Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit

Antimicrobial Agents and Chemotherapy

Volumn 59, Issue 3, 2015, Pages 1569-1582

  Byrn, Randal A ^a   Jones, Steven M ^a   Bennett, Hamilton B ^a   Bral, Chris ^a   Clark, Michael P ^a   Jacobs, Marc D ^a   Kwong, Ann D ^b   Ledeboer, Mark W ^a   Leeman, Joshua R ^a   McNeil, Colleen F ^a   Murcko, Mark A ^c   Nezami, Azin ^a   Perola, Emanuele ^a   Rijnbrand, Rene ^a   Saxena, Kumkum ^a   Tsai, Alice W ^a   Zhou, Yi ^a   Charifson, Paul S ^a  

^a VERTEX PHARMACEUTICALS   (United States)

^b InnovaTID   (United States)

^c Disruptive Biomedical   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; FAVIPIRAVIR; SIALIDASE; SIALIDASE INHIBITOR; UNCLASSIFIED DRUG; VIRUS RNA; VX 787; DNA DIRECTED RNA POLYMERASE; VIRUS PROTEIN;

ANTIVIRAL ACTIVITY; ARTICLE; CELL CULTURE; CELL VIABILITY; CONTROLLED STUDY; CRYSTAL STRUCTURE; CYTOTOXICITY ASSAY; EC50; IN VITRO SELECTION; IN VITRO STUDY; INFLUENZA; INFLUENZA VIRUS; INFLUENZA VIRUS A; ISOTHERMAL TITRATION CALORIMETRY; MDCK CELL LINE; MOUSE; NONHUMAN; PRIORITY JOURNAL; SURFACE PLASMON RESONANCE; VIRAL GENETICS; VIRUS LOAD; VIRUS REPLICATION; X RAY CRYSTALLOGRAPHY; ANIMAL; ANTAGONISTS AND INHIBITORS; BAGG ALBINO MOUSE; BIOAVAILABILITY; CELL LINE; DOG; DRUG EFFECTS; HEK293 CELL LINE; HUMAN; INFLUENZA A VIRUS; INFLUENZA, HUMAN; MALE; ORAL DRUG ADMINISTRATION; ORTHOMYXOVIRIDAE INFECTIONS; VIROLOGY;

ADMINISTRATION, ORAL; ANIMALS; ANTIVIRAL AGENTS; BIOLOGICAL AVAILABILITY; CELL LINE; DNA-DIRECTED RNA POLYMERASES; DOGS; HEK293 CELLS; HUMANS; INFLUENZA A VIRUS; INFLUENZA, HUMAN; MADIN DARBY CANINE KIDNEY CELLS; MALE; MICE; MICE, INBRED BALB C; ORTHOMYXOVIRIDAE INFECTIONS; VIRAL PROTEINS;

EID: 84923234062     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.04623-14     Document Type: Article

References (73)

1. Morens DM, Taubenberger JK, Folkers GK, Fauci AS. 2010. Pandemic influenza's 500th anniversary. Clin Infect Dis 51:1442-1444. http://dx.doi.org/10.1086/657429.
2. Centers for Disease Control and Prevention. 2010. Estimates of deaths associated with seasonal influenza-United States, 1976-2007. MMWR Morb Mortal Wkly Rep 59:1057-1062.
3. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. 2003. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289:179-186. http://dx.doi.org/10.1001/jama.289.2.179.
4. Fiore AE, Bridges CB, Cox NJ. 2009. Seasonal influenza vaccines. Curr Top Microbiol Immunol 333:43-82. http://dx.doi.org/10.1007/978-3-540-92165-3-3.
5. Lambert LC, Fauci AS. 2010. Influenza vaccines for the future. N Engl J Med 363:2036-2044. http://dx.doi.org/10.1056/NEJMra1002842.
6. Flannery B, Thaker SN, Clippard J, Monto AS, Ohmit SE, Zimmerman RK, Nowalk MP, Gaglani M, Jackson ML, Jackson LA, Belongia EA, McLean HQ, Berman L, Foust A, Sessions W, Spencer S, Fry AM, Centers for Disease Control and Prevention. 2014. Interim estimates of 2013-14 seasonal influenza vaccine effectiveness-United States, February 2014. MMWR Morb Mortal Wkly Rep 63:137-142.
7. Janjua NZ, Skowronski DM, De Serres G, Dickinson J, Crowcroft NS, Taylor M, Winter AL, Hottes TS, Fonseca K, Charest H, Drews SJ, Sabaiduc S, Bastien N, Li Y, Gardy JL, Petric M. 2012. Estimates of influenza vaccine effectiveness for 2007-2008 from Canada's sentinel surveillance system: cross-protection against major and minor variants. J Infect Dis 205:1858-1868. http://dx.doi.org/10.1093/infdis/jis283.
8. World Health Organization. 2009, posting date. Pandemic influenza vaccine manufacturing and process timeline: pandemic (H1N1) briefing note 7. WHO, Geneva, Switzerland. http://www.who.int/csr/disease/swineflu/notes/h1n1-vaccine-20090806/en/.
9. Carrat F, Flahault A. 2007. Influenza vaccine: the challenge of antigenic drift. Vaccine 25:6852-6862. http://dx.doi.org/10.1016/j.vaccine.2007.07.027.
10. Partridge J, Kieny MP. 2013. Global production capacity of seasonal influenza vaccine in 2011. Vaccine 31:728-731. http://dx.doi.org/10.1016/j.vaccine.2012.10.111.
11. Li Q, Zhou L, Zhou M, Chen Z, Li F, Wu H, Xiang N, Chen E, Tang F, Wang D, Meng L, Hong Z, Tu W, Cao Y, Li L, Ding F, Liu B, Wang M, Xie R, Gao R, Li X, Bai T, Zou S, He J, Hu J, Xu Y, Chai C, Wang S, Gao Y, Jin L, Zhang Y, Luo H, Yu H, Gao L, Pang X, Liu G, Shu Y, Yang W, Uyeki TM, Wang Y, Wu F, Feng Z. 2014. Epidemiology of the avian influenza A (H7N9) outbreak in China. N Engl J Med 370:520-532. http://dx.doi.org/10.1056/NEJMoa1304617.
12. Fouchier RA, Schneeberger PM, Rozendaal FW, Broekman JM, Kemink SA, Munster V, Kuiken T, Rimmelzwaan GF, Schutten M, Van Doornum GJ, Koch G, Bosman A, Koopmans M, Osterhaus AD. 2004. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci U S A 101:1356-1361. http://dx.doi.org/10.1073/pnas.0308352100.
13. Koopmans M, Wilbrink B, Conyn M, Natrop G, van der Nat H, Vennema H, Meijer A, van Steenbergen J, Fouchier R, Osterhaus A, Bosman A. 2004. Transmission of H7N7avian influenza Avirus tohumanbeings during a large outbreak in commercial poultry farms in the Netherlands. Lancet 363:587-593. http://dx.doi.org/10.1016/S0140-6736(04)15589-X.
14. Chen H, Yuan H, Gao R, Zhang J, Wang D, Xiong Y, Fan G, Yang F, Li X, Zhou J, Zou S, Yang L, Chen T, Dong L, Bo H, Zhao X, Zhang Y, Lan Y, Bai T, Dong J, Li Q, Wang S, Zhang Y, Li H, Gong T, Shi Y, Ni X, Li J, Zhou J, Fan J, Wu J, Zhou X, Hu M, Wan J, Yang W, Li D, Wu G, Feng Z, Gao GF, Wang Y, Jin Q, Liu M, Shu Y. 2014. Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: a descriptive study. Lancet 383:714-721. http://dx.doi.org/10.1016/S0140-6736(14)60111-2.
15. Abdelwhab EM, Veits J, Mettenleiter TC. 2014. Prevalence and control of H7 avian influenza viruses in birds and humans. Epidemiol Infect 142: 896-920. http://dx.doi.org/10.1017/S0950268813003324.
16. Longini IM, Jr, Nizam A, Xu S, Ungchusak K, Hanshaoworakul W, Cummings DA, Halloran ME. 2005. Containing pandemic influenza at the source. Science 309:1083-1087. http://dx.doi.org/10.1126/science.1115717.
17. Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM, Louie J, Doyle TJ, Crockett M, Lynfield R, Moore Z, Wiedeman C, Anand M, Tabony L, Nielsen CF, Waller K, Page S, Thompson JM, Avery C, Springs CB, Jones T, Williams JL, Newsome K, Finelli L, Jamieson DJ; Pandemic H1N1 Influenza in Pregnancy Working Group. 2010. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 303:1517-1525. http://dx.doi.org/10.1001/jama.2010.479.
18. Louie JK, Yang S, Acosta M, Yen C, Samuel MC, Schechter R, Guevara H, Uyeki TM. 2012. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis 55:1198-1204. http://dx.doi.org/10.1093/cid/cis636.
19. Muthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Al Khuwaitir TS, Al Mamun A, Anovadiya AP, Azziz-Baumgartner E, Baez C, Bassetti M, Beovic B, Bertisch B, Bonmarin I, Booy R, Borja-Aburto VH, Burgmann H, Cao B, Carratala J, Denholm JT, Dominguez SR, Duarte PA, Dubnov-Raz G, Echavarria M, Fanella S, Gao Z, Gerardin P, Giannella M, Gubbels S, Herberg J, Iglesias AL, Hoger PH, Hu X, Islam QT, Jimenez MF, Kandeel A, Keijzers G, Khalili H, Knight M, Kudo K, Kusznierz G, Kuzman I, Kwan AM, Amine IL, Langenegger E, Lankarani KB, Leo YS, Linko R, Liu P, Madanat F, et al. 2014. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet ii:395-404.
20. Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya I, Mahtani KR, Nunan D, Howick J, Heneghan CJ. 2014. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 4:CD008965. http://dx.doi.org/10.1002/14651858.CD008965.pub4.
21. Michiels B, Van Puyenbroeck K, Verhoeven V, Vermeire E, Coenen S. 2013. The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews. PLoS One 8:e60348. http://dx.doi.org/10.1371/journal.pone.0060348.
22. Weinstock DM, Zuccotti G. 2009. The evolution of influenza resistance and treatment. JAMA 301:1066-1069. http://dx.doi.org/10.1001/jama.2009.324.
23. Hurt AC. 2014. The epidemiology and spread of drug resistant human influenza viruses. Curr Opin Virol 8:22-29. http://dx.doi.org/10.1016/j.coviro.2014.04.009.
24. Thorlund K, Awad T, Boivin G, Thabane L. 2011. Systematic review of influenza resistance to the neuraminidase inhibitors. BMC Infect Dis 11: 134. http://dx.doi.org/10.1186/1471-2334-11-134.
25. Chao DL, Bloom JD, Kochin BF, Antia R, Longini IM, Jr. 2012. The global spread of drug-resistant influenza. J R Soc Interface 9:648-656. http://dx.doi.org/10.1098/rsif.2011.0427.
26. WHO. 2002. WHO manual on animal influenza diagnosis and surveillance. WHO, Geneva, Switzerland.
27. Wathen MW, Barro M, Bright RA. 2013. Antivirals in seasonal and pandemic influenza-future perspectives. Influenza Other Resp Vir 7(Suppl 1):S76-S80. http://dx.doi.org/10.1111/irv.12049.
28. Clark MP, Ledeboer MW, Davies I, Byrn RA, Jones SM, Perola E, Tsai A, Jacobs M, Nti-Addae K, Bandarage UK, Boyd MJ, Bethiel RS, Court JJ, Deng H, Duffy JP, Dorsch WA, Farmer LJ, Gao H, Gu W, Jackson K, Jacobs DH, Kennedy JM, Ledford B, Liang J, Maltais F, Murcko M, Wang T, Wannamaker MW, Bennett HB, Leeman JR, McNeil C, Taylor WT, Memmott C, Jiang M, Rijnbrand R, Bral C, Germann U, Nezami A, Zhang Y, Salituro FG, Bennani YL, Charifson PS. 2014. The discovery of a novel, first-in-Class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2. J Med Chem 57:6668-6678. http://dx.doi.org/10.1021/jm5007275.
29. Guilligay D, Tarendeau F, Resa-Infante P, Coloma R, Crepin T, Sehr P, Lewis J, Ruigrok RW, Ortin J, Hart DJ, Cusack S. 2008. The structural basis for cap binding by influenza virus polymerase subunit PB2. Nat Struct Mol Biol 15:500-506. http://dx.doi.org/10.1038/nsmb.1421.
30. Fechter P, Mingay L, Sharps J, Chambers A, Fodor E, Brownlee GG. 2003. Two aromatic residues in the PB2 subunit of influenza A RNA polymerase are crucial for cap binding. J Biol Chem 278:20381-20388. http://dx.doi.org/10.1074/jbc.M300130200.
31. Palese PS, Shaw ML. 2007. Orthomyxoviridae: the viruses and their replication, p 1647-1689. In Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE (ed), Fields virology, 5th ed. Lippincott Williams & Wilkins, Philadelphia, PA.
32. Egawa H, Furuta Y, Sugita J, Uehara S, Hamamoto S, Yonezawa T. October 2004. Pyrazine derivatives or salts thereof, pharmaceutical composition containing the same, and production intermediates thereof. US patent 6,800,629.
33. Sidwell RW, Smee DF. 2000. In vitro and in vivo assay systems for study of influenza virus inhibitors. Antiviral Res 48:1-16. http://dx.doi.org/10.1016/S0166-3542(00)00125-X.
34. Noah JW, Severson W, Noah DL, Rasmussen L, White EL, Jonsson CB. 2007. A cell-based luminescence assay is effective for high-throughput screening of potential influenza antivirals. Antiviral Res 73:50-59. http://dx.doi.org/10.1016/j.antiviral.2006.07.006.
35. Division of AIDS, National Institute of Allergy and Infectious Diseases. 1997. DAIDS virology manual for HIV laboratories, p 87, publication NIH-97-3828. U.S. Department of Health and Human Services, Washington, DC.
36. Wagaman PC, Leong MA, Simmen KA. 2002. Development of a novel influenza A antiviral assay. J Virol Methods 105:105-114. http://dx.doi.org/10.1016/S0166-0934(02)00088-5.
37. Neumann G, Watanabe T, Ito H, Watanabe S, Goto H, Gao P, Hughes M, Perez DR, Donis R, Hoffmann E, Hobom G, Kawaoka Y. 1999. Generation of influenza A viruses entirely from cloned cDNAs. Proc Natl Acad Sci U S A 96:9345-9350. http://dx.doi.org/10.1073/pnas.96.16.9345.
38. Lutz A, Dyall J, Olivo PD, Pekosz A. 2005. Virus-inducible reporter genes as a tool for detecting and quantifying influenza A virus replication. J Virol Methods 126:13-20. http://dx.doi.org/10.1016/j.jviromet.2005.01.016.
39. Okomo-Adhiambo M, Sleeman K, Ballenger K, Nguen HT, VP M. 2010. Neuraminidase inhibitor susceptibility testing in human influenza viruses: a laboratory surveillance perspective. Viruses 2:2269-2289. http://dx.doi.org/10.3390/v2102269.
40. Goldoni M, Johansson C. 2007. A mathematical approach to study combined effects of toxicants in vitro: evaluation of the Bliss independence criterion and the Loewe additivity model. Toxicol In Vitro 21:759-769. http://dx.doi.org/10.1016/j.tiv.2007.03.003.
41. Prichard MN, Shipman C, Jr. 1990. A three-dimensional model to analyze drug-drug interactions. Antiviral Res 14:181-205.
42. Chou TC, Talalay P. 1984. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27-55. http://dx.doi.org/10.1016/0065-2571(84)90007-4.
43. Ilyushina NA, Khalenkov AM, Seiler JP, Forrest HL, Bovin NV, Marjuki H, Barman S, Webster RG, Webby RJ. 2010. Adaptation of pandemic H1N1 influenza viruses in mice. J Virol 84:8607-8616. http://dx.doi.org/10.1128/JVI.00159-10.
44. De Clercq E. 2006. Antiviral agents active against influenza A viruses. Nat Rev Drug Discov 5:1015-1025. http://dx.doi.org/10.1038/nrd2175.
45. Gong J, Fang H, Li M, Liu Y, Yang K, Liu Y, Xu W. 2009. Potential targets and their relevant inhibitors in anti-influenza fields. Curr Med Chem 16:3716-3739. http://dx.doi.org/10.2174/092986709789104984.
46. Gorman OT, Donis RO, Kawaoka Y, Webster RG. 1990. Evolution of influenza A virus PB2 genes: implications for evolution of the ribonucleoprotein complex and origin of human influenza A virus. J Virol 64:4893-4902.
47. Hooker L, Sully R, Handa B, Ono N, Koyano H, Klumpp K. 2003. Quantitative analysis of influenza virus RNP interaction with RNA cap structures and comparison to human cap binding protein eIF4E. Biochemistry 42:6234-6240. http://dx.doi.org/10.1021/bi027081r.
48. Pautus S, Sehr P, Lewis J, Fortune A, Wolkerstorfer A, Szolar O, Guilligay D, Lunardi T, Decout JL, Cusack S. 2013. New 7-methylguanine derivatives targeting the influenza polymerase PB2 cap-binding domain. J Med Chem 56:8915-8930. http://dx.doi.org/10.1021/jm401369y.
49. Severson WE, McDowell M, Ananthan S, Chung DH, Rasmussen L, Sosa MI, White EL, Noah J, Jonsson CB. 2008. High-throughput screening of a 100,000-compound library for inhibitors of influenza A virus (H3N2). J Biomol Screen 13:879-887. http://dx.doi.org/10.1177/108705 7108323123.
50. Maddry JA, Chen X, Jonsson CB, Ananthan S, Hobrath J, Smee DF, Noah JW, Noah D, Xu X, Jia F, Maddox C, Sosa MI, White EL, Severson WE. 2011. Discovery of novel benzoquinazolinones and thiazoloimidazoles, inhibitors of influenza H5N1 and H1N1 viruses, from a cell-based high-throughput screen. J Biomol Screen 16:73-81. http://dx.doi.org/10.1177/1087057110384613.
51. Gerritz SW, Cianci C, Kim S, Pearce BC, Deminie C, Discotto L, McAuliffe B, Minassian BF, Shi S, Zhu S, Zhai W, Pendri A, Li G, Poss MA, Edavettal S, McDonnell PA, Lewis HA, Maskos K, Mortl M, Kiefersauer R, Steinbacher S, Baldwin ET, Metzler W, Bryson J, Healy MD, Philip T, Zoeckler M, Schartman R, Sinz M, Leyva-Grado VH, Hoffmann HH, Langley DR, Meanwell NA, Krystal M. 2011. Inhibition of influenza virus replication via small molecules that induce the formation of higher-order nucleoprotein oligomers. Proc Natl Acad Sci U S A 108:15366-15371. http://dx.doi.org/10.1073/pnas.1107906108.
52. Atkins C, Evans CW, White EL, Noah JW. 2012. Screening methods for influenza antiviral drug discovery. Expert Opin Drug Discov 7:429-438. http://dx.doi.org/10.1517/17460441.2012.674510.
53. Shih SR, Chu TY, Reddy GR, Tseng SN, Chen HL, Tang WF, Wu MS, Yeh JY, Chao YS, Hsu JT, Hsieh HP, Horng JT. 2010. Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity. J Biomed Sci 17:13. http://dx.doi.org/10.1186/1423-0127-17-13.
54. Min JY, Subbarao K. 2010. Cellular targets for influenza drugs. Nat Biotechnol 28:239-240. http://dx.doi.org/10.1038/nbt0310-239.
55. Lee SM, Yen HL. 2012. Targeting the host or the virus: current and novel concepts for antiviral approaches against influenza virus infection. Antiviral Res 96:391-404. http://dx.doi.org/10.1016/j.antiviral.2012.09.013.
56. Shaw ML. 2011. The host interactome of influenza virus presents new potential targets for antiviral drugs. Rev Med Virol 21:358-369. http://dx.doi.org/10.1002/rmv.703.
57. Heiny AT, Miotto O, Srinivasan KN, Khan AM, Zhang GL, Brusic V, Tan TW, August JT. 2007. Evolutionarily conserved protein sequences of influenza A viruses, avian and human, as vaccine targets. PLoS One 2:e1190. http://dx.doi.org/10.1371/journal.pone.0001190.
58. Yamada S, Hatta M, Staker BL, Watanabe S, Imai M, Shinya K, Sakai-Tagawa Y, Ito M, Ozawa M, Watanabe T, Sakabe S, Li C, Kim JH, Myler PJ, Phan I, Raymond A, Smith E, Stacy R, Nidom CA, Lank SM, Wiseman RW, Bimber BN, O'Connor DH, Neumann G, Stewart LJ, Kawaoka Y. 2010. Biological and structural characterization of a hostadapting amino acid in influenza virus. PLoS Pathog 6:e1001034. http://dx.doi.org/10.1371/journal.ppat.1001034.
59. Vreede FT, Chan AY, Sharps J, Fodor E. 2010. Mechanisms and functional implications of the degradation of host RNA polymerase II in influenza virus infected cells. Virology 396:125-134. http://dx.doi.org/10.1016/j.virol.2009.10.003.
60. Vreede FT, Fodor E. 2010. The role of the influenza virus RNA polymerase in host shut-off. Virulence 1:436-439. http://dx.doi.org/10.4161/viru.1.5.12967.
61. Hayden FG. 2013. Newer influenza antivirals, biotherapeutics and combinations. Influenza Other Respir Viruses 7(Suppl 1):63-75. http://dx.doi.org/10.1111/irv.12045.
62. Takahashi K, Furuta Y, Fukuda Y, Kuno M, Kamiyama T, Kozaki K, Nomura N, Egawa H, Minami S, Shiraki K. 2003. In vitro and in vivo activities of T-705 and oseltamivir against influenza virus. Antivir Chem Chemother 14:235-241.
63. Govorkova EA, Leneva IA, Goloubeva OG, Bush K, Webster RG. 2001. Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Antimicrob Agents Chemother 45:2723-2732. http://dx.doi.org/10.1128/AAC.45.10.2723-2732.2001.
64. Mendel DB, Tai CY, Escarpe PA, Li W, Sidwell RW, Huffman JH, Sweet C, Jakeman KJ, Merson J, Lacy SA, Lew W, Williams MA, Zhang L, Chen MS, Bischofberger N, Kim CU. 1998. Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets against influenza infection. Antimicrob Agents Chemother 42:640-646.
65. Sidwell RW, Huffman JH, Barnard DL, Bailey KW, Wong MH, Morrison A, Syndergaard T, Kim CU. 1998. Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor. Antiviral Res 37:107-120. http://dx.doi.org/10.1016/S0166-3542(97)00065-X.
66. Sidwell RW, Bailey KW, Bemis PA, Wong MH, Eisenberg EJ, Huffman JH. 1999. Influence of treatment schedule and viral challenge dose on the in vivo influenza virus-inhibitory effects of the orally administered neuraminidase inhibitor GS 4104. Antivir Chem Chemother 10:187-193.
67. Leneva IA, Roberts N, Govorkova EA, Goloubeva OG, Webster RG. 2000. The neuraminidase inhibitor GS4104 (oseltamivir phosphate) is efficacious against A/Hong Kong/156/97 (H5N1) and A/Hong Kong/1074/99 (H9N2) influenza viruses. Antiviral Res 48:101-115. http://dx.doi.org/10.1016/S0166-3542(00)00123-6.
68. Sidwell RW, Smee DF, Huffman JH, Barnard DL, Bailey KW, Morrey JD, Babu YS. 2001. In vivo influenza virus-inhibitory effects of the cyclopentane neuraminidase inhibitor RJW-270201. Antimicrob Agents Chemother 45:749-757. http://dx.doi.org/10.1128/AAC.45.3.749-757.2001.
69. Sidwell RW, Smee DF, Huffman JH, Barnard DL, Morrey JD, Bailey KW, Feng WC, Babu YS, Bush K. 2001. Influence of virus strain, challenge dose, and time of therapy initiation on the in vivo influenza inhibitory effects of RWJ-270201. Antiviral Res 51:179-187. http://dx.doi.org/10.1016/S0166-3542(01)00149-8.
70. Yen HL, Monto AS, Webster RG, Govorkova EA. 2005. Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 influenza virus in mice. J Infect Dis 192:665-672. http://dx.doi.org/10.1086/432008.
71. Smee DF, Wong MH, Bailey KW, Sidwell RW. 2006. Activities of oseltamivir and ribavirin used alone and in combination against infections in mice with recent isolates of influenza A (H1N1) and B viruses. Antivir Chem Chemother 17:185-192.
72. Yun NE, Linde NS, Zacks MA, Barr IG, Hurt AC, Smith JN, Dziuba N, Holbrook MR, Zhang L, Kilpatrick JM, Arnold CS, Paessler S. 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 374:198-209. http://dx.doi.org/10.1016/j.virol.2007.12.029.
73. Sidwell RW, Barnard DL, Day CW, Smee DF, Bailey KW, Wong MH, Morrey JD, Furuta Y. 2007. Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice. Antimicrob Agents Chemother 51:845-851. http://dx.doi.org/10.1128/AAC.01051-06.