Sheikh, and, M. Symmonds-Abrahams. 2007. Neuraminidase inhibitors for preventing and treating influenza in children. Cochrane Database Syst. Rev. 2007:CD002744.
115. Matrosovich, M.,, A. Tuzikov,, N. Bovin,, A. Gambaryan,, A. Klimov,, M. R. Castrucci,, I. Donatelli, and, Y. Kawaoka. 2000. Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. J. Virol. 74:85028512.
116. Matrosovich, M. N.,, T. Y. Matrosovich,, T. Gray,, N. A. Roberts, and, H. D. Klenk. 2004. Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J. Virol. 78:1266512667.
117. McKimm-Breschkin, J.,, T. Trivedi,, A. Hampson,, A. Hay,, A. Klimov,, M. Tashiro,, F. Hayden, and, M. Zambon. 2003. Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob. Agents Chemother. 47:22642272.
118. McKimm-Breschkin, J. L.,, T. J. Blick,, A. Sahasrabudhe,, T. Tiong,, D. Marshall,, G. J. Hart,, R. C. Bethell, and, C. R. Penn. 1996. Generation and characterization of variants of NWS/G70C influenza virus after in vitro passage in 4-amino-Neu5Ac2en and 4-guanidino-Neu5Ac2en. Antimicrob. Agents Chemother. 40:4046.
119. McKimm-Breschkin, J. L.,, M. McDonald,, T. J. Blick, and, P. M. Colman. 1996. Mutation in the influenza virus neuraminidase gene resulting in decreased sensitivity to the neuraminidase inhibitor 4-guanidino-Neu5Ac2en leads to instability of the enzyme. Virology 225:240242.
120. Mendel, D. B., and, R. W. Sidwell. 1998. Influenza virus resistance to neuraminidase inhibitors. Drug Resist. Updates 1:184189.
121. Mendel, D. B.,, C. Y. Tai,, P. A. Escarpe,, W. Li,, R. W. Sidwell,, J. H. Huffman,, C. Sweet,, K. J. Jakeman,, J. Merson,, S. A. Lacy,, W. Lew,, M. A. Williams,, L. Zhang,, M. S. Chen,, N. Bischofberger, and, C. U. Kim. 1998. Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets against influenza infection. Antimicrob. Agents Chemother. 42:640646.
122. Molla, A.,, W. Kati,, R. Carrick,, K. Steffy,, Y. Shi,, D. Montgomery,, N. Gusick,, V. S. Stoll,, K. D. Stewart,, T. I. Ng,, C. Maring,, D. J. Kempf, and, W. Kohlbrenner. 2002. In vitro selection and characterization of influenza A (A/N9) virus variants resistant to a novel neuraminidase inhibitor, A-315675. J. Virol. 76:53805386.
123. Moscona, A. 2008. Medical management of influenza infection. Annu. Rev. Med. 59:397413.
124. Mould, J. A.,, H. C. Li,, C. S. Dudlak,, J. D. Lear,, A. Pekosz,, R. A. Lamb, and, L. H. Pinto. 2000. Mechanism for proton conduction of the M(2) ion channel of influenza A virus. J. Biol. Chem. 275:85928599.
125. Mould, J. A.,, R. G. Paterson,, M. Takeda,, Y. Ohigashi,, P. Venkataraman,, R. A. Lamb, and, L. H. Pinto. 2003. Influenza B virus BM2 protein has ion channel activity that conducts protons across membranes. Dev. Cell 5:175184.
126. Nedyalkova, M. S.,, F. G. Hayden,, R. G. Webster, and, L. V. Gubareva. 2002. Accumulation of defective neuraminidase (NA) genes by influenza A viruses in the presence of NA inhibitors as a marker of reduced dependence on NA. J. Infect. Dis. 185:591598.
127. Noda, T.,, H. Sagara,, A. Yen,, A. Takada,, H. Kida,, R. H. Cheng, and, Y. Kawaoka. 2006. Architecture of ribonucleoprotein complexes in influenza A virus particles. Nature 439:490492.
128. Ohuchi, M.,, N. Asaoka,, T. Sakai, and, R. Ohuchi. 2006. Roles of neuraminidase in the initial stage of influenza virus infection. Microbes Infect. 8:12871293.
129. Oxford, J. S. 1975. Inhibition of the replication of influenza A and B viruses by a nucleoside analogue (ribavirin). J. Gen. Virol. 28:409414.
130. Palese, P., and, R. W. Compans. 1976. Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetyl-neuraminic acid (FANA): mechanism of action. J. Gen. Virol. 33:159163.
131. Palese, P., and, J. Schulman. 1977. Inhibitors of viral neuraminidase as potential antiviral drugs, p. 189–205. In J. S. Oxford (ed.), Chemoprophylaxis and Virus Infection of the Upper Respiratory Tract, vol. 1. CRC Press, Boca Raton, FL.
132. Palese, P.,, K. Tobita,, M. Ueda, and, R. W. Compans. 1974. Characterization of temperature-sensitive influenza virus mutants defective in neuraminidase. Virology 61:397410.
133. Park, H. E.,, J. A. Gruenke, and, J. M. White. 2003. Leash in the groove mechanism of membrane fusion. Nat. Struct. Biol. 10:10481053.
134. Peltola, V. T.,, K. L. Boyd,, J. L. McAuley,, J. E. Rehg, and, J. A. McCullers. 2006. Bacterial sinusitis and otitis media following influenza virus infection in ferrets. Infect. Immun. 74:25622567.
135. Pinto, L. H.,, G. R. Dieckmann,, C. S. Gandhi,, C. G. Papworth,, J. Braman,, M. A. Shaughnessy,, J. D. Lear,, R. A. Lamb, and, W. F. DeGrado. 1997. A functionally defined model for the M2 proton channel of influenza A virus suggests a mechanism for its ion selectivity. Proc. Natl. Acad. Sci. USA 94:1130111306.
136. Pinto, L. H., and, R. A. Lamb. 2006. The M2 proton channels of influenza A and B viruses. J. Biol. Chem. 281:89979000.
137. Randall, R. E., and, S. Goodbourn. 2008. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J. Gen. Virol. 89:147.
138. Reece, P. A. 2007. Neuraminidase inhibitor resistance in influenza viruses. J. Med. Virol. 79:15771586.
139. Rodriguez, A.,, A. Perez-Gonzalez, and, A. Nieto. 2007. Influenza virus infection causes specific degradation of the largest subunit of cellular RNA polymerase II. J. Virol. 81:53155324.
140. Rogers, G. N., and, J. C. Paulson. 1983. Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin. Virology 127:361373.
141. Rogers, G. N.,, J. C. Paulson,, R. S. Daniels,, J. J. Skehel,, I. A. Wilson, and, D. C. Wiley. 1983. Single amino acid substitutions in influenza haemagglutinin change receptor binding specificity. Nature 304:7678.
142. Russell, R. J.,, L. F. Haire,, D. J. Stevens,, P. J. Collins,, Y. P. Lin,, G. M. Blackburn,, A. J. Hay,, S. J. Gamblin, and, J. J. Skehel. 2006. The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. Nature 443:4549.
143. Rust, M. J.,, M. Lakadamyali,, F. Zhang, and, X. Zhuang. 2004. Assembly of endocytic machinery around individual influenza viruses during viral entry. Nat. Struct. Mol. Biol. 11:567573.
144. Saito, R.,, D. Li,, Y. Suzuki,, I. Sato,, H. Masaki,, H. Nishimura,, T. Kawashima,, Y. Shirahige,, C. Shimomura,, N. Asoh,, S. Degawa,, H. Ishikawa,, M. Sato,, Y. Shobugawa, and, H. Suzuki. 2007. High prevalence of amantadine-resistance influenza A (H3N2) in six prefectures, Japan, in the 2005-2006 season. J. Med. Virol. 79:15691576.
145. Schmidtke, M.,, R. Zell,, K. Bauer,, A. Krumbholz,, C. Schrader,, J. Suess, and, P. Wutzler. 2006. Amantadine resistance among porcine H1N1, H1N2, and H3N2 influenza A viruses isolated in Germany between 1981 and 2001. Intervirolog. 49:286293.
146. Schnell, J. R., and, J. J. Chou. 2008. Structure and mechanism of the M2 proton channel of influenza A virus. Nature 451:591595.
147. Sha, B., and, M. Luo. 1997. Structure of a bifunctional membrane-RNA binding protein, influenza virus matrix protein M1. Nat. Struct. Biol. 4:239244.
148. Shiryaev, S. A.,, A. G. Remacle,, B. I. Ratnikov,, N. A. Nelson,, A. Y. Savinov,, G. Wei,, M. Bottini,, M. F. Rega,, A. Parent,, R. Desjardins,, M. Fugere,, R. Day,, M. Sabet,, M. Pellecchia,, R. C. Liddington,, J. W. Smith,, T. Mustelin,, D. G. Guiney,, M. Lebl, and, A. Y. Strongin. 2007. Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens. J. Biol. Chem. 282:2084720853.
149. Sidwell, R. W.,, D. L. Barnard,, C. W. Day,, D. F. Smee,, K. W. Bailey,, M. H. Wong,, J. D. Morrey, and, Y. Furuta. 2007. Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice. Antimicrob. Agents Chemother. 51:845851.
150. Smith, P. W.,, S. L. Sollis,, P. D. Howes,, P. C. Cherry,, I. D. Starkey,, K. N. Cobley,, H. Weston,, J. Scicinski,, A. Merritt,, A. Whittington,, P. Wyatt,, N. Taylor,, D. Green,, R. Bethell,, S. Madar,, R. J. Fenton,, P. J. Morley,, T. Pateman, and, A. Beresford. 1998. Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 1. Discovery, synthesis, biological activity, and structure-activity relationships of 4-guanidino- and 4-amino-4H-pyran-6-carboxamides. J. Med. Chem. 41:787797.
151. Sparks, M. A.,, K. W. Williams, and, G. M. Whitesides. 1993. Neuraminidase-resistant hemagglutination inhibitors: acrylamide copolymers containing a C-glycoside of N-acetylneuraminic acid. J. Med. Chem. 36:778783.
152. Staschke, K. A.,, J. M. Colacino,, A. J. Baxter,, G. M. Air,, A. Bansal,, W. J. Hornback,, J. E. Munroe, and, W. G. Laver. 1995. Molecular basis for the resistance of influenza viruses to 4-guanidinoNeu5Ac2en. Virology 214:642646.
153. Staschke, K. A.,, S. D. Hatch,, J. C. Tang,, W. J. Hornback,, J. E. Munroe,, J. M. Colacino, and, M. A. Muesing. 1998. Inhibition of influenza virus hemagglutinin-mediated membrane fusion by a compound related to podocarpic acid. Virology 248:264274.
154. Stevens, J.,, O. Blixt,, L. Glaser,, J. K. Taubenberger,, P. Palese,, J. C. Paulson, and, I. A. Wilson. 2006. Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities. J. Mol. Biol. 355:11431155.
155. Stevens, J.,, O. Blixt,, T. M. Tumpey,, J. K. Taubenberger,, J. C. Paulson, and, I. A. Wilson. 2006. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312:404410.
156. Stevens, J.,, A. L. Corper,, C. F. Basler,, J. K. Taubenberger,, P. Palese, and, I. A. Wilson. 2004. Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science 303:18661870.
157. Stieneke-Grober, A.,, M. Vey,, H. Angliker,, E. Shaw,, G. Thomas,, C. Roberts,, H. D. Klenk, and, W. Garten. 1992. Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. EMBO J. 11:24072414.
158. Stouffer, A. L.,, R. Acharya,, D. Salom,, A. S. Levine,, L. Di Costanzo,, C. S. Soto,, V. Tereshko,, V. Nanda,, S. Stayrook, and, W. F. DeGrado. 2008. Structural basis for the function and inhibition of an influenza virus proton channel. Nature 451:596599.
159. Stray, S. J.,, R. D. Cummings, and, G. M. Air. 2000. Influenza virus infection of desialylated cells. Glycobiology 10:649658.
160. Subbarao, K.,, A. Klimov,, J. Katz,, H. Regnery,, W. Lim,, H. Hall,, M. Perdue,, D. Swayne,, C. Bender,, J. Huang,, M. Hemphill,, T. Rowe,, M. Shaw,, X. Xu,, K. Fukuda, and, N. Cox. 1998. Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279:393396.
161. Sun, C.,, X. Zhang,, H. Huang, and, P. Zhou. 2006. Synthesis and evaluation of a new series of substituted acyl(thio)urea and thiadiazolo [2,3-a] pyrimidine derivatives as potent inhibitors of influenza virus neuraminidase. Bioorg. Med. Chem. 14:85748581.
162. Tang, Y.,, F. Zaitseva,, R. A. Lamb, and, L. H. Pinto. 2002. The gate of the influenza virus M2 proton channel is formed by a single tryptophan residue. J. Biol. Chem. 277:3988039886.
163. Taylor, N. R.,, A. Cleasby,, O. Singh,, T. Skarzynski,, A. J. Wonacott,, P. W. Smith,, S. L. Sollis,, P. D. Howes,, P. C. Cherry,, R. Bethell,, P. Colman, and, J. Varghese. 1998. Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 2. Crystallographic and molecular modeling study of complexes of 4-amino-4H-pyran-6-carboxamides and sialidase from influenza virus types A and B. J. Med. Chem. 41:798807.
164. Tian, C.,, P. F. Gao,, L. H. Pinto,, R. A. Lamb, and, T. A. Cross. 2003. Initial structural and dynamic characterization of the M2 protein transmembrane and amphipathic helices in lipid bilayers. Protein Sci. 12:25972605.
165. Tisdale, M.,, M. Ellis,, K. Klumpp,, S. Court, and, M. Ford. 1995. Inhibition of influenza virus transcription by 2’-deoxy-2’-fluoroguanosine. Antimicrob. Agents Chemother. 39:24542458.
166. Tomassini, J. E.,, M. E. Davies,, J. C. Hastings,, R. Lingham,, M. Mojena,, S. L. Raghoobar,, S. B. Singh,, J. S. Tkacz, and, M. A. Goetz. 1996. A novel antiviral agent which inhibits the endonuclease of influenza viruses. Antimicrob. Agents Chemother. 40:11891193.
167. Toogood, P. L.,, P. K. Galliker,, G. D. Glick, and, J. R. Knowles. 1991. Monovalent sialosides that bind tightly to influenza A virus. J. Med. Chem. 34:31383140.
168. Torreira, E.,, G. Schoehn,, Y. Fernandez,, N. Jorba,, R. W. Ruigrok,, S. Cusack,, J. Ortin, and, O. Llorca. 2007. Three-dimensional model for the isolated recombinant influenza virus polymerase heterotrimer. Nucleic Acids Res. 35:37743783.
169. Varghese, J. N.,, W. G. Laver, and, P. M. Colman. 1983. Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9A resolution. Nature 303:3540.
170. Varghese, J. N.,, J. L. McKimm-Breschkin,, J. B. Caldwell,, A. A. Kortt, and, P. M. Colman. 1992. The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor. Proteins 14:327332.
171. Venkataraman, P.,, R. A. Lamb, and, L. H. Pinto. 2005. Chemical rescue of histidine selectivity filter mutants of the M2 ion channel of influenza A virus. J. Biol. Chem. 280:2146321472.
172. von Itzstein, M. 2007. The war against influenza: discovery and development of sialidase inhibitors. Nat. Rev. Drug Discov. 6:967974.
173. von Itzstein, M.,, W. Y. Wu,, G. B. Kok,, M. S. Pegg,, J. C. Dyason,, B. Jin,, T. Van Phan,, M. L. Smythe,, H. F. White,, S. W. Oliver,, P. M. Colman,, J. N. Varghese,, D. M. Ryan,, J. M. Woods,, R. C. Bethell,, V. J. Hotham,, J. M. Cameron, and, C. R. Penn. 1993. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363:418423.
174. [Reference deleted.]
175. Walker, J. A.,, S. S. Molloy,, G. Thomas,, T. Sakaguchi,, T. Yoshida,, T. M. Chambers, and, Y. Kawaoka. 1994. Sequence specificity of furin, a proprotein-processing endoprotease, for the hemagglutinin of a virulent avian influenza virus. J. Virol. 68:12131218.
176. Wang, C.,, K. Takeuchi,, L. H. Pinto, and, R. A. Lamb. 1993. Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block. J. Virol. 67:55855594.
177. Wang, G. T.,, S. Wang,, R. Gentles,, T. Sowin,, C. J. Maring,, D. J. Kempf,, W. M. Kati,, V. Stoll,, K. D. Stewart, and, G. Laver. 2005. Design, synthesis, and structural analysis of inhibitors of influenza neuraminidase containing a 2,3-disubstituted tetrahydrofuran-5-carboxylic acid core. Bioorg. Med. Chem. Lett. 15:125128.
178. Wang, M. Z.,, C. Y. Tai, and, D. B. Mendel. 2002. Mechanism by which mutations at His274 alter sensitivity of influenza A virus N1 neuraminidase to oseltamivir carboxylate and zanamivir. Antimicrob. Agents Chemother. 46:38093816.
179. Watowich, S. J.,, J. J. Skehel, and, D. C. Wiley. 1994. Crystal structures of influenza virus hemagglutinin in complex with high-affinity receptor analogs. Structure 2:719731.
180. Weinstock, D. M.,, L. V. Gubareva, and, G. Zuccotti. 2003. Prolonged shedding of multidrug-resistant influenza A virus in an immunocompromised patient. N. Engl. J. Med. 348:867868.
181. Weis, W.,, J. H. Brown,, S. Cusack,, J. C. Paulson,, J. J. Skehel, and, D. C. Wiley. 1988. Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid. Nature 333:426431.
182. Weis, W. I.,, A. T. Brunger,, J. J. Skehel, and, D. C. Wiley. 1990. Refinement of the influenza virus hemagglutinin by simulated annealing. J. Mol. Biol. 212:737761.
183. Wiley, D. C.,, I. A. Wilson, and, J. J. Skehel. 1981. Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature 289:373378.
184. Wilson, I. A.,, J. J. Skehel, and, D. C. Wiley. 1981. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution. Nature 289:366373.
185. World Health Organization. 2008. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. World Health Organization, Geneva, Switzerland. http://www.who.int/csr/disease/avian_influenza/country/en/.
186. Ye, Q.,, R. M. Krug, and, Y. J. Tao. 2006. The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature 444:10781082.
187. Yen, H. L.,, L. M. Herlocher,, E. Hoffmann,, M. N. Matrosovich,, A. S. Monto,, R. G. Webster, and, E. A. Govorkova. 2005. Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrob. Agents Che-mother. 49:40754084.
188. Yin, C.,, J. A. Khan,, G. V. Swapna,, A. Ertekin,, R. M. Krug,, L. Tong, and, G. T. Montelione. 2007. Conserved surface features form the double-stranded RNA binding site of non-structural protein 1 (NS1) from influenza A and B viruses. J. Biol. Chem. 282:2058420592.
189. Yun, N. E.,, N. S. Linde,, M. A. Zacks,, I. G. Barr,, A. C. Hurt,, J. N. Smith,, N. Dziuba,, M. R. Holbrook,, L. Zhang,, J. M. Kilpat-rick,, C. S. Arnold, and, S. Paessler. 2008. Injectable peramivir mitigates disease and promotes survival in ferrets and mice infected with the highly virulent influenza virus, A/Vietnam/1203/04 (H5N1). Virology 374:198209.
190. Zhang, H. 2008. Concerns of using sialidase fusion protein as an experimental drug to combat seasonal and pandemic influenza. J. Antimicrob. Chemother. 62:219223.
191. Zhirnov, O. P.,, M. R. Ikizler, and, P. F. Wright. 2002. Cleavage of influenza A virus hemagglutinin in human respiratory epithelium is cell associated and sensitive to exogenous antiproteases. J. Virol. 76:86828689.
192. Zhirnov, O. P.,, A. V. Ovcharenko, and, A. G. Bukrinskaya. 1984. Suppression of influenza virus replication in infected mice by protease inhibitors. J. Gen. Virol. 65:191196.
193. Zhou, H.,, M. Jin,, Z. Yu,, X. Xu,, Y. Peng,, H. Wu,, J. Liu,, H. Liu,, S. Cao, and, H. Chen. 2007. Effective small interfering RNAs targeting matrix and nucleocapsid protein gene inhibit influenza A virus replication in cells and mice. Antivir. Res. 76:186193.
194. Ziegler, T.,, M. L. Hemphill,, M. L. Ziegler,, G. Perez-Oronoz,, A. I. Klimov,, A. W. Hampson,, H. L. Regnery, and, N. J. Cox. 1999. Low incidence of rimantadine resistance in field isolates of influenza A viruses. J. Infect. Dis. 180:935939.
195. Zoidis, G.,, C. Fytas,, I. Papanastasiou,, G. B. Foscolos,, G. Fytas,, E. Padalko,, E. De Clercq,, L. Naesens,, J. Neyts, and, N. Kolocouris. 2006. Heterocyclic rimantadine analogues with antiviral activity. Bioorg. Med. Chem. 14:33413348.
196. Zuker, M. 2003. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31:34063415.
197. Zurcher, T.,, P. J. Yates,, J. Daly,, A. Sahasrabudhe,, M. Walters,, L. Dash,, M. Tisdale, and, J. L. McKimm-Breschkin. 2006. Mutations conferring zanamivir resistance in human influenza virus N2 neuraminidases compromise virus fitness and are not stably maintained in vitro. J. Antimicrob. Chemother. 58:723732.


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Table 1.

Functions of NS1, with various subsets shown by individual influenza A and B viruses

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11
Generic image for table
Table 2.

Mutations inducing resistance to NA inhibitors

Citation: Air G, Brouillette W. 2009. Influenza Virus Antiviral Targets, p 187-207. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch11

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