Download PDF
Semin Liver Dis 2014; 34(01): 009-021
DOI: 10.1055/s-0034-1371006
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Targets for Antiviral Therapy of Hepatitis C

Daniel Rupp
1   Department for Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany
2   German Centre for Infection Research, Heidelberg University
,
Ralf Bartenschlager
1   Department for Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany
2   German Centre for Infection Research, Heidelberg University
› Author Affiliations
Further Information

Publication History

Publication Date:
29 April 2014 (online)

   Permissions and Reprints

Abstract

Presently, interferon- (IFN-) containing treatment regimens are the standard of care for patients with hepatitis C virus (HCV) infections. Although this therapy eliminates the virus in a substantial proportion of patients, it has numerous side effects and contraindications. Recent approval of telaprevir and boceprevir, targeting the protease residing in nonstructural protein 3 (NS3) of the HCV genome, increased therapy success when given in combination with pegylated IFN and ribavirin, but side effects are more frequent and the management of treatment is complex. This situation will change soon with the introduction of new highly potent direct-acting antivirals. They target, in addition to the NS3 protease, NS5A, which is required for RNA replication and virion assembly and the NS5B RNA-dependent RNA polymerase. Moreover, host-cell factors such as cyclophilin A or microRNA-122, essential for HCV replication, have been pursued as therapeutic targets. In this review, the authors briefly summarize the main features of viral and cellular factors involved in HCV replication that are utilized as therapy targets for chronic hepatitis C.

Keywords

NS3 protease - NS5A - NS5B - miR-122 - cyclophilin A
 

  • References

  • 1 Thomas DL. Global control of hepatitis C: where challenge meets opportunity. Nat Med 2013; 19 (7) 850-858
    CrossrefPubMedGoogle Scholar
  • 2 Schaefer EA, Chung RT. The impact of human gene polymorphisms on HCV infection and disease outcome. Semin Liver Dis 2011; 31 (4) 375-386
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Ghany MG, Strader DB, Thomas DL, Seeff LB ; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49 (4) 1335-1374
    CrossrefPubMedGoogle Scholar
  • 4 McHutchison JG, Everson GT, Gordon SC , et al; PROVE1 Study Team. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360 (18) 1827-1838
    CrossrefPubMedGoogle Scholar
  • 5 Kanwal F, White DL, Tavakoli-Tabasi S , et al. Many patients with interleukin 28B genotypes associated with response to therapy are ineligible for treatment because of comorbidities. Clin Gastroenterol Hepatol 2014; 12 (2) 327-333, e1
    CrossrefPubMedGoogle Scholar
  • 6 Hoffmann L, Ramos JA, Souza EV , et al. Dynamics of resistance mutations to NS3 protease inhibitors in a cohort of Brazilian patients chronically infected with hepatitis C virus (genotype 1) treated with pegylated interferon and ribavirin: a prospective longitudinal study. Virol J 2013; 10: 57
    CrossrefPubMedGoogle Scholar
  • 7 Poordad F, McCone Jr J, Bacon BR , et al; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364 (13) 1195-1206
    CrossrefPubMedGoogle Scholar
  • 8 Bacon BR, Gordon SC, Lawitz E , et al; HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364 (13) 1207-1217
    CrossrefPubMedGoogle Scholar
  • 9 Zeuzem S, Andreone P, Pol S , et al; REALIZE Study Team. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364 (25) 2417-2428
    CrossrefPubMedGoogle Scholar
  • 10 Jacobson IM, McHutchison JG, Dusheiko G , et al; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364 (25) 2405-2416
    CrossrefPubMedGoogle Scholar
  • 11 Kieffer TL, Sarrazin C, Miller JS , et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007; 46 (3) 631-639
    CrossrefPubMedGoogle Scholar
  • 12 Aloia AL, Locarnini S, Beard MR. Antiviral resistance and direct-acting antiviral agents for HCV. Antivir Ther 2012; 17 (6 Pt B): 1147-1162
    CrossrefPubMedGoogle Scholar
  • 13 Simmonds P. The origin of hepatitis C virus. Curr Top Microbiol Immunol 2013; 369: 1-15
    PubMedGoogle Scholar
  • 14 André P, Komurian-Pradel F, Deforges S , et al. Characterization of low- and very-low-density hepatitis C virus RNA-containing particles. J Virol 2002; 76 (14) 6919-6928
    CrossrefPubMedGoogle Scholar
  • 15 Alvisi G, Madan V, Bartenschlager R. Hepatitis C virus and host cell lipids: an intimate connection. RNA Biol 2011; 8 (2) 258-269
    CrossrefPubMedGoogle Scholar
  • 16 Zeisel MB, Felmlee DJ, Baumert TF. Hepatitis C virus entry. Curr Top Microbiol Immunol 2013; 369: 87-112
    PubMedGoogle Scholar
  • 17 Lupberger J, Zeisel MB, Xiao F , et al. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat Med 2011; 17 (5) 589-595
    CrossrefPubMedGoogle Scholar
  • 18 Sainz Jr B, Barretto N, Martin DN , et al. Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor. Nat Med 2012; 18 (2) 281-285
    CrossrefPubMedGoogle Scholar
  • 19 Moradpour D, Penin F. Hepatitis C virus proteins: from structure to function. Curr Top Microbiol Immunol 2013; 369: 113-142
    PubMedGoogle Scholar
  • 20 Gentzsch J, Brohm C, Steinmann E , et al. Hepatitis C virus p7 is critical for capsid assembly and envelopment. PLoS Pathog 2013; 9 (5) e1003355
    CrossrefPubMedGoogle Scholar
  • 21 Egger D, Wölk B, Gosert R , et al. Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex. J Virol 2002; 76 (12) 5974-5984
    CrossrefPubMedGoogle Scholar
  • 22 Gosert R, Egger D, Lohmann V , et al. Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons. J Virol 2003; 77 (9) 5487-5492
    CrossrefPubMedGoogle Scholar
  • 23 Romero-Brey I, Merz A, Chiramel A , et al. Three-dimensional architecture and biogenesis of membrane structures associated with hepatitis C virus replication. PLoS Pathog 2012; 8 (12) e1003056
    CrossrefPubMedGoogle Scholar
  • 24 Barba G, Harper F, Harada T , et al. Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc Natl Acad Sci U S A 1997; 94 (4) 1200-1205
    CrossrefPubMedGoogle Scholar
  • 25 Miyanari Y, Atsuzawa K, Usuda N , et al. The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol 2007; 9 (9) 1089-1097
    CrossrefPubMedGoogle Scholar
  • 26 Chang KS, Jiang J, Cai Z, Luo G. Human apolipoprotein e is required for infectivity and production of hepatitis C virus in cell culture. J Virol 2007; 81 (24) 13783-13793
    CrossrefPubMedGoogle Scholar
  • 27 Bartenschlager R, Penin F, Lohmann V, André P. Assembly of infectious hepatitis C virus particles. Trends Microbiol 2011; 19 (2) 95-103
    CrossrefPubMedGoogle Scholar
  • 28 Lindenbach BD. Virion assembly and release. Curr Top Microbiol Immunol 2013; 369: 199-218
    PubMedGoogle Scholar
  • 29 Jones CT, Catanese MT, Law LM , et al. Real-time imaging of hepatitis C virus infection using a fluorescent cell-based reporter system. Nat Biotechnol 2010; 28 (2) 167-171
    CrossrefPubMedGoogle Scholar
  • 30 Witteveldt J, Evans MJ, Bitzegeio J , et al. CD81 is dispensable for hepatitis C virus cell-to-cell transmission in hepatoma cells. J Gen Virol 2009; 90 (Pt 1) 48-58
    CrossrefPubMedGoogle Scholar
  • 31 Brimacombe CL, Grove J, Meredith LW , et al. Neutralizing antibody-resistant hepatitis C virus cell-to-cell transmission. J Virol 2011; 85 (1) 596-605
    CrossrefPubMedGoogle Scholar
  • 32 Meylan E, Curran J, Hofmann K , et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 2005; 437 (7062) 1167-1172
    CrossrefPubMedGoogle Scholar
  • 33 Li K, Foy E, Ferreon JC , et al. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A 2005; 102 (8) 2992-2997
    CrossrefPubMedGoogle Scholar
  • 34 Bartenschlager R, Lohmann V, Penin F. The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection. Nat Rev Microbiol 2013; 11 (7) 482-496
    CrossrefPubMedGoogle Scholar
  • 35 Wölk B, Sansonno D, Kräusslich HG , et al. Subcellular localization, stability, and trans-cleavage competence of the hepatitis C virus NS3-NS4A complex expressed in tetracycline-regulated cell lines. J Virol 2000; 74 (5) 2293-2304
    CrossrefPubMedGoogle Scholar
  • 36 Zhu H, Briggs JM. Mechanistic role of NS4A and substrate in the activation of HCV NS3 protease. Proteins 2011; 79 (8) 2428-2443
    CrossrefPubMedGoogle Scholar
  • 37 Love RA, Parge HE, Wickersham JA , et al. The crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site. Cell 1996; 87 (2) 331-342
    CrossrefPubMedGoogle Scholar
  • 38 Kim JL, Morgenstern KA, Lin C , et al. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 1996; 87 (2) 343-355
    CrossrefPubMedGoogle Scholar
  • 39 De Francesco R, Steinkühler C. Structure and function of the hepatitis C virus NS3-NS4A serine proteinase. Curr Top Microbiol Immunol 2000; 242: 149-169
    PubMedGoogle Scholar
  • 40 Delang L, Neyts J, Vliegen I, Abrignani S, Neddermann P, De Francesco R. Hepatitis C virus-specific directly acting antiviral drugs. Curr Top Microbiol Immunol 2013; 369: 289-320
    PubMedGoogle Scholar
  • 41 Brass V, Berke JM, Montserret R, Blum HE, Penin F, Moradpour D. Structural determinants for membrane association and dynamic organization of the hepatitis C virus NS3-4A complex. Proc Natl Acad Sci U S A 2008; 105 (38) 14545-14550
    CrossrefPubMedGoogle Scholar
  • 42 Clark VC, Peter JA, Nelson DR. New therapeutic strategies in HCV: second-generation protease inhibitors. Liver Int 2013; 33 (Suppl. 01) 80-84
    CrossrefPubMedGoogle Scholar
  • 43 Romano KP, Ali A, Aydin C , et al. The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors. PLoS Pathog 2012; 8 (7) e1002832
    CrossrefPubMedGoogle Scholar
  • 44 Llinàs-Brunet M, Bailey M, Fazal G , et al. Peptide-based inhibitors of the hepatitis C virus serine protease. Bioorg Med Chem Lett 1998; 8 (13) 1713-1718
    CrossrefPubMedGoogle Scholar
  • 45 Steinkühler C, Biasiol G, Brunetti M , et al. Product inhibition of the hepatitis C virus NS3 protease. Biochemistry 1998; 37 (25) 8899-8905
    CrossrefPubMedGoogle Scholar
  • 46 Lamarre D, Anderson PC, Bailey M , et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003; 426 (6963) 186-189
    CrossrefPubMedGoogle Scholar
  • 47 Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010; 138 (2) 447-462
    CrossrefPubMedGoogle Scholar
  • 48 Susser S, Welsch C, Wang Y , et al. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology 2009; 50 (6) 1709-1718
    CrossrefPubMedGoogle Scholar
  • 49 Halfon P, Locarnini S. Hepatitis C virus resistance to protease inhibitors. J Hepatol 2011; 55 (1) 192-206
    CrossrefPubMedGoogle Scholar
  • 50 Cento V, Mirabelli C, Salpini R , et al. HCV genotypes are differently prone to the development of resistance to linear and macrocyclic protease inhibitors. PLoS ONE 2012; 7 (7) e39652
    CrossrefPubMedGoogle Scholar
  • 51 López-Labrador FX, Moya A, Gonzàlez-Candelas F. Mapping natural polymorphisms of hepatitis C virus NS3/4A protease and antiviral resistance to inhibitors in worldwide isolates. Antivir Ther 2008; 13 (4) 481-494
    PubMedGoogle Scholar
  • 52 Summa V, Ludmerer SW, McCauley JA , et al. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 2012; 56 (8) 4161-4167
    CrossrefPubMedGoogle Scholar
  • 53 Ali A, Aydin C, Gildemeister R , et al. Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance. ACS Chem Biol 2013; ; epub ahead of print
    PubMedGoogle Scholar
  • 54 Abian O, Vega S, Sancho J, Velazquez-Campoy A. Allosteric inhibitors of the NS3 protease from the hepatitis C virus. PLoS ONE 2013; 8 (7) e69773
    CrossrefPubMedGoogle Scholar
  • 55 Yang W, Zhao Y, Fabrycki J , et al. Selection of replicon variants resistant to ACH-806, a novel hepatitis C virus inhibitor with no cross-resistance to NS3 protease and NS5B polymerase inhibitors. Antimicrob Agents Chemother 2008; 52 (6) 2043-2052
    CrossrefPubMedGoogle Scholar
  • 56 Yang W, Sun Y, Hou X , et al. ACH-806, an NS4A antagonist, inhibits hepatitis C virus replication by altering the composition of viral replication complexes. Antimicrob Agents Chemother 2013; 57 (7) 3168-3177
    CrossrefPubMedGoogle Scholar
  • 57 Saalau-Bethell SM, Woodhead AJ, Chessari G , et al. Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function. Nat Chem Biol 2012; 8 (11) 920-925
    PubMedGoogle Scholar
  • 58 He Y, Staschke KA, Tan SL. HCV NS5A: A multifunctional regulator of cellular pathways and virus replication. In: Tan SL, , ed. Hepatitis C Viruses: Genomes and Molecular Biology. Norfolk, UK: Horizon Bioscience; 2006: 267-292
    Google Scholar
  • 59 Penin F, Brass V, Appel N , et al. Structure and function of the membrane anchor domain of hepatitis C virus nonstructural protein 5A. J Biol Chem 2004; 279 (39) 40835-40843
    CrossrefPubMedGoogle Scholar
  • 60 Tellinghuisen TL, Marcotrigiano J, Gorbalenya AE, Rice CM. The NS5A protein of hepatitis C virus is a zinc metalloprotein. J Biol Chem 2004; 279 (47) 48576-48587
    CrossrefPubMedGoogle Scholar
  • 61 Tellinghuisen TL, Marcotrigiano J, Rice CM. Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature 2005; 435 (7040) 374-379
    CrossrefPubMedGoogle Scholar
  • 62 Love RA, Brodsky O, Hickey MJ, Wells PA, Cronin CN. Crystal structure of a novel dimeric form of NS5A domain I protein from hepatitis C virus. J Virol 2009; 83 (9) 4395-4403
    CrossrefPubMedGoogle Scholar
  • 63 Verdegem D, Badillo A, Wieruszeski JM , et al. Domain 3 of NS5A protein from the hepatitis C virus has intrinsic alpha-helical propensity and is a substrate of cyclophilin A. J Biol Chem 2011; 286 (23) 20441-20454
    CrossrefPubMedGoogle Scholar
  • 64 Hanoulle X, Verdegem D, Badillo A, Wieruszeski JM, Penin F, Lippens G. Domain 3 of non-structural protein 5A from hepatitis C virus is natively unfolded. Biochem Biophys Res Commun 2009; 381 (4) 634-638
    CrossrefPubMedGoogle Scholar
  • 65 Appel N, Zayas M, Miller S , et al. Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly. PLoS Pathog 2008; 4 (3) e1000035
    CrossrefPubMedGoogle Scholar
  • 66 Tellinghuisen TL, Foss KL, Treadaway J. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLoS Pathog 2008; 4 (3) e1000032
    CrossrefPubMedGoogle Scholar
  • 67 Masaki T, Suzuki R, Murakami K , et al. Interaction of hepatitis C virus nonstructural protein 5A with core protein is critical for the production of infectious virus particles. J Virol 2008; 82 (16) 7964-7976
    CrossrefPubMedGoogle Scholar
  • 68 Moradpour D, Evans MJ, Gosert R , et al. Insertion of green fluorescent protein into nonstructural protein 5A allows direct visualization of functional hepatitis C virus replication complexes. J Virol 2004; 78 (14) 7400-7409
    CrossrefPubMedGoogle Scholar
  • 69 Appel N, Pietschmann T, Bartenschlager R. Mutational analysis of hepatitis C virus nonstructural protein 5A: potential role of differential phosphorylation in RNA replication and identification of a genetically flexible domain. J Virol 2005; 79 (5) 3187-3194
    CrossrefPubMedGoogle Scholar
  • 70 Schaller T, Appel N, Koutsoudakis G , et al. Analysis of hepatitis C virus superinfection exclusion by using novel fluorochrome gene-tagged viral genomes. J Virol 2007; 81 (9) 4591-4603
    CrossrefPubMedGoogle Scholar
  • 71 Kaneko T, Tanji Y, Satoh S , et al. Production of two phosphoproteins from the NS5A region of the hepatitis C viral genome. Biochem Biophys Res Commun 1994; 205 (1) 320-326
    CrossrefPubMedGoogle Scholar
  • 72 Quintavalle M, Sambucini S, Summa V , et al. Hepatitis C virus NS5A is a direct substrate of casein kinase I-alpha, a cellular kinase identified by inhibitor affinity chromatography using specific NS5A hyperphosphorylation inhibitors. J Biol Chem 2007; 282 (8) 5536-5544
    CrossrefPubMedGoogle Scholar
  • 73 Pietschmann T, Zayas M, Meuleman P , et al. Production of infectious genotype 1b virus particles in cell culture and impairment by replication enhancing mutations. PLoS Pathog 2009; 5 (6) e1000475
    CrossrefPubMedGoogle Scholar
  • 74 Gao M, Nettles RE, Belema M , et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465 (7294) 96-100
    CrossrefPubMedGoogle Scholar
  • 75 Targett-Adams P, Graham EJ, Middleton J , et al. Small molecules targeting hepatitis C virus-encoded NS5A cause subcellular redistribution of their target: insights into compound modes of action. J Virol 2011; 85 (13) 6353-6368
    CrossrefPubMedGoogle Scholar
  • 76 Lee C, Ma H, Hang JQ , et al. The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein. Virology 2011; 414 (1) 10-18
    CrossrefPubMedGoogle Scholar
  • 77 Fridell RA, Valera L, Qiu D, Kirk MJ, Wang C, Gao M. Intragenic complementation of hepatitis C virus NS5A RNA replication-defective alleles. J Virol 2013; 87 (4) 2320-2329
    CrossrefPubMedGoogle Scholar
  • 78 Reiss S, Rebhan I, Backes P , et al. Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment. Cell Host Microbe 2011; 9 (1) 32-45
    CrossrefPubMedGoogle Scholar
  • 79 Paul D, Hoppe S, Saher G, Krijnse-Locker J, Bartenschlager R. Morphological and biochemical characterization of the membranous hepatitis C virus replication compartment. J Virol 2013; 87 (19) 10612-10627
    CrossrefPubMedGoogle Scholar
  • 80 Belda O, Targett-Adams P. Small molecule inhibitors of the hepatitis C virus-encoded NS5A protein. Virus Res 2012; 170 (1-2) 1-14
    CrossrefPubMedGoogle Scholar
  • 81 Guedj J, Dahari H, Rong L , et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci U S A 2013; 110 (10) 3991-3996
    CrossrefPubMedGoogle Scholar
  • 82 Bressanelli S, Tomei L, Rey FA, De Francesco R. Structural analysis of the hepatitis C virus RNA polymerase in complex with ribonucleotides. J Virol 2002; 76 (7) 3482-3492
    CrossrefPubMedGoogle Scholar
  • 83 Ago H, Adachi T, Yoshida A , et al. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Structure 1999; 7 (11) 1417-1426
    CrossrefPubMedGoogle Scholar
  • 84 Lesburg CA, Cable MB, Ferrari E, Hong Z, Mannarino AF, Weber PC. Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat Struct Biol 1999; 6 (10) 937-943
    CrossrefPubMedGoogle Scholar
  • 85 Mosley RT, Edwards TE, Murakami E , et al. Structure of hepatitis C virus polymerase in complex with primer-template RNA. J Virol 2012; 86 (12) 6503-6511
    CrossrefPubMedGoogle Scholar
  • 86 Madela K, McGuigan C. Progress in the development of anti-hepatitis C virus nucleoside and nucleotide prodrugs. Future Med Chem 2012; 4 (5) 625-650
    CrossrefPubMedGoogle Scholar
  • 87 Sarrazin C, Hézode C, Zeuzem S, Pawlotsky JM. Antiviral strategies in hepatitis C virus infection. J Hepatol 2012; 56 (Suppl. 01) S88-S100
    PubMedGoogle Scholar
  • 88 Powdrill MH, Bernatchez JA, Götte M. Inhibitors of the hepatitis C virus RNA-dependent RNA polymerase NS5B. Viruses 2010; 2 (10) 2169-2195
    CrossrefPubMedGoogle Scholar
  • 89 Shim J, Larson G, Lai V, Naim S, Wu JZ. Canonical 3′-deoxyribonucleotides as a chain terminator for HCV NS5B RNA-dependent RNA polymerase. Antiviral Res 2003; 58 (3) 243-251
    CrossrefPubMedGoogle Scholar
  • 90 Pockros PJ. Nucleoside/nucleotide analogue polymerase inhibitors in development. Clin Liver Dis 2013; 17 (1) 105-110
    CrossrefPubMedGoogle Scholar
  • 91 Le Pogam S, Jiang WR, Leveque V , et al. In vitro selected Con1 subgenomic replicons resistant to 2′-C-methyl-cytidine or to R1479 show lack of cross resistance. Virology 2006; 351 (2) 349-359
    CrossrefPubMedGoogle Scholar
  • 92 Pawlotsky JM. The science of direct-acting antiviral and host-targeted agent therapy. Antivir Ther 2012; 17 (6 Pt B): 1109-1117
    CrossrefPubMedGoogle Scholar
  • 93 De Francesco R, Carfí A. Advances in the development of new therapeutic agents targeting the NS3-4A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus. Adv Drug Deliv Rev 2007; 59 (12) 1242-1262
    CrossrefPubMedGoogle Scholar
  • 94 Davis BC, Thorpe IF. Thumb inhibitor binding eliminates functionally important dynamics in the hepatitis C virus RNA polymerase. Proteins 2013; 81 (1) 40-52
    CrossrefPubMedGoogle Scholar
  • 95 Di Marco S, Volpari C, Tomei L , et al. Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site. J Biol Chem 2005; 280 (33) 29765-29770
    CrossrefPubMedGoogle Scholar
  • 96 Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 2005; 309 (5740) 1577-1581
    CrossrefPubMedGoogle Scholar
  • 97 Jopling CL, Schütz S, Sarnow P. Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome. Cell Host Microbe 2008; 4 (1) 77-85
    CrossrefPubMedGoogle Scholar
  • 98 Jopling CL. Regulation of hepatitis C virus by microRNA-122. Biochem Soc Trans 2008; 36 (Pt 6) 1220-1223
    CrossrefPubMedGoogle Scholar
  • 99 Li Y, Masaki T, Lemon SM. miR-122 and the hepatitis C RNA genome: more than just stability. RNA Biol 2013; 10 (6) 919-923
    CrossrefPubMedGoogle Scholar
  • 100 Shimakami T, Yamane D, Jangra RK , et al. Stabilization of hepatitis C virus RNA by an Ago2-miR-122 complex. Proc Natl Acad Sci U S A 2012; 109 (3) 941-946
    CrossrefPubMedGoogle Scholar
  • 101 Henke JI, Goergen D, Zheng J , et al. microRNA-122 stimulates translation of hepatitis C virus RNA. EMBO J 2008; 27 (24) 3300-3310
    CrossrefPubMedGoogle Scholar
  • 102 Randall G, Panis M, Cooper JD , et al. Cellular cofactors affecting hepatitis C virus infection and replication. Proc Natl Acad Sci U S A 2007; 104 (31) 12884-12889
    CrossrefPubMedGoogle Scholar
  • 103 Lanford RE, Hildebrandt-Eriksen ES, Petri A , et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 2010; 327 (5962) 198-201
    CrossrefPubMedGoogle Scholar
  • 104 Janssen HL, Reesink HW, Lawitz EJ , et al. Treatment of HCV infection by targeting microRNA. N Engl J Med 2013; 368 (18) 1685-1694
    CrossrefPubMedGoogle Scholar
  • 105 Tsai WC, Hsu SD, Hsu CS , et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest 2012; 122 (8) 2884-2897
    CrossrefPubMedGoogle Scholar
  • 106 Hsu SH, Wang B, Kota J , et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest 2012; 122 (8) 2871-2883
    CrossrefPubMedGoogle Scholar
  • 107 Galat A, Bua J. Molecular aspects of cyclophilins mediating therapeutic actions of their ligands. Cell Mol Life Sci 2010; 67 (20) 3467-3488
    CrossrefPubMedGoogle Scholar
  • 108 Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 2003; 38 (5) 1282-1288
    CrossrefPubMedGoogle Scholar
  • 109 Watashi K, Ishii N, Hijikata M , et al. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell 2005; 19 (1) 111-122
    CrossrefPubMedGoogle Scholar
  • 110 Yang F, Robotham JM, Nelson HB, Irsigler A, Kenworthy R, Tang H. Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro. J Virol 2008; 82 (11) 5269-5278
    CrossrefPubMedGoogle Scholar
  • 111 Kaul A, Stauffer S, Berger C , et al. Essential role of cyclophilin A for hepatitis C virus replication and virus production and possible link to polyprotein cleavage kinetics. PLoS Pathog 2009; 5 (8) e1000546
    CrossrefPubMedGoogle Scholar
  • 112 Chatterji U, Bobardt M, Selvarajah S , et al. The isomerase active site of cyclophilin A is critical for hepatitis C virus replication. J Biol Chem 2009; 284 (25) 16998-17005
    CrossrefPubMedGoogle Scholar
  • 113 Liu Z, Yang F, Robotham JM, Tang H. Critical role of cyclophilin A and its prolyl-peptidyl isomerase activity in the structure and function of the hepatitis C virus replication complex. J Virol 2009; 83 (13) 6554-6565
    CrossrefPubMedGoogle Scholar
  • 114 Foster TL, Gallay P, Stonehouse NJ, Harris M. Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner. J Virol 2011; 85 (14) 7460-7464
    CrossrefPubMedGoogle Scholar
  • 115 Hopkins S, Bobardt M, Chatterji U, Garcia-Rivera JA, Lim P, Gallay PA. The cyclophilin inhibitor SCY-635 disrupts hepatitis C virus NS5A-cyclophilin A complexes. Antimicrob Agents Chemother 2012; 56 (7) 3888-3897
    CrossrefPubMedGoogle Scholar
  • 116 Ciesek S, Steinmann E, Wedemeyer H , et al. Cyclosporine A inhibits hepatitis C virus nonstructural protein 2 through cyclophilin A. Hepatology 2009; 50 (5) 1638-1645
    CrossrefPubMedGoogle Scholar
  • 117 Madan V, Paul D, Lohmann V, Bartenschlager R. Inhibition of HCV replication by cyclophilin antagonists is linked to replication fitness and occurs by inhibition of membranous web formation. Gastroenterology 2014; Jan 30. [Epub ahead of print]
    PubMedGoogle Scholar
  • 118 Inoue K, Sekiyama K, Yamada M, Watanabe T, Yasuda H, Yoshiba M. Combined interferon alpha2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial. J Gastroenterol 2003; 38 (6) 567-572
    PubMedGoogle Scholar
  • 119 Flisiak R, Jaroszewicz J, Flisiak I, Łapiński T. Update on alisporivir in treatment of viral hepatitis C. Expert Opin Investig Drugs 2012; 21 (3) 375-382
    CrossrefPubMedGoogle Scholar
  • 120 Pfefferle S, Schöpf J, Kögl M , et al. The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors. PLoS Pathog 2011; 7 (10) e1002331
    CrossrefPubMedGoogle Scholar
  • 121 Goto K, Watashi K, Inoue D, Hijikata M, Shimotohno K. Identification of cellular and viral factors related to anti-hepatitis C virus activity of cyclophilin inhibitor. Cancer Sci 2009; 100 (10) 1943-1950
    CrossrefPubMedGoogle Scholar
  • 122 Chatterji U, Lim P, Bobardt MD , et al. HCV resistance to cyclosporin A does not correlate with a resistance of the NS5A-cyclophilin A interaction to cyclophilin inhibitors. J Hepatol 2010; 53 (1) 50-56
    CrossrefPubMedGoogle Scholar
  • 123 Puyang X, Poulin DL, Mathy JE , et al. Mechanism of resistance of hepatitis C virus replicons to structurally distinct cyclophilin inhibitors. Antimicrob Agents Chemother 2010; 54 (5) 1981-1987
    CrossrefPubMedGoogle Scholar
  • 124 Yang F, Robotham JM, Grise H , et al. A major determinant of cyclophilin dependence and cyclosporine susceptibility of hepatitis C virus identified by a genetic approach. PLoS Pathog 2010; 6 (9) e1001118
    CrossrefPubMedGoogle Scholar
  • 125 Coelmont L, Hanoulle X, Chatterji U , et al. DEB025 (Alisporivir) inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerisation in domain II of NS5A. PLoS ONE 2010; 5 (10) e13687
    CrossrefPubMedGoogle Scholar
  • 126 Zeisel MB, Fofana I, Fafi-Kremer S, Baumert TF. Hepatitis C virus entry into hepatocytes: molecular mechanisms and targets for antiviral therapies. J Hepatol 2011; 54 (3) 566-576
    CrossrefPubMedGoogle Scholar
  • 127 Angus AG, Patel AH. Immunotherapeutic potential of neutralizing antibodies targeting conserved regions of the HCV envelope glycoprotein E2. Future Microbiol 2011; 6 (3) 279-294
    CrossrefPubMedGoogle Scholar
  • 128 Meuleman P, Bukh J, Verhoye L , et al. In vivo evaluation of the cross-genotype neutralizing activity of polyclonal antibodies against hepatitis C virus. Hepatology 2011; 53 (3) 755-762
    CrossrefPubMedGoogle Scholar
  • 129 Giang E, Dorner M, Prentoe JC , et al. Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. Proc Natl Acad Sci U S A 2012; 109 (16) 6205-6210
    CrossrefPubMedGoogle Scholar
  • 130 Keck ZY, Xia J, Wang Y , et al. Human monoclonal antibodies to a novel cluster of conformational epitopes on HCV E2 with resistance to neutralization escape in a genotype 2a isolate. PLoS Pathog 2012; 8 (4) e1002653
    CrossrefPubMedGoogle Scholar
  • 131 OuYang B, Xie S, Berardi MJ , et al. Unusual architecture of the p7 channel from hepatitis C virus. Nature 2013; 498 (7455) 521-525
    CrossrefPubMedGoogle Scholar
  • 132 Chandler DE, Penin F, Schulten K, Chipot C. The p7 protein of hepatitis C virus forms structurally plastic, minimalist ion channels. PLOS Comput Biol 2012; 8 (9) e1002702
    CrossrefPubMedGoogle Scholar
  • 133 Luik P, Chew C, Aittoniemi J , et al. The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy. Proc Natl Acad Sci U S A 2009; 106 (31) 12712-12716
    CrossrefPubMedGoogle Scholar
  • 134 Steinmann E, Pietschmann T. Hepatitis C virus p7-a viroporin crucial for virus assembly and an emerging target for antiviral therapy. Viruses 2010; 2 (9) 2078-2095
    CrossrefPubMedGoogle Scholar
  • 135 Wozniak AL, Griffin S, Rowlands D , et al. Intracellular proton conductance of the hepatitis C virus p7 protein and its contribution to infectious virus production. PLoS Pathog 2010; 6 (9) e1001087
    CrossrefPubMedGoogle Scholar
  • 136 Steinmann E, Penin F, Kallis S, Patel AH, Bartenschlager R, Pietschmann T. Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions. PLoS Pathog 2007; 3 (7) e103
    CrossrefPubMedGoogle Scholar
  • 137 Carlsson T, Lindahl K, Schvarcz R , et al. 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. J Viral Hepat 2000; 7 (6) 409-413
    CrossrefPubMedGoogle Scholar
  • 138 Piai G, Rocco P, Tartaglione MT , et al. Triple (interferon, ribavirin, amantadine) versus double (interferon, ribavirin) re-therapy for interferon relapser genotype 1b HCV chronic active hepatitis patients. Hepatol Res 2003; 25 (4) 355-363
    CrossrefPubMedGoogle Scholar
  • 139 Tabone M, Ercole E, Zaffino C, Sallio Bruno F, Pera A, Bonino F. Amantadine hydrochloride decreases serum ALT activity without effects on serum HCV-RNA in chronic hepatitis C patients. Ital J Gastroenterol Hepatol 1998; 30 (6) 611-613
    PubMedGoogle Scholar
  • 140 Lundin M, Lindström H, Grönwall C, Persson MA. Dual topology of the processed hepatitis C virus protein NS4B is influenced by the NS5A protein. J Gen Virol 2006; 87 (Pt 11) 3263-3272
    CrossrefPubMedGoogle Scholar
  • 141 Gouttenoire J, Roingeard P, Penin F, Moradpour D. Amphipathic alpha-helix AH2 is a major determinant for the oligomerization of hepatitis C virus nonstructural protein 4B. J Virol 2010; 84 (24) 12529-12537
    CrossrefPubMedGoogle Scholar
  • 142 Paul D, Romero-Brey I, Gouttenoire J , et al. NS4B self-interaction through conserved C-terminal elements is required for the establishment of functional hepatitis C virus replication complexes. J Virol 2011; 85 (14) 6963-6976
    CrossrefPubMedGoogle Scholar
  • 143 Einav S, Gerber D, Bryson PD , et al. Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat Biotechnol 2008; 26 (9) 1019-1027
    CrossrefPubMedGoogle Scholar
  • 144 Jones DM, Patel AH, Targett-Adams P, McLauchlan J. The hepatitis C virus NS4B protein can trans-complement viral RNA replication and modulates production of infectious virus. J Virol 2009; 83 (5) 2163-2177
    CrossrefPubMedGoogle Scholar
  • 145 Zhang X, Zhang N, Chen G , et al. Discovery of novel HCV inhibitors: synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B. Bioorg Med Chem Lett 2013; 23 (13) 3947-3953
    CrossrefPubMedGoogle Scholar
  • 146 Cho NJ, Dvory-Sobol H, Lee C , et al. Identification of a class of HCV inhibitors directed against the nonstructural protein NS4B. Sci Transl Med 2010; 2 (15) ra6
    PubMedGoogle Scholar
  • 147 Bryson PD, Cho NJ, Einav S , et al. A small molecule inhibits HCV replication and alters NS4B's subcellular distribution. Antiviral Res 2010; 87 (1) 1-8
    CrossrefPubMedGoogle Scholar
  • 148 Ferenci P, Scherzer TM, Kerschner H , et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology 2008; 135 (5) 1561-1567
    CrossrefPubMedGoogle Scholar
  • 149 Beinhardt S, Rasoul-Rockenschaub S, Scherzer TM, Ferenci P. Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in a patient with chronic hepatitis C. J Hepatol 2011; 54 (3) 591-592 , author reply 592–593
    CrossrefPubMedGoogle Scholar
  • 150 Bárcena R, Moreno A, Rodríguez-Gandía MA , et al; Hospital Ramón y Cajal Liver Transplant Group. Safety and anti-HCV effect of prolonged intravenous silibinin in HCV genotype 1 subjects in the immediate liver transplant period. J Hepatol 2013; 58 (3) 421-426
    CrossrefPubMedGoogle Scholar
  • 151 Wagoner J, Negash A, Kane OJ , et al. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology 2010; 51 (6) 1912-1921
    CrossrefPubMedGoogle Scholar
  • 152 Blaising J, Lévy PL, Gondeau C , et al. Silibinin inhibits hepatitis C virus entry into hepatocytes by hindering clathrin-dependent trafficking. Cell Microbiol 2013; 15 (11) 1866-1882
    PubMedGoogle Scholar
  • 153 Mehrab-Mohseni M, Sendi H, Steuerwald N, Ghosh S, Schrum LW, Bonkovsky HL. Legalon-SIL downregulates HCV core and NS5A in human hepatocytes expressing full-length HCV. World J Gastroenterol 2011; 17 (13) 1694-1700
    CrossrefPubMedGoogle Scholar
  • 154 Polyak SJ, Oberlies NH, Pécheur EI, Dahari H, Ferenci P, Pawlotsky JM. Silymarin for HCV infection. Antivir Ther 2013; 18 (2) 141-147
    CrossrefPubMedGoogle Scholar
  • 155 Ahmed-Belkacem A, Ahnou N, Barbotte L , et al. Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase. Gastroenterology 2010; 138 (3) 1112-1122
    CrossrefPubMedGoogle Scholar
  • 156 Esser-Nobis K, Romero-Brey I, Ganten TM , et al. Analysis of hepatitis C virus resistance to silibinin in vitro and in vivo points to a novel mechanism involving nonstructural protein 4B. Hepatology 2013; 57 (3) 953-963
    CrossrefPubMedGoogle Scholar
  • 157 Guedj J, Dahari H, Pohl RT, Ferenci P, Perelson AS. Understanding silibinin's modes of action against HCV using viral kinetic modeling. J Hepatol 2012; 56 (5) 1019-1024
    CrossrefPubMedGoogle Scholar