Hepatitis C virus therapies: Current treatments, targets and future perspectives

Antiviral Chemistry and Chemotherapy

Volumn 14, Issue 1, 2003, Pages 1-21

  Walker, Michelle P ^a   Appleby, Todd C ^a   Zhong, Weidong ^a   Lau, Johnson Y N ^a   Hong, Zhi ^a  

^a Ribapharm Inc   (United States)

Author keywords

HCV replicon; Helicase; Inhibitor; Interferon; Protease; RdRp; Ribavirin

Indexed keywords

1,1' [1,4 PHENYLENEBIS(METHYLENE)]BIS(1,4,8,11 TETRAAZACYCLOTETRADECANE); ALPHA INTERFERON; AMANTADINE; ANTIVIRUS AGENT; CILUPREVIR; CONSENSUS INTERFERON; GAMMA INTERFERON; GW 0569; GW 2549; GW 3112; HELICASE; HISTAMINE; IDDB3; INOSINATE DEHYDROGENASE INHIBITOR; ISIS 14803; LEVOVIRIN; MERIMEPODIB; N [4 [[[6,7 DIHYDRO 2 (4 METHYLPHENYL) 5H BENZOCYCLOHEPTEN 8 YL]CARBONYL]AMINO]BENZYL] N,N DIMETHYL 2H TETRAHYDROPYRAN 4 AMINIUM CHLORIDE; NUCLEOSIDE DERIVATIVE; PEGINTERFERON ALPHA2A; PEGINTERFERON ALPHA2B; PEPTIDE ALPHA KETO ACID; PEPTIDE DERIVATIVE; PROTEINASE INHIBITOR; PYRROLIDINE 5,5 LACTAM; PYRROLIDINE DERIVATIVE; RECOMBINANT ALPHA2A INTERFERON; RECOMBINANT ALPHA2B INTERFERON; RECOMBINANT INTERLEUKIN 12; RIBAMIDINE; RIBAVIRIN; RIBOZYME; RNA POLYMERASE; SERINE PROTEINASE; THYMOSIN ALPHA1; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; CHIMPANZEE; CHRONIC LIVER DISEASE; CLINICAL TRIAL; CRYSTAL STRUCTURE; DRUG EFFICACY; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERANCE; HEMOLYTIC ANEMIA; HEPATITIS C; HEPATITIS GB VIRUS B; HUMAN; IC 50; IMMUNOMODULATION; INTERNAL RIBOSOME ENTRY SITE; MONOTHERAPY; NONHUMAN; PRIORITY JOURNAL; REPLICON; REVIEW; RNA TRANSLATION; SIDE EFFECT; STRUCTURE ACTIVITY RELATION; TRANSGENIC MOUSE; TREATMENT FAILURE; TREATMENT INDICATION; TREATMENT OUTCOME; UNTRANSLATED REGION; VIRUS ASSEMBLY; VIRUS LOAD; VIRUS REPLICATION;

EID: 0038707388     PISSN: 09563202     EISSN: None     Source Type: Journal    
DOI: 10.1177/095632020301400101     Document Type: Review

References (208)

1. Agnello V, Abel G, Elfahal M, Knight GB & Zhang Q-X (1999) Hepatitis C virus and other Flaviviridae viruses enter cells via low density lipoprotein receptor. Proceedings of the National Academy of Sciences, USA 96:12766-12771.
2. Ago H, Adachi T, Yoshida A, Yamamoto M, Habuka N, Yatsunamik & Miyano M (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Structure with Folding Design 7(11):1417-1426.
3. Alaoui-Ismaili MH, Gervais C, Brunette S, Gouin G, Hamel M, Rando RF & Bedard J (2000) A novel high throughput screening assay for HCV NS3 helicase activity. Antiviral Research 46(3):181-193.
4. Archer SJ, Camac DM, Wuz J, Farrow NA, Domaille PJ, Wasserman ZR, Bukhtiyarova M, Rizzo C, Jagannathan S, Mersinger LJ & Kettner CA (2002) Hepatitis C virus NS3 protease requires its NS4A cofactor peptide for optimal binding of a boronic acid inhibitor as shown by NMR. Chemistry & Biology 9(1):79-92.
5. Baker DE (2001) Pegylated interferons. Reviews in Gastroenterological Disorders 1(2):87-99.
6. Bartenschlager R, Ahlborn-Laake L, Mous J & Jacobsen H (1993) Nonstructural protein 3 of the hepatitis C virus encodes a serine-type proteinase required for cleavage at the NS3/4 and NS4/5 junctions. Journal of Virology 67:3835-3844.
7. Beames B, Chavez D, Guerra B, Notvall L, Brasky KM & Lanford RE (2000) Development of a primary tamarin hepatocyte culture system for GB virus-B: a surrogate model for hepatitis C virus. Journal of Virology 74:11764-11772.
8. Behrens S-E, Tomei L & De Francesco R (1996) Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. EMBO Journal 15(1):12-22.
9. Benhamou Y, Hinrichsen H, Sentijens R, Reiser M, Manns MP, Forns X, Avendano C, Cronlein J, Nehmiz G & Steinmann G (2002) Safety, tolerability and antiviral effect of BILN 2061, a novel HCV serine protease inhibitor, after oral treatment over 2 days in patients with chronic hepatitis C, genotype 1, with advanced liver fibrosis. Hepatology 36(4):304A.
10. Bhat B, Bosserman M, Carroll SS, Eldrup AB, Getty K, Lafemina R, Migliaccio G, Olsen DB, Shim S, Stahlhut MW & Tomassini JE (2002) Nucleoside analogues inhibit HCV replication in cells. Antiviral Therapy 7:L103.
11. Bianchi E, Urbani A, Biasiol G, Brunetti M, Pessi A, De Francesco R & Steinkuhler C (1997) Complex formation between the hepatitis C virus serine protease and a synthetic NS4A cofactor peptide. Biochemistry 36(25):7890-7897.
12. Billich A (2002) Thymosin α-1, SciClone Pharmaceuticals. Current Opinion in Investigational Drugs 3(5):698-707.
13. Bitko V & Barik S (2001) Phenotypic silencing of cytoplasmic genes using sequence-specific double-stranded short interfering RNA and its application in the reverse genetics of wild type negativestrand RNA viruses. BMC Microbiology 1(1):34.
14. Bjorko K, Bell H, Myrvang B, Skaug K, Raknerud N, Sandvei P, Storseth S, Ritland S, Lund-Tonnesen S, Bucher A & Hellum KB (2002) Effect of interferon-α induction therapy on genotype 2b/3a and low viral load hepatitis C virus infection. A randomized multicentre study. Scandinavian Journal of Gastroenterology 37(3):344-349.
15. Blanchard E, Brand D, Trassard S, Goudeau A & Roingeard P (2002) Hepatitis C virus-like particle morphogenesis. Journal of Virology 76(8):4073-4079.
16. Blight KJ, Kolykhalov AA & Rice CM (2000) Efficient initiation of HCV RNA replication in cell culture. Science 290(5498):1972-1974.
17. Bodenheimer HCJ, Lindsay KL, Davis GL, Lewis JH, Thung SN & Seeff LB (1997) Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 26(2):473-477.
18. Borowski P, Schalinski S & Schmitz H (2002) Nucleotide triphosphatase/helicase of hepatitis C virus as a target for antiviral therapy. Antiviral Research 55(3):397.
19. Brass V, Bieck E, Montserret R, Wolk B, Hellings JA, Blum HE, Penin F & Moradpour D (2002) An amino-terminal amphipathic α-helix mediates membrane association of the hepatitis C virus nonstructural protein 5A. Journal of Biological Chemistry 277(10):8130-8139.
20. Bressanelli S, Tomei L, Roussel A, Incitti I, Vitale RL, Mathieu M, De Francesco R & Rey FA (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Proceedings of the National Academy of Sciences, USA 96(23):13034-13039.
21. Bukh J, Apgar CL & Yanagi M (1999) Toward a surrogate model for hepatitis C virus: an infectious molecular clone of the GB virus-B hepatitis agent. Virology 262(2):470-478.
22. Bukh J, Miller RH & Purcell RH (1995) Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Seminars in Liver Diseases 15(1):41-63.
23. Butcher SJ, Grimes JM, Makeyev EV, Bamford DH & Stuart DI (2001) A mechanism for initiating RNA-dependent RNA polymerization. Nature 410(6825):235-240.
24. Buti M & Esteban R (2000) What to do when standard therapy fails. Forum (Genova) 10(1):63-69.
25. Butkiewicz N, Yao N, Zhong W, Wright-Minogue J, Ingravallo P, Zhang R, Durkin J, Standring DN, Baroudy BM, Sangar DV, Lemon SM, Lau JY & Hong Z (2000) Virus-specific cofactor requirement and chimeric hepatitis C virus/GB virus B nonstructural protein 3. Journal of Virology 74(9):4291-4301.
26. Carlsson T, Lindahl K, Schvarcz R, Wejstal R, Uhnoo I, Shev S & Reichard O (2000) HCV RNA levels during therapy with amantadine in addition to interferon and ribavirin in chronic hepatitis C patients with previous nonresponse or response/relapse to interferon and ribavirin. Journal of Viral Hepatitis 7(6):409-413.
27. Carmichael GG (2002) Medicine: silencing viruses with RNA. Nature 418(6896):379-380.
28. Carrer-Kremer S, Montpellier-Pala C, Cocquerel L, Wychowski C, Penin F & Dubuisson J (2002) Subcellular localization and topology of the p7 polypeptide of hepatitis C virus. Journal of Virology 76(8):3720-3730.
29. Carroll SS, Bhat B, Bosserman M, Eldrup AB, Getty K, Lafemina R, Hall D, Simcoe AL, Rutkowski CA, Shim S, Stahlhut MW, Migliaccio G, Tomassini JE & Olsen DB (2002) Nucleoside analogues as inhibitors or HCV RNA polymerase. Antiviral Therapy 7:L103.
30. Cassidy LF & Patterson JL (1989) Mechanism of La Crosse virus inhibition by ribavirin. Antimicrobial Agents & Chemotherapy 33:2009-2011.
31. Chan J, O'Riordan K & Wiley TE (2002) Amantadine's viral kinetics in chronic hepatitis C infection. Digestive Disease Science 47(2):438-442.
32. Cheney WI, Lai VC, Zhong W, Brodhag T, Dempsey S, Lim C, Hong Z, Lau JY & Tam RC (2002) Comparative analysis of antihepatitis C virus activity and gene expression mediated by α, β, and γ interferons. Journal of Virology 76:11148-11154.
33. Chu M, Mierzwa R, He L, King A, Patel M, Pichardo J, Hart A, Butkiewicz N & Puar MS (1999) Isolation and structure of Sch 315633: a novel HCV NS3 serine protease inhibitor from the fungus Penicillium griseofulvum. Bioorganic & Medicinal Chemistry Letters 9:1949-1952.
34. Collett MS, Larson R, Gold C, Strick D, Anderson DK & Purchio AF (1988) Molecular cloning and nucleotide sequence of the pestivirus bovine viral diarrhea virus. Virology 165:191-199.
35. Corritori S, Lau JYN & Lin CC (2001) Safety studies of levovirin a second generation ribavirin candidate, showed excellent safety profiles. Hepatology 34(2):219A.
36. Cramp ME, Rossol S, Chokshi S, Carucci P, Williams R & Naoumov NV (2000) Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C. Gastroenterology 118:346-355.
37. Crotty S, Cameron CE & Andino R (2001) RNA virus error catastrophe: direct molecular test by using ribavirin. Proceedings of the National Academy of Sciences, USA 98:6895-6900.
38. Crotty S, Maag D, Arnold JJ, Zhong W, Lau JYN, Hong Z, Andino R & Cameron CE (2000) The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nature Medicine 6:1375-1379.
39. Davis GL, Eesteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, Shiffman ML, Zeuzem S, Craxi A, Ling MH & Albrecht J (1998) Interferon α-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. New England Journal of Medicine 339(21):1493-1499.
40. De Clercq E (2002) Highlights in the development of new antiviral agents. Mini Reviews in Medicinal Chemistry 2(2):163-175.
41. Dhanak D, Duffy K, Johnston V, Lin-Goerke J, Darcy M, Shaw A, Gu B, Silverman C, Gates A, Nonnemacher M, Earnshaw D, Casper D, Kaura A, Baker A, Greenwood C, Gutshall L, Maley D, Del Vecchio AM, Macarron R, Hofmann G, Alnoah Z, Cheng H, Chan G, Khandekar S, Keenan R & Sarisky RT (2002) Identification and biological characterization of heterocyclic inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. Journal of Biological Chemistry 277(41):38322-38327.
42. Diana GD & Bailey TR (1997) Compounds, compositions and methods for treatment of hepatitis C. In: WIPO, pp. 1. Viropharma, Inc., USA.
43. Diana GD, Bailey TR & Nitz TJ (1997) Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment of hepatitis C. In: WIPO, pp. 1-24. Viropharma, Inc., USA.
44. Du MX, Johnson RB, Sun XL, Staschke K, Colacino JM & Wang QM (2002) Comparative characterization of two DEAD-box RNA helicases in superfamily II: human translation-initiation factor 4A and hepatitis C virus non-structural protein 3 (NS3) helicase. Biochemistry Journal 363(1):147-155.
45. Dusheiko G, Main J, Thomas H, Reichard O, Lee C, Dhillon A, Rassam S, Fryden A, Reesink H, Bassendine M, Norkrans G, Cuypers T, Lelie N, Telfer P, Watson J, Weegink C, Sillikens P & Weiland O (1996) Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study. Journal of Hepatology 25(5):591-598.
46. Eriksson B, Helgstrand E, Johansson NG, Larsson A, Misiorny A, Noren JO, Philipson L, Stenberg K, Stening G, Stridh S & Oberg B (1977) Inhibition of influenza virus ribonucleic acid polymerase by ribavirin triphosphate. Antimicrobial Agents & Chemotherapy 11(6):946-951.
47. Failla C, Tomei L & De Francesco R (1994) Both NS3 and NS4A are required for proteolytic processing of hepatitis C virus non-structural proteins. Journal of Virology 68(6):3753-3760.
48. Farci P, Alter HJ, Govindarajan S, Wong DC, Engle R, Lesniewski RR, Mushahwar IK, Desai SM, Miller RH, Ogata N & Purcell RH (1992) Lack of protective immunity against reinfection with hepatitis C virus. Science 258:135-140.
49. Fausto N (2001) A mouse model for hepatitis C virus infection? Nature Medicine 7(8):890-891.
50. Ferrari E, Wright-Minogue J, Fang JW, Baroudy BM, Lau JY & Hong Z (1999) Characterization of soluble hepatitis C virus RNA-dependent RNA polymerase expressed in Escherichia coli. Journal of Virology 73(2):1649-1654.
51. Flint M, Quinn ER & Levy S (2001) In search of hepatitis C virus receptor(s). Clinical Liver Diseases 5(4):873-893.
52. Frese M, Schwarzle V, Barth K, Krieger N, Lohmann V, Mihms S, Haller O & Bartenschlager R (2002) Interferon-γ inhibits replication of subgenomic and genomic hepatitis C virus RNAs. Hepatology 35(3):694-703.
53. Fried MW, Shiffman M, Reddy KR, Smith C, Marinos G, Goncales FLJ, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxia A, Lin A, Hoffman J & Yu J (2002) Peginterferon α-2a plus ribavirin for chronic hepatitis C virus infection. New England Journal of Medicine 347(13):975-982.
54. Gale MJ, Korth MJ, Tang NM, Tan SL, Hopkins DA, Dever TE, Polyak SJ, Gretch DR & Katze MG (1997) Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 230(2):217-227.
55. Gardelli C, Giuliano C, Harper S, Koch U, Narjes F, Ontoria J, Poma M, Ponzi S, Stansfield I & Summa V (2002) Dihydroxypyrimidine carboxylic acids as viral polymerase inhibitors. In: WIPO. Instituto Di Ricerche Di Biologia Molecolare P Angeletti SPA, Worldwide.
56. Germi R, Crance JM, Garin D, Guimet J, Lortat-Jacob H, Ruigrok RW, Zarski JP & Drouet E (2002) Cellular glycosaminoglycans and low density lipoprotein receptor are involved in hepatitis C virus adsorption. Journal of Medical Virology 68(2):206-215.
57. Gonzales HJ, Ho SB, Gross JB, Peine C, McKee D, Smith T & Group MHS (2002) Efficacy of daily induction dosing vs standard thrice weekly dosing of interferon-α 2B for initial treatment of chronic hepatitis C. Digestive Diseases & Sciences 47(4):784-792.
58. Goodbourn S, Didcock L & Randall RE (2000) Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. Journal of General Virology 81(Pt 10):2341-2364.
59. Grakoui A, McCourt DW, Wychowski C, Feinstone SM & Rice CM (1993) Characterization of the hepatitis C virus-encoded serine proteinase: determination of the proteinase-dependent polyprotein cleavage sites. Journal of Virology 67:2832-2843.
60. Grassmann CW, Isken O & Behrens S-E (1999) Assignment of the multifunctional NS3 protein of bovine viral diarrhea virus during RNA replication: an in vitro and in vivo study. Journal of Virology 73(11):9196-9205.
61. Gu B, Liu CT, Lin-Goerke J, Maley DR, Gutshall LL, Feltenberger CA & Del Vecchio AM (2000) The RNA helicase and nucleotide triphosphate activities of the bovine diarrhea virus NS3 protease are essential for viral replication. Journal of Virology 74:1794-1800.
62. Gwack Y, Kim DW, Han JH & Choe J (1996) Characterization of RNA binding activity and RNA helicase activity of the hepatitis C virus NS3 protein. Biochemical & Biophysical Research Communications 225:654-659.
63. He Q, Flaherty J, Cheney CP, Tam RC & Koziel MK (2000) Enhancement of hepatitis c virus-specific type 1 cytokine and T cell proliferative responses by ribavirin and levovirin (ICN17261) in vitro. Hepatology 32:394A.
64. Helbling B, Stamenic I, Viani F, Gonvers JJ, Dufour JF, Reichen J, Cathomas G, Steuerwald M, Borovicka J, Sagmeister M & Renner EL (2002) Interferon and amantadine in naive chronic hepatitis C: a double-blind, randomized, placebo-controlled trial. Hepatology 35(2):447-454.
65. Hijikata M, Mizushima H, Akagi T, Mori S, Kakiuchi N, Kato N, Tanaka T, Kimura K & Shimotohno K (1993a) Two distinct proteinase activities required for the processing of a putative nonstrucrural precursor protein of hepatitis C virus. Journal of Virology 67:4665-4675.
66. Hijikata M, Mizushima H, Tanji Y, Komoda Y, Hirowatari Y, Akagi T, Kato N, Kimura K & Shimotohno K (1993b) Proteolytic processing and membrane association of putative nonstructural proteins of hepatitis C virus. Proceedings of the National Academy of Sciences, USA 90:10773-10777.
67. Hinrichsen H, Benhamou Y, Reiser M, Sentjens R, Wedemeyer H, Calleja JL, Forns X, Cronlein J, Nehmiz G & Steinmann G (2002) First report on the antiviral efficacy of BILN 2061, a novel oral HCV serine protease inhibitor, in patients with chronic hepatitis C genotype 1. Hepatology 36(4):866A.
68. Hiromasa H, Kenji M & Hitoshi Y (2001) Fused ring compound and its pharmaceutical application. In: Japanese Patent Office Japanese Tobacco, Inc., Japan.
69. Honda M, Beard MR, Ping LH & Lemon SM (1999) A phylogenetically conserved stem-loop structure at the 5′ border of the internal ribosome entry site of hepatitis C virus is required for cap-independent viral translation. Journal of Virology 73(2):1165-1174.
70. Hong Z, Beaudet-Miller M, Lanford RE, Guerra B, Wright-Minogue J, Skeleton A, Baroudy BM, Reyes GR & Lau JYN (1999) Generation of transmissible hepatitis C virions from a molecular clone in chimpanzees. Virology 256(1):36-44.
71. Hong Z & Cameron CE (2002) Pleiotropic mechanisms of ribavirin antiviral activities. Progress in Drug Research 59:43-69.
72. Hong Z, Cameron CE, Walker MP, Castro C, Yao N, Lau JY & Zhong W (2001a) A novel mechanism to ensure terminal initiation by hepatitis C virus NS5B polymerase. Virology 285(1):6-11.
73. Hong Z, Ferrari E, Wright-Minogue J, Chase R, Risano C, Seelig G, Lee C-G & Kwong AD (1996) Enzymatic characterization of hepatitis C virus NS3/4A complexes expressed in mammalian cells using the herpes simplex virus amplicon system. Journal of Virology 70(7):4261-4268.
74. Hong Z, Zhong W, Hamatake RK, Tam RC, Lai VCH, Ramasamy K, Cheney W, Zhang Z, Raney A, Horscroft N, Huggins J & Lau JYN (2001b) Antiviral activities of a new generation of ribavirin analogs: levovirin and viramidine. Hepatology 34(2):415A.
75. Hoofnagle JH (2002) Course and outcome of hepatitis C. Hepatology 36(5):S21-S29.
76. Houghton M (1996) Hepatitis C viruses. In: Virology 3rd ed.n; pp. 1035-1058. Edited by BN Fields, DM Knipe & PM Howley. New York: Raven Press.
77. Hsu CC, Hwang LH, Huang YW, Chi WK, Chu YD & Chen DS (1998) An ELISA for RNA helicase activity: application as an assay of the NS3 helicase of hepatitis C virus. Biochemical & Biophysical Research Communications 253(3):594-599.
78. Hugle T, Fehrmann F, Bieck E, Kohara M, Krausslich HG, Rice CM, Blum HE & Moradpour D (2001) The hepatitis C virus nonstructural protein 4B is an integral endoplasmic reticulum membrane protein. Virology 284(1):70-81.
79. IDDB3 (2001) HSV inhibitor, Bayer, Vol. 2001. The Investigational Drugs Database.
80. Ikeda M, Sakai T, Tsuai S, Zuao I, Ryan H, Iyan S, Kai Y, Kako Y, Tsukada I & Yanagisa M (1996) Agent for the prevention and treatment of hepatitis C. Japanese Patent. Eisai Co. Ltd., Japan.
81. Iingallinella P, Altamura S, Bianchi E, Taliani M, Ingenito R, Cortese R, De Francesco R, Steinkuhler C & Pessi A (1998) Potent peptide inhibitors of human hepatitis C virus NS3 protease are obtained by optimizing the cleavage products. Biochemistry 37(25):8906-8914.
82. Iingallinella P, Fattori D, Altamura S, Steinkuhler C, Koch U, Cicero DO, Bazzo R, Cortese R, Bianchi E & Pessi A (2002) Prime site binding inhibitors of a serine protease: NS3/4A of hepatitis C virus. Biochemistry 41:5483-5492.
83. Ishii K, Tanaka Y, Yap CC, Aizaki H, Matsuura Y & Miyamura T (1999) Expression of hepatitis C virus NS5B protein: characterization of its RNA polymerase activity and RNA binding. Hepatology 29(4):1227-1235.
84. Ismaili HMA, Cheng Y, Lavallee J, Siddiqui A & Storer R (2002) Method for the treatment or prevention of flavivirus infections using nucleoside analogues. United States Patent Offices, USA.
85. Janetka JW, Ledford BE & MulEcan MD (2000) Pentacyclic compounds useful as inhibitors of hepatitis C virus NS3 helicase. pp. 1-60. Vertex Pharmaceuticals, Inc.
86. Jean J, Peper DE, Powers JP, Walker NP & Li Y (2001) NS5B HCV polymerase inhibitors. In: WIPO. Tularik, worldwide.
87. Johansson A, Hubatsch I, Akerblom E, Lindberg G, Winiwarter S, Danielson UH & Hallberg A (2001) Inhibition of hepatitis C virus NS3 protease activity by product-based peptides is dependent on helicase domain. Bioorganic & Medicinal Chemistry Letters 11(2):203-206.
88. Jubin R, Murray MG, Howe AY, Butkiewicz N, Hong Z & Lau JY (2000) Amantadine and rimantadine have no direct inhibitory effects against hepatitis C viral protease, helicase, ATPase, polymerase, and internal ribosomal entry site-mediated translation. Journal of Infectious Diseases 181(1):331-334.
89. Kakiuchi N, Komoda Y, Komoda K, Takeshita N, Okada S, Tani T & Shimotohno K (1998) Non-peptide inhibitors of HCV serine protease. FEBS Letters 421:217-220.
90. Kao JH, Chen PJ, Lai MY & Chen DS (2000) Efficacy of consensus interferon in the treatment of chronic hepatitis C. Journal of Gastroenterology & Hepatology 15(12):1418-1423.
91. Kieft JS, Zhou K, Jubin R & Doudna JA (2001) Mechanism of ribosome recruitment by hepatitis C IRES RNA. RNA 7(2):194-206.
92. Kim DW, Gwack Y, Han JH & Choe J (1995) C-terminal domain of the hepatitis C virus NS3 protein contains an RNA helicase activity. Biochemical & Biophysical Research Communication 215:160-166.
93. Kim DW, Gwack Y, Han JH & Choe J (1997a) Towards defining a minimal functional domain for NTPase and RNA helicase activities of the hepatitis C virus NS3 protein. Virus Research 49(1):17-25.
94. Kim DW, Kim J, Gwack Y, Han JH & Choe J (1997b) Mutational analysis of the hepatitis C virus RNA helicase. Journal of Virology 71:9400-9409.
95. Kim JL, Morgenstern KA, Griffith JP, Dwyer MD, Thomson JA, Murcko MA, Lin C & Caron PR (1998) Hepatitis C virus NS3 RNA helicase domain with a bound oligonucleotide: the crystal structure provides insights into the mode of unwinding. Structure 6(1):89-100.
96. Kim JL, Morgenstern KA, Lin C, Fox T, Dwyer MD, Landro JA, Chambers SP, Marklans W, Lepre CA, O'Malley ET, Harbeson SL, Rice CM, Murcko MA, Caron PR & Thomson JA (1996) Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 87(2):343-355.
97. Kita M, Tanaka K, Uoshima N, Kobayashi Y, Ozawa M, Kondo M & Imanishi J (1997) Determination of interferon-α2 allele composition in the genomic DNA from healthy volunteers and leukemic patients in Japan. Journal of Interferon Cytokine Research 17(3):135-140.
98. Kolykhalov AA, Agapov EV, Blight KJ, Mihalik K, Feinstone SM & Rice CM (1997) Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science 277:570-574.
99. Kolykhalov AA, Mihalik K, Feinstone SM & Rice CM (2000) Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo. Journal of Virology 74(4):2046-2051.
100. Lai MM, Mazzoleni AP, Argiolu F, De Virgilis S, Balestrieri A, Purcell RH, Cao A & Farci P (1994) Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children. Lancet 343(8894):388-390.
101. Lamarre D, Bailey M, Bolger G, Cameron DR, Cartier M, Faucher A-M, Goudreau N, Kukolj G, Lagace L, Pause A, Rancourt J, Thibeault D, Tsantrizos Y & Llinas-Brunet M (2002) The discovery of BILN-2061 - an orally available small molecule inhibitor of the HCV serine protease and a promising antiviral for treatment of hepatitis C. Hepatology 36(4):464.
102. Lambot M, Fretier S, Op De Beeck A, Quatannens B, Lestavel S, Clavey V & Dubuisson J (2002) Reconstitution of hepatitis C virus envelope glycoprotein into liposomes as a surrogate model to study virus attachment. Journal of Biological Chemistry 277(23):20625-20630.
103. Lau JYN, Davis GL, Kniffen J, Qian KP, Urdea MS, Chan CS, Mizokami M, Neuwald PD & Wilber JC (1993) Significance of serum hepatitis C virus RNA levels in chronic hepatitis C. Lancet 341(8859):1501-1504.
104. Lauer G & Walker BD (2001) Hepatitis C virus infection. New England Journal of Medicine 345:41-52.
105. Lee JH, Von Wagner M, Roth WK, Teuber G, Sarrazin C & Zeuzem S (1998) Effect of ribavirin on virus load and quasispecies distribution in patients infected with hepatitis C virus. Journal of Hepatology 29(1):29-35.
106. Lesburg CA, Cable MB, Ferrari E, Hong Z, Mannarino AF & Weber PC (1999) Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nature Structural Biology 6(10):937-943.
107. Lin C, Thomson JA & Rice CM (1995) A central region in the hepatitis C virus NS4A protein allows formation of an active NS3-NS4A serine proteinase complex in vivo and in vitro. Journal of Virology 69:4373-4380.
108. Lin CC & Lau JYN (2001) A novel in vitro partition approach to evaluate RBC accumulation of ribavirin and its analogs. Hepatology 34(2):218A.
109. Lin CC, Luu K, Lourenco D, Corritori S, Hong Z & Lau JYN (2001) Viramidine, a prodrug of ribavirin, demonstrated superior liver-targeting properties and a much improved toxicity profile in cynomolgus monkey studies. Hepatology 34(4):453A.
110. Lindsay KL,Trepo C, Heintges T, Shiffman ML, Gordon SC, Hoefs JC, Schiff ER, Goodman ZD, Laughlin M, Yao R, Albrecht JK &The Hepatitis Interventional Therapy Group (2001) A randomized, double-blind trial comparing pegylated interferon α-2b to interferon α-2b as initial treatment for chronic hepatitis C. Hepatology 34(2):395-403.
111. Llinas-Brunet M, Bailey M, Cameron DR, Ghiro E, Goudeau A, Poupart MA, Rancourt J & Tsantrizos Y (2000a) Hepatitis C inhibitor peptides. In: WIPO, pp. 145. Boehringer Ingelheim Ltd, USA.
112. Llinas-Brunet M, Bailey M, Cameron DR, Faucher A-M, Ghiro E, Goudeau N, Halmos T, Poupart M-A, Rancourt J, Tsantrizos YS, Wernic DM & Simoneau B (2000b) Hepatitis C inhibitor tri-peptides. In: WIPO. Boehringer Ingelheim Ltd.
113. Lohmann V, Korner F, Dobierzewska A & Bartenschlager R (2001) Mutations in hepatitis C virus RNAs conferring cell culture adaptation. Journal of Virology 75(3):1437-1449.
114. Lohmann V, Korner F, Herian U & Bartenschlager R (1997) Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity. Journal of Virology 71(11):8416-8428.
115. Lohmann V, Korner F, Koch J, Herian U, Theilmann L & Bartenschlager R (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285(5424):110-113.
116. Lohmann V, Roos A, Korner F, Koch JO & Bartenschlager R (1998) Biochemical and kinetic analyses of NS5B RNA-dependent RNA polymerase of the hepatitis C virus. Virology 249:108-118.
117. Lohmann V, Roos A, Korner F, Koch JO & Bartenschlager R (2000) Biochemical and structural analysis of the NS5B RNA-dependent RNA polymerase of the hepatitis C virus. Journal of Viral Hepatitis 7(3):167-174.
118. Love RA, Parge HE, Wickersham JA, Hostomsky Z, Habuka N, Moomaw EW, Adachi T & Hostomska Z (1996) The crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site. Cell 87(2):331-342.
119. Luxon BA, Grace M, Brassard D & Bordens R (2002) Pegylated interferons for the treatment of chronic hepatitis C infection. Clinical Therapy 24(9):1363-1383.
120. Maag D, Castro C, Hong Z & Cameron CE (2001) Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. Journal of Biological Chemistry 276(49):46094-46098.
121. Macejak DG, Jensen KI, Bellon L, Pavco PA & Blatt LM (1999) Inhibition of viral replication by nuclease resistant hammerhead ribozymes directed against hepatitis C virus RNA. Hepatology 30:995.
122. Macejak DG, Jensen KI, Domenico K, Roberts EC, Chaudhary N, Von Carlowitz I, Bellon L & Tong MJ (2000) Inhibition of hepatitis C virus (HCV) RNA-dependent translation and replication of a chimeric HCV poliovirus using synthetic stabilized ribozyme. Hepatology 31:769-776.
123. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M & Albrecht JK (2001) Peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358:958-965.
124. Markland W, McQuaid TJ, Jain J & Kwong AD (2000) Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with α interferon. Antimicrobial Agents & Chemotherapy 44(4):859-866.
125. Martell M, Esteban JM, Quer J, Genesca J, Weiner AJ, Esteban R, Guardia J & Gomez J (1992) Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution. Journal of Virology 66(5):3225-3229.
126. McCaffrey AP, Meuse L, Pham T-TT, Conklin DS, Hannon GJ & Kay MA (2002) RNA interference in adult mice. Nature 418:38-39.
127. McHutchison JG (2002) Hepatitis C advances in antiviral therapy: what is accepted treatment now? Journal of Gastroenterology & Hepatology 17(4):431-441.
128. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S & Albrecht JK (1998) Interferon α-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. New England Journal of Medicine 339(21):1485-1492.
129. McHutchison JGS, Pockros PJ, Patel K, Nyberg L, Yu RZ, Kwoh TJ & Dorr FA (2002) A Phase IB dose escalation trial of ISIS 14803, an antisense inhibitor of HCV, in patients with chronic HCV: final report. Hepatology 36(4):303A.
130. Mehta A, Zitzmann N, Rudd PM, Block TM & Dwek RA (1998) α-Glucosidase inhibitors as potential broad based antiviral agents. FEBS Letters 430(1-2):17-22.
131. Mehta Meha SH, Cox A, Hoover DR, Wang XH, Mao Q, Ray S, Strathdee SA, Vlahov D & Thomas DL (2002) Protection against persistence of hepatitis C. Lancet 359(9316):1478-1483.
132. Melian EB & Plosker GL (2001) Interferon alphacon-1: a review of its pharmacology and therapeutic efficacy in the treatment of chronic hepatitis C. Drugs 61(11):1661-1691.
133. Mendez E, Ruggli N, Collett MS & Rice CM (1998) Infectious bovine viral diarrhea virus (strain NADL) RNA from stable cDNA clones: a cellular insert determines NS3 production and viral cytopathogenicity. Journal of Virology 72(6):4737-4745.
134. Mercer DF, Schiller DE, Elliott JF, Douglas DN, Hao C, Rinfret A Addison WR, Fischer KP, Churchill TA, Lakey JR, Tyrrell DL & Kneteman NM (2001) Hepatitis C virus replication in mice with chimeric human livers. Nature Medicine 7(8):927-933.
135. Michielsen P, Brenard R & Reynaert H (2002) Treatment of hepatitis C: impact on the virus, quality of life and the natural history. Acta Gastroenterology Belgium 65(2):90-94.
136. Morris PD, Byrd AK, Tackett AJ, Cameron CE, Tanega P, Ott R, Fanning E & Raney KD (2002) Hepatitis C virus NS3 and simiar virus 40 T antigen helicases displace streptavidin from 5′-biotinylated oligonucleotides but not from 3′-biotinylated oligonucleotides: evidence for directional bias in translocation on single-stranded DNA. Biochemistry 41(7):2372-2378.
137. Muerhoff AS, Leary TP, Simons JN, Pilot-Matias TJ, Dawson GJ, Erker JC, Chalmers ML, Schlauder GG, Desai SM & Mushahwar IK (1995) Genomic organization of GB viruses A and B: two new members of the Flaviviridae associated with GB agent hepatitis. Journal of Virology 69(9):5621-5630.
138. Murphey FA (1996) Virus taxonomy. In Fundamental Virology 3rd edn; pp. 31. Edited by B Fields. New York: Lippincott-Raven.
139. Myles DC (2001) Recent advances in the discovery of small molecule therapies for HCV. Current Opinion in Drug Discovery & Development 4(4):411-416.
140. Narjes F, Brunetti M, Colarusso S, Gerlach B, Koch U, Biasiol G, Fattori D, De Francesco R, Matassa VG & Steinkuhler C (2000) α-Ketoacids are potent slow binding inhibitors of the hepatitis C virus NS3 protease. Biochemistry 39(7):1849-1861.
141. O'Brien CB, Henzel BS & Moonka DK (1998a) Dosing kinetics of single ascending doses of recombinant human interleukin-12 (rIL-12) subcutaneously administered to adults with chronic hepatitis C infection previously treated with interferon-α. Hepatology 28:575A.
142. O'Brien CB, Moonka DK & Henzel BS (1998b) A randomized, double-blind, placebo-controlled study of multiple, ascending doses of recombinant human interleukin-12 (rIL-12) in patients with chronic hepatitis C (HCV) who previously failed therapy with interferon (IFN). Hepatology 28:574A.
143. O'Brien CB, Moonka DK, Henzel BS, Caufield M & Debruin MF (2001) A pilot trial of recombinant interleukin-12 in patients with chronic hepatitis C who previously failed treatment with interfer-on-α. American Journal of Gastroenterology 96(8):2473-2479.
144. Oh JW, Ito T & Lai MM (1999) A recombinant hepatitis C virus RNA-dependent RNA polymerase capable of copying the full-length viral RNA. Journal of Virology 73(9):7694-7702.
145. Ouzounov S, Mehta A, Dwek RA, Block TM & Jordan R (2002) The combination of interferon α-2b and n-butyl deoxynojirimycin has a greater than additive antiviral effect upon production of infectious bovine viral diarrhea virus (BVDV) in vitro: implications for hepatitis C virus (HCV) therapy. Antiviral Research 55:425-435.
146. Pang PS, Jankowsky E, Planet PJ & Pyle AM (2002) The hepatitis C viral NS3 protein is a processive DNA helicase with cofactor enhanced RNA unwinding. EMBO Journal 2(15):1168-1176.
147. Parry NR, Chung V, Viner KC & Carroll AR (2002) Evaluation of
148. Pawlotsky JM & Germanidis G (1999) The non-structural 5A protein of hepatitis C virus. Journal of Viral Hepatitis 6(5):343-356.
149. Phoon CW, Ng PY, Ting AE, Yeo SL & Sim MM (2001) Biological evaluation of hepatitis C virus helicase inhibitors. Bioorganic & Medicinal Chemistry Letters 11:1647-1650.
150. Pieroni L, Santolini E, Fipaldini C, Pacini L, Migliaccio G & La Monica N (1997) In vitro study of the NS2-3 protease of hepatitis C virus. Journal of Virology 71(9):6373-6380.
151. Pietschmann T, Lohmann V, Rutter G, Kurpanek K & Bartenschlager R (2001) Characterization of cell lines carrying self-replicating hepatitis C virus RNAs. Journal of Virology 75(3):1252-1264.
152. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, Weiner AJ, Houghton M, Rosa D, Grandi G & Abrignani S (1998) Binding of hepatitis C virus to CD81. Science 282:938-941.
153. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, Heathcote J, Zeuzem S, Trepo C & Albrecht J (1998) Randomised trial of interferon α2b plus ribavirin for 48 weeks or for 24 weeks versus interferon α2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 352:1426-1432.
154. Reichard O, Norkrans G, Fryden A, Braconier JH, Sonnerborg A & Weiland O (1998) Randomised, double-blind, placebo-controlled trial of interferon α-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group. Lancet 351(9096):83-87.
155. Rice CM (1996) Flaviviridae: the viruses and their replication. In Virology 3rd edn; pp. 931-960. Edited by BN Fields, DM Knipe & PM Howley. New York: Raven Press.
156. Roberts EC, Malmstrom TA & Pavco PA (1998) Synthesis and testing of nuclease resistant hammerhead ribozyme directed against hepatitis C virus RNA. Hepatology 28:398.
157. Robertson B, Myers G, Howard C, Brettin T, Bukh J, Gaschen B, Gojobori T, Maertens G, Mizokami M, Nainan O, Netesov S, Nishioka K, Shini T, Simmonds P, Smith DB, Stuyver L & Weiner AJ (1998) Classification, nomenclature and database development for hepatitis C virus (HCV) and related viruses: proposals for standardization. Archives of Virology 143(12):2493-2503.
158. Rossi S, Wright TL, Lin CC, Lau JYN, Edalatpour N & Fang JWS (2001) Phase I clinical studies of levovirin - a second generation ribavirin candidate. Hepatology 33:620A.
159. Rost KL, Wierich W, Masayuki F, Tuthill CW, Horwitz DL & Herrmann WM (1999) Pharmacokinetics of thymosin α-1 after subcutaneous injection of three different formulations in healthy volunteers. International Journal of Clinical Pharmacology & Therapeutics 37(1):51-57.
160. Saito I, Miyamura T, Ohbayashia A, Harada H, Katayama T, Kikuchi S, Watanabe TY, Koi S, Onji M, Ohta Y, Choo Q-L, Houghton M & Kuo G (1990) Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proceedings of the National Academy of Sciences, USA 87:6547-6549.
161. Sbardellati A, Scarselli E, Verschoor E, De Tomassi A, Lazzaro D & Traboni C (2001) Generation of infectious and transmissible virions from a BG virus B full-length consensus clone in tamarins. Journal of General Virology 82(Pt 10):2437-2438.
162. Scarselli E, Ansuini H, Cerino R, Roccasecca RM, Acali S, Filocamo G, Traboni C, Nicosia A, Cortese R & Vitelli A (2002) The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO Journal 21(19):5017-5025.
163. Seeff LB (1999) Natural history of hepatitis C. American Journal of Medicine 107(6B):10S-15S.
164. Severson WE, Schmaljohn CS, Javadian A & Jonsson CB (2003) Ribavirin causes error catastrophe during Hantaan virus replication. Journal of Virology 77(1):481-488.
165. Sidwell RW, Huffmann JH, Khare GP, Allen LB, Witkowski JT & Robins RK (1972) Broad-spectrum antiviral activity of Virazole: 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science 177:705-706.
166. Simons JN, Pilot-Matias TJ, Leary TP, Dawson GJ, Desai SM, Schlauder GG, Muerhoff AS, Erker JC, Buijk SL, Chalmers ML, Van Sant CL & Mushahwar IK (1995) Identification of two flavivirus-like genomes in the GB hepatitis agent. Proceedings of the National Academy of Sciences, USA 92(8):3401-3405.
167. Slater MJ, Andrews DM, Baker GR, Bethell S, Carey SJ, Chaignot HM, Clarke BE, Coomber BA, Ellis MR, Gray NM, Hardy GW & Al E (2002) Design and synthesis of pyrrolidine-5,5-trans-lactams as novel inhibitors of hepatitis C virus protease. Antiviral Research 53:11.
168. Smith JP (1997) Treatment of chronic hepatitis C with amantadine. Digestive Diseases & Sciences 42(8):1681-1687.
169. Smith RA (1980) Mechanisms of action of ribavirin. In Ribavirin: a broad spectrum antiviral agent; pp. 99-118. Edited by RA Smith & W Kirkpatrick. New York: Academic Press.
170. Smith RM, Walton CM, Wu CH & Wu GY (2002) Secondary structure and hybridization accessibility of hepatitis C virus 3′-terminal sequences. Journal of Virology 76(19):9563-9574.
171. Sommadossi JP & LA Colla P (2001) Methods and compositions for treating hepatitis C virus. In: WIPO. Novirio Pharmaceuticals, Worldwide.
172. Sperandio D, Gangloff A, Litvak J, Goldsmith R, Hataye J, Wang V, Shelton E, Elrod K, Janc J, Clark J, Rice K, Weinheimer S, Yeung K, Meanwell N, Hernandez D, Staab A, Venables B & Spencer J (2002) Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease. Bioorganic & Medicinal Chemistry Letters 12(21):3129-3133.
173. Steinkuhler C, Biasiol G, Brunetti M, Urbani A, Koch U, Cortese R, Pessi A & De Francesco R (1998) Product inhibition of the hepatitis C virus NS3 protease. Biochemistry 37(25):8899-8905.
174. Steinkuhler C, Urbani A, Tomei L, Biasiol G, Sardana M, Bianchi E, Pessi A & De Francesco R (1996) Activity of purified hepatitis C virus protease NS3 on peptide substrates. Journal of Virology 70(10):6694-6700.
175. Streeter DG, Witkowski JT, Khare GP, Sidwell RW, Bauer RJ, Robins RK & Simon LN (1973) Mechanism of action of 1-β-D -ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent. Proceedings of the National Academy of Sciences, USA 70(4):1174-1178.
176. Sudo K, Matsumoto Y, Matsushima M, Fujiwara M, Konno K, Shimotohno K, Shigeta S & Yokota T (1997) Novel hepatitis C virus protease inhibitors: thiazolidine derivatives. Biochemical & Biophysical Research Communications 238(2):643-647.
177. Suzich JA, Tamura JK, Palmer-Hill F, Warrener P, Grakoui A, Rice CM, Feinstone SM & Collett MS (1993) Hepatitis C virus NS3 protein polynucleotide-stimulated nucleoside triphosphatase and comparison with the related pestivirus and flavivirus enzymes. Journal of Virology 67(10):6152-6158.
178. Tabone M, Laudi C, Delmastro B, Biglino A, Andreoni M, Chieppa F, Bonardi R, Cariti G, Cusumano S, Brunello F, Calleri G, Manca A, Della Monica P, Sidoli L, Rizzetto M & Pera A (2001) Interferon and amantadine in combination as initial treatment for chronic hepatitis C patients. Journal of Hepatology 35(4):517-521.
179. Tai CL, Chi WK, Chen DS & Hwang LH (1996) The helicase activity associated with hepatitis C virus nonstructural protein 3. Journal of Virology 70:8477-8484.
180. Tam RC, Lim C, Bard J & Pai B (1999a) Contact hypersensitivity responses following ribavirin treatment in vivo are influenced by type 1 cytokine polarization, regulation of IL-10 expression, and costimulatory signaling. Journal of Immunology 163:3709-3717.
181. Tam RC, Pai B, Bard J, Lim C, Averett DR, Phan UT & Milovanovic T (1999b) Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile. Journal of Hepatology 30(3):376-382.
182. Tam RC, Ramasamy K, Bard J, Pai B, Lim C & Averett DR (2000) The ribavirin analog ICN 17261 demonstrates reduced toxicity and antiviral effects with retention of both immunomodulatory activity and reduction of hepatitis-induced serum alanine aminotransferase levels. Antimicrobial Agents & Chemotherapy 44:1276-1283.
183. Thimme R, Spangenberg HC & Blum HE (2002) Bridge over troubled water: protection against hepatitis C virus persistence? Hepatology 36(6):1537-1539.
184. Tsantrizos YS, Cameron DR, Faucher A-M, Ghiro E, Goudreau N, Halmos T & Llinas-Brunet M (2000) Macrocyclic peptides active against the hepatitis C virus. In: WIPO. Boehringer Ingelheim Ltd.
185. Tsukiyama-Kohara K, Iizuka N, Kohara M & Nomoto A (1992) Internal ribosome entry site within hepatitis C virus RNA. Journal of Virology 66(3):1476-1483.
186. Vassilev VB, Collett MS & Donis RO (1997) Authentic and chimeric full-length genomic cDNA clones of bovine viral diarrhea virus that yield infectious transcripts. Journal of Virology 71(1):471-478.
187. Walker MP & Hong Z (2002) HCV RNA-dependent RNA polymerase as a target for antiviral development. Current Opinion in Pharmacology 2(5):534-540.
188. Wang YS, Youngster S, Grace M, Bausch J, Bordens R & Wyss DF (2002) Structural and biological characterization of pegylated recombinant interferon α-2b and its therapeutic implications. Advanced Drug Delivery Reviews 54(4):547-570.
189. Waxman L (2002) Methods for inhibiting hepatitis C virus (HCV) replication by the administration of an HSP 90 inhibitor. Merck & Co, Inc., World Patent. WO-00207761.
190. Whitney M, Stack JH, Darke PL, Zheng W, Terzo J, Inglese J, Strulovici B, Kuo LC & Pollock BA (2002) A collaborative screening program for the discovery of inhibitors of HCV NS2/3 cis-cleaving protease activity. Journal of Biomedical Screening 7(2):149-154.
191. Witherell GW (2001) ISIS-14803. Current Opinion in Investigational Drugs 2(11):1523-1529.
192. World Health Organization (1996) Hepatitis C. Seroprevalence of hepatitis C virus (HCV) in a population sample. Weekly Epidemiolical Record 71:346-349.
193. Yagura M & Harada H (2001) Treatment of chronic hepatitis C patients with amantadine. Journal of Gastroenterology 36(11):759-763.
194. Yamashita T, Kaneko S, Shirota Y, Qin W, Nomura T, Kobayashi K & Murakami S (1998) RNA-dependent RNA polymerase activity of the soluble recombinant hepatitis C virus NS5B protein truncated at the C-terminal region. Journal of Biological Chemistry 273(25):15479-15486.
195. Yan Y, Li Y, Munshi S, Sardana V, Cole JL, Sardana M, Steinkuehler C, Tomei L, De Francesco R, Kuo LC & Chen Z (1998) Complex of NS3 protease and NS4A peptide of BK strain hepatitis C virus: a 2.2 Å resolution structure in a hexagonal crystal form. Protein Science 7(4):837-847.
196. Yanagi M, Purcell RH, Emerson SU & Bukh J (1997) Transcripts from a single full-length cDNA clone of hepatitis C virus are infectious when directly transfected into the liver of a chimpanzee. Proceedings of the National Academy of Sciences, USA 94(16):8738-8743.
197. Yao N, Hesson T, Cable M, Hong Z, Kwong AD, Le HV & Weber PC (1997) Structure of the hepatitis C virus RNA helicase domain. Nature Structural Biology 4(6):463-467.
198. Yao N, Hong Z & Lau JY (2002) Application of structural biology tools in the study of viral hepatitis and the design of antiviral therapy. Gastroenterology 123(4):1350-1363.
199. Yao N, Reichert P, Taremi S, Prosise WW & Weber PC (1999) Molecular views of viral polyprotein processing revealed by the crystal structure of the hepatitis C virus bifunctional protease-helicase. Structure 7(11):1353-1363.
200. Yeung K, Meanwell N, Qui Z, Hernandez D, Zhang S, McPhee F, Weinheimer S, Clark JM & Janc JW (2001) Structure-activity relationship studies of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of HCV NS3 serine protease. Bioorganic & Medicinal Chemistry Letters 11(17):2355-2359.
201. Yuan ZH, Kumar U, Thomas HC, Wen YM & Monjardino J (1997) Expression, purification, and partial characterization of HCV RNA polymerase. Biochemical & Biophysical Research Communications 232:231-235.
202. Zeuzem S & Carreno V (2001) Interleukin-12 in the treatment of chronic hepatitis B and C. Antiviral Research 52(2):181-188.
203. Zeuzem S, Heathcote JE, Martin N, Neiforth K & Modi M (2001) Peginterferon α-2a (40 kDa) monotherapy: a novel agent for chronic hepatitis C therapy. Expert Opinion on Investigational Drugs 10(12):2201-2213.
204. Zeuzem S, Teuber G, Naumann U, Berg T, Raedle J, Hartmann S & Hopf U (2000) Randomized, double-blind, placebo-controlled trial of interferon α2a with and without amantadine as initial treatment for chronic hepatitis C. Hepatology 32(4 Pt 1):835-841.
205. Zhong W, Ferrari E, Lesburg CA, Maag D, Ghosh SK, Cameron CE, Lau JYN & Hong Z (2000a) Template/primer requirements and single nucleotide incorporation by hepatitis C virus nonstructural protein 5B polymerase. Journal of Virology 74(19):9134-9143.
206. Zhong W, Uss AS, Ferrari E, Lau JY & Hong Z (2000b) De novo initiation of RNA synthesis by hepatitis C virus nonstructural protein 5B polymerase. Journal of Virology 74(4):2017-2022.
207. Zilly M, Lingenauber C, Desch S, Vath T, Klinker H & Langmann P (2002) Triple antiviral re-therapy for chronic hepatitis C with interferon-α, ribavirin and amantadine in nonresponders to interferon-α and ribavirin. European Journal of Medical Research 7(4):149-154.
208. Zitzmann N, Mehta AS, Carrouee S, Butters TD, Platt FM, McCauley J, Blumberg BS, Dwek RA & Block TM (1999) Imino sugars inhibit the formation and secretion of bovine viral diarrhea virus, a pestivirus model of hepatitis C virus: implications for the development of broad spectrum anti-hepatitis virus agents. Proceedings of the National Academy of Sciences, USA 96(21):11878-11882.