Browse > Article

Nonstructural Protein 5B of Hepatitis C Virus  

Lee, Jong-Ho (Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies)
Nam, In Young (Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies)
Myung, Heejoon (Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies)
Publication Information
Molecules and Cells / v.21, no.3, 2006 , pp. 330-336 More about this Journal
Abstract
Since its identification in 1989, hepatitis C virus has been the subject of extensive research. The biology of the virus and the development of antiviral drugs are closely related. The RNA polymerase activity of nonstructural protein 5B was first demonstrated in 1996. NS5B is believed to localize to the perinuclear region, forming a replicase complex with other viral proteins. It has a typical polymerase structure with thumb, palm, and finger domains encircling the active site. A de novo replication initiation mechanism has been suggested. To date, many small molecule inhibitors are known including nucleoside analogues, non-nucleoside analogues, and pyrophosphate mimics. NS5B interacts with other viral proteins such as core, NS3, 4A, 4B, and 5A. The helicase activity of NS3 seems necessary for RNA strand unwinding during replication, with other nonstructural proteins performing modulatory roles. Cellular proteins interacting with NS5B include VAMP-associated proteins, heIF4AII, hPLIC1, nucleolin, PRK2, ${\alpha}$-actinin, and p68 helicase. The interactions of NS5B with these proteins might play roles in cellular trafficking, signal transduction, and RNA polymerization, as well as the regulation of replication/translation processes.
Keywords
Hepatitis C Virus; Inhibitor; Interacting Proteins; NS5B; RNA Dependent RNA Polymerase; Structure;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
Times Cited By Web Of Science : 10  (Related Records In Web of Science)
연도 인용수 순위
1 Zhong, W., Uss, A. S., Ferrari, E., Lau, J. Y., and Hong, Z. (2000) De novo initiation of RNA synthesis by hepatitis C virus nonstructural protein 5B polymerase. J. Virol. 74, 2017-2022   DOI   ScienceOn
2 Alexopoulou, L., Holt, A. C., Medzhitov, R., and Flavell, R. A. (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413, 732-738   DOI   ScienceOn
3 Bost, A. G., Venable, D., Liu, L., and Heinz, B. A. (2003) Cytoskeletal requirements for hepatitis C virus (HCV) RNA synthesis in the HCV replicon cell culture system. J. Virol. 77, 4401-4408
4 Bressanelli, S., Tomei, L., Rey, F. A., and De Francesco, R. (2002) Structural analysis of the hepatitis C virus RNA polymerase in complex with ribonucleotides. J. Virol. 76, 3482-3492   DOI   ScienceOn
5 Causevic, M., Hislop, R. G., Kernohan, N. M., Carey, F. A., Kay, R. A., et al. (2001) Overexpression and poly-ubiquitylation of the DEAD-box RNA helicase p68 in colorectal tumors. Oncogene 20, 7734-7743   DOI   ScienceOn
6 Choi, K. H., Groarke, J. M., Young, D. C., Kuhn, R. J., Smith, J. L., et al. (2004) The structure of the RNA-dependent RNA polymerase from bovine viral diarrhea virus establishes the role of GTP in de novo initiation. Proc. Nat. Acad. Sci. USA 101, 4425-4430   DOI   ScienceOn
7 Endoh, H., Maruyama, K., Masuhiro, Y., Kobayashi, Y., Goto, M., et al. (1999) Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor $\alpha$. Mol. Cell. Biol. 19, 5363-5372   DOI
8 Ferrari, E., Wright-Minogue, J., Fang, J. W., Baroudy, B. M., Lau, J. Y., et al. (1999) Characterization of soluble hepatitis C virus RNA-dependent RNA polymerase expressed in Escherichia coli. J. Virol. 73, 1649-1654
9 Goh, P.-Y., Tan, Y.-J., Lim, S. P., Han, Y. H., Lim, S. G., et al. (2004) Cellular RNA helicase p68 relocalization and interaction with the hepatitis C virus (HCV) NS5B protein and the potential role of p68 in HCV RNA replication. J. Virol. 78, 5288-52   DOI   ScienceOn
10 Hagedorn, C. H., Beers, E. H., and De Staercke, C. (2000) Hepatitis C virus RNA-dependent RNA polymerase. Curr. Top. Microbiol. Immunol. 242, 225-260
11 Hong, Z., Cameron, C. E., Walker, M. P., Castro, C., Yao, N., et al. (2001) A novel mechanism to ensure terminal initiation by hepatitis C virus NS5B polymerase. Virology 285, 6-11   DOI   ScienceOn
12 Ishido, S., Fujita, T., and Hotta, H. (1998) Complex formation of NS5B with NS3 and NS4A proteins of hepatitis C virus. Biochem. Biophys. Res. Commun. 244, 35-40   DOI   ScienceOn
13 Kim, S.-J., Kim, J.-H., Kim, Y.-G., Lim, H.-S., and Oh, J. W. (2004) Protein kinase C-related kinase 2 regulates hepatitis C virus RNA polymerase function by phosphorylation. 279, 50031-50041   DOI   ScienceOn
14 Lee, K. J., Choi, J., Ou, J.-H., and Lai, M. M. C. (2004) The Cterminal transmembrane domain of hepatitis C virus (HCV) RNA polymerase is essential for HCV replication in vivo. J. Virol. 78, 3797-3802   DOI   ScienceOn
15 Lesburg, C. A., Cable, M. B., Ferrari, E., Hong, Z., Mannarino, A. F., et al. (1999) Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat. Struct. Biol. 6, 937-943   DOI   ScienceOn
16 Migliaccio, G., Tomassini, J. E., Carroll, S. S., Tomei, L., Altamura, S., et al. (2003) Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J. Biol. Chem. 278, 49164-49170   DOI   ScienceOn
17 Love, R. A., Parge, H. E., Yu, X., Hickey, M. J., Diehl, W., et al. (2003) Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C virus NS5B RNA polymerase enzyme. J. Virol. 77, 7575-7581   DOI   ScienceOn
18 Love, R. A., Maegley, K. A., Yu, X., Ferre, R. A., Lingardo, L. K., et al. (2004) The crystal structure of the RNA-dependent RNA polymerase from human rhinovirus: a dual function target for common cold antiviral therapy. Structure 12, 1533-1544   DOI   ScienceOn
19 McHutchison, J. G., Gordon, S. C., Schiff, E. R., Shiffman, M. L., Lee, W. M., et al. (1998) Interferon R-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis. Interventional Therapy Group. N. Engl. J. Med. 339, 1485-1492   DOI   ScienceOn
20 Miller, R. H. and Purcell, R. H. (1990) Hepatitis C virus shares amino acid sequence similarity with pestiviruses and flaviviruses as well as members of two plant virus supergroups. Proc. Natl. Acad. Sci. USA 87, 2057-2061   DOI   ScienceOn
21 Nisole, S., Krust, B., Callebaut, C., Guichard, G., Muller, S., et al. (1999) The anti-HIV pseudopeptide HB-19 forms a complex with the cell-surface-expressed nucleolin independent of heparah sulfate proteoglycans. J. Biol. Chem. 274, 27875-27884   DOI
22 Oh, J. W., Ito, T., and Lai, M. M. (1999) A recombinant hepatitis C virus RNA-dependent RNA polymerase capable of copying the full-length viral RNA. J. Virol. 73, 7694-7702
23 Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T., and Seya, 336 HCV NS5B T. (2003) TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated inferferon-beta induction. Nat. Immunol. 4, 161-167   DOI   ScienceOn
24 Piccininni, S., Varaklioti, A., Nardelli, M., Dave, B., Raney, K. D., et al. (2002) Modulation of the hepatitis C virus RNAdependent RNA polymerase activity by the non-structural (NS) 3 helicase and the NS4B membrane protein. J. Biol. Chem. 277, 45670-45679   DOI   ScienceOn
25 Ruggieri, A., Harada, T., Matsuura, Y., and Miyamura, T. (1997) Sensitization to Fas-mediated apoptosis by hepatitis C virus core protein. Virology 229, 68-76   DOI   ScienceOn
26 Summa, V., Petrocchi, A., Pace, P., Matassa, V. G., De Francesco, R., et al. (2004) Discovery of alpha,gamma-diketo acids as potent selective and reversible inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase. J. Med. Chem. 47, 14-17   DOI   ScienceOn
27 Selby, M. J., Glazer, E., Masiarz, F., and Houghton, M. (1994) Complex processing and protein:protein interactions in the E2:NS2 region of HCV. Virology 204, 114-122   DOI   ScienceOn
28 Shim, J., Larson, G., Lai, V., Naim, S., and Wu, J. Z. (2003) Canonical 3′-deoxyribonucleotides as a chain terminator for HCV NS5B RNA-dependent RNA polymerase. Antiviral Res. 58, 243-251   DOI   ScienceOn
29 Shirota, Y., Luo, H., Qin, W., Kaneko, S., Yamashita, T., et al. (2002) Hepatitis C virus (HCV) NS5A binds RNA-dependent RNA polymerase (RdRP) NS5B and modulates RNA-dependent RNA polymerase activity. J. Biol. Chem. 277, 11149- 11155   DOI   ScienceOn
30 Tai, C. L., Chi, W. K., Chen, D. S., and Hwang, L. H. (1996) The helicase activity associated with hepatitis C virus nonstructural protein 3 (NS3). J. Virol. 70, 8477-8484
31 Thompson, A. A. and Peersen, O. B. (2004) Structural basis for proteolysis-dependent activation of the poliovirus RNAdependent RNA polymerase. EMBO J. 23, 3462-3471
32 Tomei, L., Vitale, R. L., Incitti, I., Serafini, S., Altamura, S., et al. (2000) Biochemical characterization of a hepatitis C virus RNA-dependent RNA polymerase mutant lacking the Cterminal hydrophobic sequence. J. Gen. Virol. 81, 759-767   DOI
33 Tomei, L., Altamura, S., Bartholomew, L., Bisbocci, M., Bailey, C., et al. (2004) Characterization of the inhibition of hepatitis C virus RNA replication by nonnucleosides. J. Virol. 78, 938- 946   DOI   ScienceOn
34 Vincent, S. and Settleman, J. (1997) The PRK2 kinase is a potential effector target of both Rho and Rac GTPases and regulates actin cytoskeletal organization. Mol. Cell. Biol. 17, 2247-2256   DOI
35 Wang, M., Ng, K. K., Cherney, M. M., Chan, L., Yannopoulos, C. G., et al. (2003) Non-nucleoside analogue inhibitors bind to an allosteric site on HCV NS5B polymerase. Crystal structures and mechanism of inhibition. J. Biol. Chem. 278, 9489-9495   DOI   ScienceOn
36 Ishii, K., Tanaka, Y., Yap, C. C., Aizaki, H., Matsuura, Y., et al. (1999) Expression of hepatitis C virus NS5B protein: characterization of its RNA polymerase activity and RNA binding. Hepatology 29, 1227-1235   DOI
37 Blight, K. J. and Rice, C. M. (1997) Secondary structure determination of the conserved 98-base sequence at the 3' terminus of hepatitis C virus genome RNA. J. Virol. 71, 7345-7352
38 Johnson, R. B., Sun, X. L., Hockman, M. A., Villarreal, E. C., Wakulchik, M., et al. (2000) Specificity and mechanism analysis of hepatitis C virus RNA-dependent RNA polymerase. Arch. Biochem. Biophys. 377, 129-134   DOI   ScienceOn
39 Shi, S. T., Lee, K. J., Aizaki, H., Hwang, S. B., and Lai, M. M. (2003) Hepatitis C virus RNA replication occurs on a detergent- resistant membrane that cofractionates with caveolin-2. J. Virol. 77, 4160-4168   DOI   ScienceOn
40 Butcher, S. J., Grimes, J. M., Makeyev, E. V., Bamford, D. H., and Stuart, D. I. (2001) A mechanism for initiating RNA-dependent RNA polymerization. Nature 410, 235-240   DOI   ScienceOn
41 Ismaili, H. M. A., Cheng, Y. X., Lavallee, J. F., Siddiqui, A., and Storer, R. (2001) Method for the treatment or prevention of flavivirus infections using nucleoside analogues. WO 20010- 60315
42 Flynn, P., Mellor, H., Casamassima, A., and Parker, P. J. (2000) Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase. J. Biol. Chem. 275, 11064-11070   DOI   ScienceOn
43 Harms, G., Kraft, R., Grelle, G., Volz, B., Dernedde, J., et al. (2001) Identification of nucleolin as a new L-selectin ligand. Biochem. J. 360, 531−538   DOI   ScienceOn
44 Takeda, K., Kaisho, T., and Akira, S. (2003) Toll-like receptors. Annu. Rev. Immunol. 21, 335-376   DOI   ScienceOn
45 Appleby, T. C., Luecke, H., Shim, J. H., Wu, J. Z., Cheney, I. W., et al. (2005) Crystal structure of complete rhinovirus RNA polymerase suggests front loading of protein primer. J. Virol. 79, 277-288   DOI   ScienceOn
46 Crotty, S., Maag, D., Arnold, J. J., Zhong, W., Lau, J. Y., et al. (2000) The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat. Med. 6, 1375-1379   DOI   ScienceOn
47 Ng, K. K., Pendas-Franco, N., Rojo, J., Boga, J. A., Machin, A., et al. (2004) Crystal structure of norwalk virus polymerase reveals the carboxyl terminus in the active site cleft. J. Biol. Chem. 279, 16638-16645   DOI   ScienceOn
48 Ray, R. B., Lagging, L. M., Meyer, K., and Ray, R. (1996) Hepatitis C virus core protein cooperates with Ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J. Virol. 70, 4438-4443
49 Butcher, S. J., Makeyev, E. V., Grimes, J. M., Stuart, D. I., and Bamford, D. H. (2000) Crystallization and preliminary X-ray crystallographic studies on the bacteriophage phi6 RNAdependent RNA polymerase. Acta Crystallogr. D Biol. Crystallogr. 56, 1473-1475   DOI   ScienceOn
50 Gao, L., Tu, H., Shi, S. T., Lee, K. J., Asanaka, M., et al. (2003) Interaction with a ubiquitin-like protein enhances the ubiquitination and degradation of hepatitis C virus RNA-dependent RNA polymerase. J. Virol. 77, 4149-4159   DOI   ScienceOn
51 Medzhitov, R. (2001) Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1, 135-145   DOI   ScienceOn
52 Ago, H., Adachi, T., Yoshida, A., Yamamoto, M., Habuka, N., et al. (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Structure 7, 1417-1426   DOI   ScienceOn
53 Luo, G., Hamatake, R. K., Mathis, D. M., Racela, J., Rigat, K. L., et al. (2000) De novo initiation of RNA synthesis by the RNAdependent RNA polymerase (NS5B) of hepatitis C virus. J. Virol. 74, 851-863   DOI   ScienceOn
54 Storer, R. (2001) Method for the treatment or prevention of Flaviviridae viral infection using nucleoside analogs. WO 20010-32153
55 Dhanak, D., Duffy, K. J., Johnston, V. K., Lin-Goerke, J., Darcy, M., et al. (2002) Identification and biological characterization of heterocyclic inhibitors of the hepatitis C virus RNAdependent RNA polymerase. J. Biol. Chem. 277, 38322-38327   DOI   ScienceOn
56 Nguyen, T. T., Gates, A. T., Gutshall, L. L., Johnston, V. K., Gu, B., et al. (2003) Resistance profile of a hepatitis C virus RNAdependent RNA polymerase benzothiadiazine inhibitor. Antimicrob. Agents Chemother. 47, 3525-3530   DOI   ScienceOn
57 Lan, S., Wang, H., Jiang, H., Mao, H., Zhang, X., et al. (2003) Direct interaction between $\alpha$-actinin and hepatitis C virus NS5B. FEBS Lett. 554, 289-294   DOI   ScienceOn
58 Behrens, S. E., Tomei, L., and De Francesco, R. (1996) Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. EMBO J. 15, 12-22
59 Pace, P., Nizi, E., Pacini, B., Pesci, S., Matassa, V., et al. (2004) The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase. Bioorg. Med. Chem. Lett. 14, 3257-3261   DOI   ScienceOn
60 Yamashita, T., Kaneko, S., Shirota, Y., Qin, W., Nomura, T., et al. (1998) RNA-dependent RNA polymerase activity of the soluble recombinant hepatitis C virus NS5B protein truncated at the C-terminal region. J. Biol. Chem. 273, 15479-15486   DOI   ScienceOn
61 Hamamoto, I., Nishimura, Y., Okamoto, T., Aizaki, H., Liu, M., et al. (2005) HumanVAP-B is involved in hepatitis C virus replication through interaction with NS5A and NS5B. J. Virol. 79, 13473-13482   DOI   ScienceOn
62 Kao, C. C., Yang, X., Kline, A., Wang, Q. M., Barket, D., et al. (2000) Template requirements for RNA synthesis by a recombinant hepatitis C virus RNA-dependent RNA polymerase. 74, 11121-11128   DOI   ScienceOn
63 Lin, C., Wu, J. W., Hsiano, K., and Su, M. S. (1997) The hepatitis C virus NS4A: interactions with the NS4B and NS5A proteins. J. Viol. 71, 6465-6471
64 Stuyver, L. J., Whitaker, T., McBrayer, T. R., Hernandez- Santiago, B. I., Lostia, S., et al. (2003) Ribonucleoside analogue that blocks replicaton of bovine viral diarrhea and hepatitis C viruses in culture. Antimicrob. Agents Chemother. 47, 244-254   DOI   ScienceOn
65 Laurila, M. R., Makeyev, E. V., and Bamford, D. H. (2002) Bacteriophage phi 6 RNA-dependent RNA polymerase: molecular details of initiating nucleic acid synthesis without primer. J. Biol. Chem. 277, 17117-17124   DOI   ScienceOn
66 Choo, Q. L., Kuo, G., Weiner, A. J., Overby, L. R., Bradley, D. W., et al. (1989) Isolation of a cDNA clone derived from a bloodborne non-A, non-B viral hepatitis genome. Science 244, 359-362   DOI
67 Sun, X. L., Johnson, R. B., Hockman, M. A., and Wang, Q. M. (2000a) De novo RNA synthesis catalyzed by HCV RNAdependent RNA polymerase. Biochem. Biophys. Res. Commun. 268, 798-803   DOI   ScienceOn
68 Sun, W., Vincent, S., Settleman, J., and Johnson, G. L. (2000b) MEK kinase 2 binds and activates protein kinase C-related kinase2. Bifurcation of kinase regulatory pathways at the level of an MAPK kinase kinase. J. Biol. Chem. 275, 24421-24428   DOI   ScienceOn
69 Wasley, A. and Alter, M. J. (2000) Epidemiology of hepatitis C: geographic differences and temporal trends. Semin. Liver Dis. 20, 1-16   DOI   ScienceOn
70 Uchida, M., Hino, N., Yamanaka, T., Fukushima, H., Imanishi, T., et al. (2002) Hepatitis C virus core protein binds to a Cterminal region of NS5B RNA polymerase. Hepatol. Res. 22, 297-306   DOI   ScienceOn
71 Maag, D., Castro, C., Hong, Z., and Cameron, C. E. (2001) Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. J. Biol. Chem. 276, 46094-46098   DOI   ScienceOn
72 Naka, K., Dansako, H., Kobayashi, N., Ikeda, M., and Kato, N. (2005) Hepatitis C virus NS5B delays cell cycle progression by inducing interferon-$\beta$ via toll-like receptor 3 signaling pathway without replicating viral genomes. Virology (in press)
73 Bond, A. T., Mangus, D. A., He, F., and Jacobson, A. (2001) Absence of Dbp2p alters both nonsense-mediated mRNA decay and rRNA processing. Mol. Cell. Biol. 21, 7366-7379   DOI   ScienceOn
74 Carroll, S. S., Tomassini, J. E., Bosserman, M., Getty, K., Stahlhut, M. W., et al. (2003) Inhibition of hepatitis C virus RNA replication by 2′-modified nucleoside analogs. J. Biol. Chem. 278, 11979-11984   DOI   ScienceOn
75 Lin, C., Lindenbach, B. D., Pragai, B. M., McCourt, D. W., and Rice, C. M. (1994) Processing in the hepatitis C virus E2-NS2 region: identification of p7 and two distinct E2-specific products with different C termini. J. Virol. 67, 3835-3844
76 Beaulieu, P. L. and Tsantrizos, Y. S. (2004) Inhibitors of the HCV NS5B polymerase: new hope for the treatment of hepatitis C infections. Curr. Opin. Investig. Drugs 5, 838-850
77 Bonifacino, J. S. and Weissman, A. M. (1998) Ubiquitin and the control of protein fate in the secretory and endocytic pathways. Annu. Rev. Cell. Dev. Biol. 14, 19-57
78 Izumi, R. E., Valdez, B., Banerjee, R., Srivastava, M., and Dasgupta, A. (2001) Nucleolin stimulates viral internal ribosome entry site-mediated translation. Virus Res. 76, 17-29   DOI   ScienceOn
79 McKercher, G., Beaulieu, P. L., Lamarre, D., Laplante, S., Lefebvre, S., et al. (2004) Specific inhibitors of HCV polymerase identified using an NS5B with lower affinity for template/ primer substrate. Nucleic Acids Res. 32, 422-431   DOI   ScienceOn
80 Ng, K. K., Cherney, M. M., Vazquez, A. L., Machin, A., Alonso, J. M., et al. (2002) Crystal structures of active and inactive conformations of a caliciviral RNA-dependent RNA polymerase. J. Biol. Chem. 277, 1381-1387   DOI   ScienceOn
81 Quilliam, L. A., Lambert, Q. T., Mickelson-Young, L. A., Westwick, J. K., Sparks, A. B., et al. (1996) Isolation of a NCKassociated kinase, PRK2, an SH3-binding protein and potential effector of Rho protein signaling. J. Biol. Chem. 271, 28772-28776   DOI   ScienceOn
82 Tu, H., Gao, L., Shi, S. T., Taylor, D. R., Yang, T., et al. (1999) Hepatitis C virus RNA polymerase and NS5A complex with a SNARE-like protein. Virology 263, 30-41   DOI   ScienceOn
83 Olsen, D. B., Eldrup, A. B., Bartholomew, L., Bhat, B., Bosserman, M. R., et al. (2004) A 7-deaza-adenosine analogue is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrob. Agents Chemother. 48, 3944-3953   DOI   ScienceOn
84 Stansfield, I., Avolio, S., Colarusso, S., Gennari, N., Narjes, F., et al. (2004) Active site inhibitors of HCV NS5B polymerase. The development and pharmacophore of 2-thienyl-5,6-dihydroxypyrimidine- 4-carboxylic acid. Bioorg. Med. Chem. Lett. 14, 5085-5088   DOI   ScienceOn
85 De Francesco, R., Tomei, L., Altamura, S., Summa, V., and Migliaccio, G. (2003) Approaching a new era for hepatitis C virus therapy: inhibitors of the NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase. Antiviral Res. 58, 1-16   DOI   ScienceOn
86 Lau, J. Y. N., Tam, R. C., Liang, T. J., and Hong, Z. (2002) Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology 35, 1002-1009   DOI
87 Shimakami, T., Hijikata, M., Luo, H., Ma, Y. Y., Kaneko, S., et al. (2004) Effect of interaction between hepatitis C virus NS5A and NS5B on hepatitis C virus RNA replication with the hepatitis C virus replicon. J. Virol. 78, 2738-2748   DOI   ScienceOn
88 Kamer, G. and Argos, P. (1984) Primary structural comparison of RNA-dependent polymerases from plant, animal and bacterial viruses. Nucleic Acids Res. 12, 7269-7282   DOI   ScienceOn
89 Kyono, K., Miyashiro, M., and Taguchi, I. (2002) Human eukaryotic initiation factor 4AII associates with hepatitis C virus NS5B protein in vitro. Biochem. Biophys. Res. Commun. 292, 659-666   DOI   ScienceOn
90 Tomei, L., Altamura, S., Bartholomew, L., Biroccio, A., Ceccacci, A., et al. (2003) Mechanism of action and antiviral activity of benzimidazole-based allosteric inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. J. Virol. 77, 13225- 13231   DOI   ScienceOn
91 Cheng, J.-C., Chang, M.-F., and Chang, S. C. (1999) Specific interaction between the hepatitis C virus NS5B RNA polymerase and the 3′ end of the viral RNA. J. Virol. 73, 7044 - 7049
92 Manns, M. P., McHutchison, J. G., Gordon, S. C., Rustgi, V. K., Shiffman, M., et al. (2001) Peginterferon $\alpha$-2b plus ribavirin compared with interferon $\alpha$-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 358, 958-965   DOI
93 Ni, Z. J. and Wagman, A. S. (2004) Progress and development of small molecule HCV antivirals. Curr. Opin. Drug Discov. Dev. 7, 446-459
94 Ferrer-Orta, C., Arias, A., Perez-Luque, R., Escarmis, C., Domingo, E., et al. (2004) Structure of foot-and-mouth disease virus RNA-dependent RNA polymerase and its complex with a template-primer RNA. J. Biol. Chem. 279, 47212-47221   DOI   ScienceOn
95 Lohmann, V., Korner, F., Herian, U., and 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. J. Virol. 71, 8416-8428
96 Suzich, J. A., Tamura, J. K., Palmer-Hill, F., Warrener, P., Grakoui, A., et al. (1993) Hepatitis Cvirus NS3 protein polynucleotide-stimulated nucleoside triphosphatase and comparison with the related pestivirus and flavivirus enzymes. J. Virol. 67, 6152-6158
97 Matsumoto, M., Kikkawa, S., Kohase, M., Miyake, K., and Seya, T. (2002) Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNAmediated signaling. Biochem. Biophys. Res. Commun. 293, 1364- 1369   DOI   ScienceOn
98 Gopalsamy, A., Lim, K., Ciszewski, G., Park, K., Ellingboe, J. W., et al. (2004) Discovery of pyrano[3,4-b]indoles as potent and selective HCV NS5B polymerase inhibitors. J. Med. Chem. 47, 6603-6608   DOI   ScienceOn
99 Hirano, M., Kaneko, S., Yamashita, T., Luo, H., Qin, W., et al. (2003) Direct interaction between nucleolin and hepatitis C virus NS5B. J. Biol. Chem. 278, 5109-5115   DOI   ScienceOn