Advertisement

Hepatitis C Virus-Specific Directly Acting Antiviral Drugs

  • Leen Delang
  • Johan Neyts
  • Inge Vliegen
  • Sergio Abrignani
  • Petra Neddermann
  • Raffaele De Francesco
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 369)

Abstract

The major targets for direct-acting antivirals (DAAs) are the NS3/4A protease, the NS5A protein, and the NS5B polymerase. The latter enzyme offers several target sites: the catalytic domain for nucleoside/nucleotide analogs and different allosteric sites for non-nucleoside inhibitors. Two protease inhibitors have already been approved and more than 40 new NS3/4A, NS5A, or NS5B inhibitors are in development pipeline. Not only these agents can achieve very high cure rates when combined with PEG-IFN and RBV, but have also started to provide promising results when combined in IFN-free, all-oral combinations. In addition to the more canonical drug targets, new alternative viral targets for small molecule drug development are emerging, such as p7 or NS4B. Current research is focusing on defining the most efficacious DAA combination regimens, i.e., those which provide the highest rates of viral eradication, broadest spectrum of action, minimal or no clinical resistance, shortest treatment duration, and good tolerability.

Keywords

Sustained Viral Response NS5A Inhibitor Sustained Viral Response Rate Thumb Domain Palm Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Afdhal N, O’Brien C, Godofsky E et al (2007) Valopicitabine (NM283), alone or with peginterferon, compared to peg interferon/ribavirin (pegIFN/RBV) retreatment in patients with HCV-1 infection and prior non-response to pegIFN/RBV: one-year results. J Hepatol 46:S5CrossRefGoogle Scholar
  2. Agarwal A, Zhang B, Olek E et al (2012) Rapid and sharp decline in hepatitis C virus upon monotherapy with NS3 protease inhibitor, ACH-1625. Antivirus Therapy, in press. doi: 10.3851/IMP2359
  3. Aghemo A, Degasperi E, Colombo M (2012) Directly acting antivirals for the treatment of chronic hepatitis C: unresolved topics from registration trials. Digistive and liver disease, in press. doi: 10.1016/j.dld.2012.05.002
  4. Assis DN, Lim JK (2012) New pharmacotherapy for hepatitis C. Clin Pharmacol Ther 92:294–305PubMedCrossRefGoogle Scholar
  5. Beaulieu PL (2006) The discovery of finger loop inhibitors of the hepatitis C virus NS5B polymerase: status and prospects for novel HCV therapeutics. IDrugs 9:39–43PubMedGoogle Scholar
  6. Beaulieu PL, Bos M, Cordingley MG et al (2012) Discovery of the first thumb pocket 1 NS5B polymerase inhibitor (BILB 1941) with demonstrated antiviral activity in patients chronically infected with genotype 1 hepatitis C virus (HCV). J Med Chem 55:7650–7666PubMedCrossRefGoogle Scholar
  7. Belda O, Targett-Adams P (2012) Small molecule inhibitors of the hepatitis C virus-encoded NS5A protein. Virus Research, in press. doi: 10.1016/j.virusres.2012.09.007
  8. Benhamou Y, Moussalli J, Ratziu V et al (2009) Results of a proof-of-concept study (C210) of telaprevir monotherapy and in combination with peginterfern alfa-2a and ribavirin in treatment-naive genotype 4 HCV patients. J Hepatol 50(1):S6CrossRefGoogle Scholar
  9. Berger C, Romero-Brey I, Zayas M et al (2012) HCV NS5A inhibitors alter membranous web formation and reduce PI4P induction in cells expressing HCV non-structural proteins. In: Abstracts O23 of the 19th international symposium on hepatitis C virus and related viruses, Venice, Italy, 5–9 Octo 2012Google Scholar
  10. Berke JM, Vijgen L, Lachau-Durand S et al (2011) Antiviral activity and mode of action of TMC647078, a novel nucleoside inhibitor of the hepatitis C virus NS5B polymerase. Antimicrob Agents Chemother 55:3812–3820PubMedCrossRefGoogle Scholar
  11. Brainard DM, Anderson MS, Petry A et al (2009) Safety and antiviral activity of NS5B polymerase inhibitor MK-3281, in treatment-naïve genotype 1a, 1b and 3 HCV-infected patients. Hepatology 50:1026A–1027AGoogle Scholar
  12. Brainard DM, Petry A, Van Dyck K et al (2010) Safety and antiviral activity of MK-5172, a novel HCV NS3/4A protease inhibitor with potent activity against known resistance mutants in genotype 1 and 3 HCV-infected patients. Hepatology 52(1):706A–707AGoogle Scholar
  13. Bressanelli S, Tomei L, Roussel A et al (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Proc Natl Acad Sci USA 96:13034–13039PubMedCrossRefGoogle Scholar
  14. Bryson PD, Cho NJ, Einav S et al (2010) A small molecule inhibits HCV replication and alters NS4B’s subcellular distribution. Antiviral Res 87:1–8PubMedCrossRefGoogle Scholar
  15. Carrere-Kremer S, Montpellier-Pala C, Cocquerel L et al (2002) Subcellular localization and topology of the p7 polypeptide of hepatitis C virus. J Virol 76:3720–3730PubMedCrossRefGoogle Scholar
  16. Carroll SS, Olsen DB (2006) Nucleoside analog inhibitors of hepatitis C virus replication. Infect Disord Drug Targets 6:17–29PubMedCrossRefGoogle Scholar
  17. Carroll SS, Tomassini JE, Bosserman M et al (2003) Inhibition of hepatitis C virus RNA replication by 2′-modified nucleoside analogs. J Biol Chem 278:11979–11984PubMedCrossRefGoogle Scholar
  18. Chang MH, Gordon LA, Fung HB (2012) Boceprevir: a protease inhibitor for the treatment of hepatitis C. Clin Ther 34:2021–2038PubMedCrossRefGoogle Scholar
  19. Chatel-Chaix L, Germain MA, Gotte M, Lamarre D (2012) Direct-acting and host-targeting HCV inhibitors: current and future directions. Curr Opin Virol 2:588–598PubMedCrossRefGoogle Scholar
  20. Chen SH, Tan SL (2005) Discovery of small-molecule inhibitors of HCV NS3-4A protease as potential therapeutic agents against HCV infection. Curr Med Chem 12:2317–2342PubMedCrossRefGoogle Scholar
  21. Cho NJ, Dvory-Sobol H, Lee C et al (2010) Identification of a class of HCV inhibitors directed against the nonstructural protein NS4B. Sci Transl Med 2:15–16CrossRefGoogle Scholar
  22. Choong IC, Cory D, Glenn JS, Yang W (2010) Methods and compositions of treating a Flaviviridae family viral infection. WO/2010/107739Google Scholar
  23. Conte I, Giuliano C, Ercolani C et al (2009) Synthesis and SAR of piperazinyl-N-phenylbenzamides as inhibitors of hepatitis C virus RNA replication in cell culture. Bioorg Med Chem Lett 19:1779–1783PubMedCrossRefGoogle Scholar
  24. Cooper C, Lawitz EJ, Ghali P et al (2009) Evaluation of VCH-759 monotherapy in hepatitis C infection. J Hepatol 51:39–46PubMedCrossRefGoogle Scholar
  25. De Francesco R, Steinkuhler C (2000) Structure and function of the hepatitis C virus NS3-NS4A serine proteinase. Curr Top Microbiol Immunol 242:149–169PubMedCrossRefGoogle Scholar
  26. Delang L, Froeyen M, Herdewijn P, Neyts J (2012) Identification of a novel resistance mutation for benzimidazole inhibitors of the HCV RNA-dependent RNA polymerase. Antiviral Res 93:30–38PubMedCrossRefGoogle Scholar
  27. Deltenre P, Henrion J, Canva V et al (2004) Evaluation of amantadine in chronic hepatitis C: a meta-analysis. J Hepatol 41:462–473PubMedCrossRefGoogle Scholar
  28. Devogelaere B, Berke JM, Vijgen L et al (2012) TMC647055, a potent nonnucleoside hepatitis C virus NS5B polymerase inhibitor with cross-genotypic coverage. Antimicrob Agents Chemother 56:4676–4684PubMedCrossRefGoogle Scholar
  29. Di Marco S, Volpari C, Tomei L et al (2005) Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site. J Biol Chem 280:29765–29770PubMedCrossRefGoogle Scholar
  30. Dvory-Sobol H, Wong KA, Ku KS et al (2012) Characterization of resistance to the protease inhibitor GS-9451 in hepatitis C virus-infected patients. Antimicrob Agents Chemother 56:5289–5295PubMedCrossRefGoogle Scholar
  31. Edwards PD, Bernstein PR (1994) Synthetic inhibitors of elastase. Med Res Rev 14:127–194PubMedCrossRefGoogle Scholar
  32. Einav S, Gerber D, Bryson PD et al (2008) Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat Biotechnol 26:1019–1027PubMedCrossRefGoogle Scholar
  33. Einav S, Sobol HD, Gehrig E, Glenn JS (2010) The hepatitis C virus (HCV) NS4B RNA binding inhibitor clemizole is highly synergistic with HCV protease inhibitors. J Infect Dis 202:65–74PubMedCrossRefGoogle Scholar
  34. El Hage N, Luo G (2003) Replication of hepatitis C virus RNA occurs in a membrane-bound replication complex containing nonstructural viral proteins and RNA. J Gen Virol 84:2761–2769PubMedCrossRefGoogle Scholar
  35. Erhardt A, Deterding K, Benhamou Y et al (2009) Safety, pharmacokinetics and antiviral effect of BILB 1941, a novel hepatitis C virus RNA polymerase inhibitor, after 5 days oral treatment. Antiviral Ther 14:23–32Google Scholar
  36. Everson GT, Sims KD, Rodriguez-Torres M et al (2012) An interferon-free, ribavirin-free 12 weeks regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 yielded SVR4 of 94 % in treatment-naïve patients with genotype (GT) 1 chronic hepatitis C virus (HCV) infection. In: Abstracts LB-3 of the 63rd annual meeting of the american association for the study of liver diseases, Boston, Massachusetts, 9–13 Nov 2012Google Scholar
  37. Failla C, Tomei L, De Francesco R (1994) Both NS3 and NS4A are required for proteolytic processing of hepatitis C virus nonstructural proteins. J Virol 68:3753–3760PubMedGoogle Scholar
  38. Failla C, Tomei L, De Francesco R (1995) An amino-terminal domain of the hepatitis C virus NS3 protease is essential for interaction with NS4A. J Virol 69:1769–1777PubMedGoogle Scholar
  39. Ferenci P (2012) Treatment of chronic hepatitis C: are interferons really necessary? Liver Int 32(1):108–112PubMedCrossRefGoogle Scholar
  40. Forestier N, Zeuzem S (2012) Telaprevir for the treatment of hepatitis C. Expert Opin Pharmacother 13:593–606PubMedCrossRefGoogle Scholar
  41. Forestier N, Larrey D, Guyader D et al (2011) Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: a phase 1b multiple ascending dose study. J Hepatol 54:1130–1136PubMedCrossRefGoogle Scholar
  42. Foster GR, Hezode C, Bronowicki JP et al (2011a) Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections. Gastroenterology 141(881–889):e881CrossRefGoogle Scholar
  43. Foster TL, Verow M, Wozniak AL et al (2011b) Resistance mutations define specific antiviral effects for inhibitors of the hepatitis C virus p7 ion channel. Hepatology 54:79–90PubMedCrossRefGoogle Scholar
  44. Fridell RA, Qiu D, Wang C et al (2010) Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system. Antimicrob Agents Chemother 54:3641–3650PubMedCrossRefGoogle Scholar
  45. Fridell RA, Wang C, Sun JH et al (2011) Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in humans: in vitro and in vivo correlations. Hepatology 54:1924–1935PubMedCrossRefGoogle Scholar
  46. Gane EJ, Roberts SK, Stedman CAM et al (2010) Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 376:1467–1475PubMedCrossRefGoogle Scholar
  47. Gane E, Stedman C, Hyland RH et al (2012a) Once daily sofosbuvir (GS-7977) plus ribavirin in patients with HCV genotypes 1, 2, and 3: the electron trial. In: Abstracts 229 of the 63rd annual meeting of the american association for the study of liver diseases, Boston, Massachusetts, 9–13 Nov 2012Google Scholar
  48. Gane EJ, Stedman CA, Hyland RH et al (2012b) Electron: once daily PSI-7977 plus RBV in HCV GT1/2/3. J Hepatol 56(2):S438–S439CrossRefGoogle Scholar
  49. Gao M, Nettles RE, Belema M et al (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465:96–100PubMedCrossRefGoogle Scholar
  50. Gopalsamy A, Aplasca A, Ciszewski G et al (2006) Design and synthesis of 3,4-dihydro-1H-[1]-benzothieno[2,3-c]pyran and 3,4-dihydro-1H-pyrano[3,4-b]benzofuran derivatives as non-nucleoside inhibitors of HCV NS5B RNA dependent RNA polymerase. Bioorg Med Chem Lett 16:457–460PubMedCrossRefGoogle Scholar
  51. Goudreau N, Llinas-Brunet M (2005) The therapeutic potential of NS3 protease inhibitors in HCV infection. Expert Opin Investig Drugs 14:1129–1144PubMedCrossRefGoogle Scholar
  52. Gouttenoire J, Penin F, Moradpour D (2010) Hepatitis C virus nonstructural protein 4B: a journey into unexplored territory. Rev Med Virol 20:117–129PubMedCrossRefGoogle Scholar
  53. Gray F, Amphlett E, Bright H et al (2007) GSK625433; a novel and highly potent inhibitor of the HCVNS5B polymerase. J Hepatol 46:S225CrossRefGoogle Scholar
  54. Griffin SD, Beales LP, Clarke DS et al (2003) The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, amantadine. FEBS Lett 535:34–38PubMedCrossRefGoogle Scholar
  55. Griffin S, StGelais C, Owsianka AM et al (2008) Genotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel. Hepatology 48:1779–1790PubMedCrossRefGoogle Scholar
  56. Gu B, Johnston VK, Gutshall LL et al (2003) Arresting initiation of hepatitis C virus RNA synthesis using heterocyclic derivatives. J Biol Chem 278:16602–16607PubMedCrossRefGoogle Scholar
  57. Hebner CM, Han B, Brendza KM et al (2012) The HCV Non-nucleoside inhibitor tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function. Plos One 7:e39163PubMedCrossRefGoogle Scholar
  58. Hong Z, Cameron CE, Walker MP et al (2001) A novel mechanism to ensure terminal initiation by hepatitis C virus NS5B polymerase. Virology 285:6–11PubMedCrossRefGoogle Scholar
  59. Howe AY, Bloom J, Baldick CJ et al (2004) Novel nonnucleoside inhibitor of hepatitis C virus RNA-dependent RNA polymerase. Antimicrob Agents Chemother 48:4813–4821PubMedCrossRefGoogle Scholar
  60. Howe AY, Cheng H, Thompson I et al (2006) Molecular mechanism of a thumb domain hepatitis C virus nonnucleoside RNA-dependent RNA polymerase inhibitor. Antimicrob Agents Chemother 50:4103–4113PubMedCrossRefGoogle Scholar
  61. Howe AY, Cheng H, Johann S et al (2008) Molecular mechanism of hepatitis C virus replicon variants with reduced susceptibility to a benzofuran inhibitor, HCV-796. Antimicrob Agents Chemother 52:3327–3338PubMedCrossRefGoogle Scholar
  62. Huang Y, Staschke K, De Francesco R, Tan SL (2007) Phosphorylation of hepatitis C virus NS5A nonstructural protein: a new paradigm for phosphorylation-dependent viral RNA replication? Virology 364:1–9PubMedCrossRefGoogle Scholar
  63. Huang M, Podos S, Patel D et al (2010) ACH-2684: HCV NS3 protease inhibitor with potent activity against multiple genotypes and known resistant variants. Hepatology 52(S1):1204AGoogle Scholar
  64. Jacobson I, Pockros P, Lalezari J et al (2009) Antiviral activity of filibuvir in combination with pegylated interferon alfa-2a and ribavirin for 28 days in treatment naive patients chronically infected with HCV genotype 1. J Hepatol 50:S382–S383CrossRefGoogle Scholar
  65. Kazmierski WM, Hamatake R, Duan M et al (2012) Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants. J Med Chem 55:3021–3026PubMedCrossRefGoogle Scholar
  66. Khoury G, Ewart G, Luscombe C et al (2010) Antiviral efficacy of the novel compound BIT225 against HIV-1 release from human macrophages. Antimicrob Agents Chemother 54:835–845PubMedCrossRefGoogle Scholar
  67. Kieffer TL, Sarrazin C, Miller JS et al (2007) Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 46:631–639PubMedCrossRefGoogle Scholar
  68. Kim JL, Morgenstern KA, Lin C et al (1996) Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 87:343–355PubMedCrossRefGoogle Scholar
  69. Kneteman NM, Howe AYM, Gao TJ et al (2009) HCV796: a selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity in vitro, in mice with chimeric human livers, and in humans infected with hepatitis C virus. Hepatology 49:745–752PubMedCrossRefGoogle Scholar
  70. Kowdley KV, Lawitz E, Crespo I et al (2012a) Atomic: 97 % RVR for PSI-7977 + PEG/RBV X 12 weeks regimen in HCV GT1: an end to response-guided therapy? J Hepatol 56(2):S1CrossRefGoogle Scholar
  71. Kowdley KV, Lawitz E, Poordad F et al (2012b) A 12 weeks interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR12 rates (observed data) of 99 % in treatment-naïve patients and 93 % in prior null responders with HCV genotype1 infection. In: Abstracts LB-1 of the 63rd annual meeting of the american association for the study of liver diseases, Boston, Massachusetts, 9–13 Nov 2012Google Scholar
  72. Kukolj G, McGibbon GA, McKercher G et al (2005) Binding site characterization and resistance to a class of non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase. J Biol Chem 280:39260–39267PubMedCrossRefGoogle Scholar
  73. Kwo PY, Lawitz EJ, McCone J et al (2010) Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 376:705–716PubMedCrossRefGoogle Scholar
  74. Lagace L, White PW, Bousquet C et al (2012) In vitro resistance profile of the hepatitis C virus NS3 protease inhibitor BI 201335. Antimicrob Agents Chemother 56:569–572PubMedCrossRefGoogle Scholar
  75. Lam AM, Espiritu C, Bansal S et al (2011a) Hepatitis C virus nucleotide inhibitors PSI-352938 and PSI-353661 exhibit a novel mechanism of resistance requiring multiple mutations within replicon RNA. J Virol 85:12334–12342PubMedCrossRefGoogle Scholar
  76. Lam AM, Espiritu C, Murakami E et al (2011b) Inhibition of hepatitis C virus replicon RNA synthesis by PSI-352938, a cyclic phosphate prodrug of {beta}-D-2′-deoxy-2′-{alpha}-fluoro-2′-{beta}-C-Methylguanosine. Antimicrob Agents Chemother 55:2566–2575PubMedCrossRefGoogle Scholar
  77. Lam AM, Espiritu C, Bansal S et al (2012) Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother 56:3359–3368PubMedCrossRefGoogle Scholar
  78. Lamarre D, Anderson PC, Bailey M et al (2003) An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426:186–189PubMedCrossRefGoogle Scholar
  79. Larrey DG, Benhamou Y, Lohse AW et al (2009) Bi 207127 is a potent HCV RNA polymerase inhibitor during 5 days monotherapy in patients with chronic hepatitis C. Hepatology 50:1044AGoogle Scholar
  80. Larrey D, Lohse AW, de Ledinghen V et al (2012) Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin. J Hepatol 57:39–46PubMedCrossRefGoogle Scholar
  81. Lawitz E, Nguyen T, Younes Z et al (2006) Valopicitabine (NM283) plus PEG-interferon in treatment-naive hepatitis C patients with HCV genotype-1 infection: HCV RNA clearance during 24 weeks of treatment. Hepatology 44:223AGoogle Scholar
  82. Lawitz E, Rodriguez-Torres M, DeMico M et al (2009) Antiviral activity of ANA598, a potent non-nucleoside polymerase inhibitor, in chronic hepatitis C patients. J Hepatol 50:S384CrossRefGoogle Scholar
  83. Lawitz E, Gaultier I, Poordad F et al (2010a) 4 weeks virologic response and safety of ABT-450 given with low-dose ritonavir (ABT-450r) in combination with pegylated interferon alfa 2a and ribavirin after 3 days monotherapy in HCV-infected treatment-naive subjects. Hepatology 52(1):878A–979AGoogle Scholar
  84. Lawitz E, Rodriguez-Torres M, Rustgi V et al (2010b) Safety and antiviral activity of ANA598 in combination with pegylated IFN alpha 2a plus ribavirin in treatment-naïve genotype-1 chronic HCV patients. Hepatology 52:334A–335AGoogle Scholar
  85. Lawitz E, Rodriguez-Torres M, Denning JM et al (2011) Once dialy dual-nucleotide combination of PSI-938 and PSI-7977 provides 94 % HCV RNA < LOD at day 14: first purine/pyrimidine clinical combination data (the nuclear study). J Hepatol 54:S543CrossRefGoogle Scholar
  86. Lawitz EJ, Gruener D, Hill JM et al (2012) A phase 1, randomized, placebo-controlled, 3 days, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C. J Hepatol 57:24–31PubMedCrossRefGoogle Scholar
  87. Le Pogam S, Jiang WR, Leveque V et al (2006a) In vitro selected Con1 subgenomic replicons resistant to 2′-C-methyl-cytidine or to R1479 show lack of cross resistance. Virology 351:349–359PubMedCrossRefGoogle Scholar
  88. Le Pogam S, Kang H, Harris SF et al (2006b) Selection and characterization of replicon variants dually resistant to thumb- and palm-binding nonnucleoside polymerase inhibitors of the hepatitis C virus. J Virol 80:6146–6154PubMedCrossRefGoogle Scholar
  89. Le Pogam S, Seshaadri A, Ewing A et al (2010) RG7128 alone or in combination with pegylated interferon-alpha 2a and ribavirin prevents hepatitis C virus (HCV) replication and selection of resistant variants in HCV-infected patients. J Infect Dis 202:1510–1519PubMedCrossRefGoogle Scholar
  90. Lee LY, Tong CY, Wong T, Wilkinson M (2012) New therapies for chronic hepatitis C infection: a systematic review of evidence from clinical trials. Int J Clin Pract 66:342–355PubMedCrossRefGoogle Scholar
  91. Lemm JA, O’Boyle D 2nd, Liu M et al (2010) Identification of hepatitis C virus NS5A inhibitors. J Virol 84:482–491PubMedCrossRefGoogle Scholar
  92. Lemm JA, Leet JE, O’Boyle DR 2nd et al (2011) Discovery of potent hepatitis C virus NS5A inhibitors with dimeric structures. Antimicrob Agents Chemother 55:3795–3802PubMedCrossRefGoogle Scholar
  93. Lenz O, Verbinnen T, Lin TI et al (2010) In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother 54:1878–1887PubMedCrossRefGoogle Scholar
  94. Lesburg CA, Cable MB, Ferrari E et al (1999) Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat Struct Biol 6:937–943PubMedCrossRefGoogle Scholar
  95. Li H, Tatlock J, Linton A et al (2009) Discovery of (R)-6-Cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-on e (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J Med Chem 52:1255–1258PubMedCrossRefGoogle Scholar
  96. 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. J Virol 69:4373–4380PubMedGoogle Scholar
  97. Lin C, Lin K, Luong YP et al (2004) In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J Biol Chem 279:17508–17514PubMedCrossRefGoogle Scholar
  98. Lin C, Kwong AD, Perni RB (2006) Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of hepatitis C virus NS3-4A serine protease. Infect Disord Drug Targets 6:3–16PubMedCrossRefGoogle Scholar
  99. Lin TI, Lenz O, Fanning G et al (2009) In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrob Agents Chemother 53:1377–1385PubMedCrossRefGoogle Scholar
  100. Liu R, Kong R, Mann P et al (2012) In vitro resistance analysis of HCV NS5A inhibitor MK-8742 demonstrates increased potency against clinical resistance variants ans higher resistance barrier. J Hepatol 56(2):S334–S335CrossRefGoogle Scholar
  101. Liverton NJ, Carroll SS, Dimuzio J et al (2010) MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease. Antimicrob Agents Chemother 54:305–311PubMedCrossRefGoogle Scholar
  102. Love RA, Parge HE, Wickersham JA et al (1996) The crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site. Cell 87:331–342PubMedCrossRefGoogle Scholar
  103. Love RA, Brodsky O, Hickey MJ et al (2009) Crystal structure of a novel dimeric form of NS5A domain I protein from hepatitis C virus. J Virol 83:4395–4403PubMedCrossRefGoogle Scholar
  104. Ludmerer SW, Graham DJ, Boots E et al (2005) Replication fitness and NS5B drug sensitivity of diverse hepatitis C virus isolates characterized by using a transient replication assay. Antimicrob Agents Chemother 49:2059–2069PubMedCrossRefGoogle Scholar
  105. Luik P, Chew C, Aittoniemi J et al (2009) The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy. Proc Natl Acad Sci USA 106:12712–12716PubMedCrossRefGoogle Scholar
  106. Luscombe CA, Huang Z, Murray MG et al (2010) A novel hepatitis C virus p7 ion channel inhibitor, BIT225, inhibits bovine viral diarrhea virus in vitro and shows synergism with recombinant interferon-alpha-2b and nucleoside analogues. Antiviral Res 86:144–153PubMedCrossRefGoogle Scholar
  107. Ma H, Jiang WR, Robledo N et al (2007) Characterization of the metabolic activation of hepatitis C virus nucleoside inhibitor beta-D-2′-deoxy-2′-fluoro-2′-C-methylcytidine (PSI-6130) and identification of a novel active 5′-triphosphate species. J Biol Chem 282:29812–29820PubMedCrossRefGoogle Scholar
  108. Macdonald A, Harris M (2004) Hepatitis C virus NS5A: tales of a promiscuous protein. J Gen Virol 85:2485–2502PubMedCrossRefGoogle Scholar
  109. Manns MP, Bourliere M, Benhamou Y et al (2011) Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection. J Hepatol 54:1114–1122PubMedCrossRefGoogle Scholar
  110. May MM, Brohm D, Harrenga A et al (2012) Discovery of substituted N-phenylbenzenesulphonamides as a novel class of non-nucleoside hepatitis C virus polymerase inhibitors. Antiviral Res 95:182–191PubMedCrossRefGoogle Scholar
  111. McCown MF, Rajyaguru S, Le Pogam S et al (2008) The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to nonnucleoside polymerase or protease inhibitors. Antimicrob Agents Chemother 52:1604–1612PubMedCrossRefGoogle Scholar
  112. McGuigan C, Madela K, Aljarah M et al (2010) Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus. Bioorg Med Chem Lett 20:4850–4854PubMedCrossRefGoogle Scholar
  113. McPhee F, Friborg J, Levine S et al (2012a) Resistance analysis of the hepatitis C virus NS3 protease inhibitor asunaprevir. Antimicrob Agents Chemother 56:3670–3681PubMedCrossRefGoogle Scholar
  114. McPhee F, Sheaffer AK, Friborg J et al (2012b) Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032). Antimicrob Agents Chemother 56:5387–5396PubMedCrossRefGoogle Scholar
  115. Membreno FE, Lawitz EJ (2011) The HCV NS5B nucleoside and non-nucleoside inhibitors. Clin Liver Dis 15:611–626PubMedCrossRefGoogle Scholar
  116. Migliaccio G, Tomassini JE, Carroll SS et al (2003) Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J Biol Chem 278:49164–49170PubMedCrossRefGoogle Scholar
  117. Moreno C, Berg T, Tanwandee T et al (2012) Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study. J Hepatol 56:1247–1253PubMedCrossRefGoogle Scholar
  118. Murakami E, Bao H, Ramesh M et al (2007) Mechanism of activation of beta-D-2′-deoxy-2′-fluoro-2′-c-methylcytidine and inhibition of hepatitis C virus NS5B RNA polymerase. Antimicrob Agents Chemother 51:503–509PubMedCrossRefGoogle Scholar
  119. Murakami E, Niu CR, Bao HY et al (2008) The mechanism of action of beta-D-2′-deoxy-2′-fluoro-2′-C-methylcytidme involves a second metabolic pathway leading to beta-D-2′-deoxy-2-fluoro-2′-C-methyluridine 5′-triphosphate, a potent inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Antimicrob Agents Chemother 52:458–464PubMedCrossRefGoogle Scholar
  120. Narjes F, Crescenzi B, Ferrara M et al (2011) Discovery of (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (MK-3281), a potent and orally bioavailable finger-loop inhibitor of the hepatitis C virus NS5B polymerase. J Med Chem 54:289–301PubMedCrossRefGoogle Scholar
  121. Nelson DR, Gane EJ, Jacobson IM et al (2011) VX-222/telaprevir in combination with peginterferon-alfa-2a and ribavirin in treatment-naive genotype 1 HCV patients treated for 12 weeks: zenith study, SVR12 interim analysis. Hepatology 54:1435AGoogle Scholar
  122. Nguyen TT, Gates AT, Gutshall LL et al (2003) Resistance profile of a hepatitis C virus RNA-dependent RNA polymerase benzothiadiazine inhibitor. Antimicrob Agents Chemother 47:3525–3530PubMedCrossRefGoogle Scholar
  123. Olsen DB, Eldrup AB, Bartholomew L et al (2004) A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrob Agents Chemother 48:3944–3953PubMedCrossRefGoogle Scholar
  124. Pasquinelli C, McPhee F, Eley T et al (2012) Single- and multiple-ascending-dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C. Antimicrob Agents Chemother 56:1838–1844PubMedCrossRefGoogle Scholar
  125. Pauwels F, Mostmans W, Quirynen LMM et al (2007) Binding-site identification and genotypic profiling of hepatitis C virus polymerase inhibitors. J Virol 81:6909–6919PubMedCrossRefGoogle Scholar
  126. Pawlotsky JM, Najera I, Jacobson I (2012) Resistance to mericitabine, a nucleoside analogue inhibitor of HCV RNA-dependent RNA polymerase. Antivir Ther 17:411–423PubMedCrossRefGoogle Scholar
  127. Pessoa MG, Cheinquer H, Almeida PR et al (2012) Re-treatment of previous non-responders and relapsers to interferon plus ribavirin with peginterferon alfa-2a (40KD), ribavirin ± amantadine in patients with chronic hepatitis C: randomized multicentre clinical trial. Ann Hepatol 11:52–61PubMedGoogle Scholar
  128. Pierra C, Amador A, Benzaria S et al (2006) Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2′-C-methylcytidine. J Med Chem 49:6614–6620PubMedCrossRefGoogle Scholar
  129. Pol S, Ghalib RH, Rustgi VK et al (2012) Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial. Lancet Infect Dis 12:671–677PubMedCrossRefGoogle Scholar
  130. Poordad F, Lawitz E, Kowdley KV et al (2012a) 12 weeks interferon-free regimen of ABT-450/R + ABT-333 + ribavirin achieved SVR12 in more than 90 % of treatment-naive HCV genotype-1-infected subjects and 47 % of previous non-responders. J Hepatol 56(2):S549–S550CrossRefGoogle Scholar
  131. Poordad F, Lawitz E, Kowdley KV et al (2012b) 12 weeks interferon-free regimen of ABT-450/R + ABT-333 + ribavirin achieved svr12 in more than 90 % of treatment-naive HCV genotype-1-infected subjects and 47 % of previous non-responders. J Hepatol 56:S549–S550CrossRefGoogle Scholar
  132. Qiu D, Lemm JA, O’Boyle DR 2nd et al (2011) The effects of NS5A inhibitors on NS5A phosphorylation, polyprotein processing and localization. J Gen Virol 92:2502–2511PubMedCrossRefGoogle Scholar
  133. Rai R, Deval J (2011) New opportunities in anti-hepatitis C virus drug discovery: targeting NS4B. Antiviral Res 90:93–101PubMedCrossRefGoogle Scholar
  134. Reddy MB, Chen Y, Haznedar JO et al (2012) Impact of low-dose ritonavir on danoprevir pharmacokinetics: results of computer-based simulations and a clinical drug-drug interaction study. Clin Pharmacokinet 51:457–465PubMedCrossRefGoogle Scholar
  135. Reesink HW, Fanning GC, Farha KA et al (2010) Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients. Gastroenterology 138:913–921PubMedCrossRefGoogle Scholar
  136. Reghellin V, Fenu S, Bianco A et al (2012) HCV NS5A inhibitor BMS-790052 exerts its antiviral effects by reducing phosphatidylinositol 4-phosphate levels in the virus-induced membranous web. In: Abstracts LB-9 of the 19th international symposium on hepatitis C virus and related viruses, Venice, Italy, 5–9 Octo 2012Google Scholar
  137. Reiss S, Rebhan I, Backes P et al (2011) Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment. Cell Host Microbe 9:32–45PubMedCrossRefGoogle Scholar
  138. Rodriguez-Torres M, Lawitz E, Conway B et al (2010) Safety and antiviral activity of the HCV non-nucleoside polymerase inhibitor VX-222 in treatment-naive genotype 1 HCV-infected patients. J Hepatol 52:S14CrossRefGoogle Scholar
  139. Rodriguez-Torres M, Lawitz E, Hazan L et al (2011) Antiviral activity and safety of INX-08189, a nucleotide polymerase inhibitor, following 7 days of oral therapy in naive genotype-1 chronic HCV patients. Hepatology 54:535AGoogle Scholar
  140. Romano KP, Ali A, Aydin C et al (2012) The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors. Plos Pathog 8:e1002832PubMedCrossRefGoogle Scholar
  141. Sakai A, St Claire MS, Faulk K et al (2003) The p7 polypeptide of hepatitis C virus is critical for infectivity and contains functionally important genotype-specific sequences. Proc Natl Acad Sci USA 100:11646–11651PubMedCrossRefGoogle Scholar
  142. Sarrazin C, Zeuzem S (2010) Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 138:447–462PubMedCrossRefGoogle Scholar
  143. Sarrazin C, Kieffer TL, Bartels D et al (2007) Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 132:1767–1777PubMedCrossRefGoogle Scholar
  144. Sarrazin C, Hezode C, Zeuzem S, Pawlotsky JM (2012) Antiviral strategies in hepatitis C virus infection. J Hepatol 56(1):S88–S100PubMedCrossRefGoogle Scholar
  145. Schaefer EA, Chung RT (2012) Anti-hepatitis C virus drugs in development. Gastroenterology 142(1340–1350):e1341Google Scholar
  146. Schechter I, Berger A (1967) On the size of the active site in proteases. I Papain Biochem Biophys Res Commun 27:157–162CrossRefGoogle Scholar
  147. Seiwert SD, Andrews SW, Jiang Y et al (2008) Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227). Antimicrob Agents Chemother 52:4432–4441PubMedCrossRefGoogle Scholar
  148. Sheng XC, Appleby T, Butler T et al (2012a) Discovery of GS-9451: an acid inhibitor of the hepatitis C virus NS3/4A protease. Bioorg Med Chem Lett 22:2629–2634PubMedCrossRefGoogle Scholar
  149. Sheng XC, Casarez A, Cai R et al (2012b) Discovery of GS-9256: a novel phosphinic acid derived inhibitor of the hepatitis C virus NS3/4A protease with potent clinical activity. Bioorg Med Chem Lett 22:1394–1396PubMedCrossRefGoogle Scholar
  150. Shepard CW, Finelli L, Alter MJ (2005) Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 5:558–567PubMedCrossRefGoogle Scholar
  151. Shi ST, Herlihy KJ, Graham JP et al (2009) Preclinical characterization of PF-00868554, a potent nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Antimicrob Agents Chemother 53:2544–2552PubMedCrossRefGoogle Scholar
  152. Slater MJ, Amphlett EM, Andrews DM et al (2007) Optimization of novel acyl pyrrolidine inhibitors of hepatitis C virus RNA-dependent RNA polymerase leading to a development candidate. J Med Chem 50:897–900PubMedCrossRefGoogle Scholar
  153. Smith JP (1997) Treatment of chronic hepatitis C with amantadine. Dig Dis Sci 42:1681–1687PubMedCrossRefGoogle Scholar
  154. Steinmann E, Penin F, Kallis S et al (2007a) Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions. Plos Pathog 3:962–971CrossRefGoogle Scholar
  155. Steinmann E, Whitfield T, Kallis S et al (2007b) Antiviral effects of amantadine and iminosugar derivatives against hepatitis C virus. Hepatology 46:330–338PubMedCrossRefGoogle Scholar
  156. Stuyver LJ, McBrayer TR, Tharnish PM et al (2006) Inhibition of hepatitis C replicon RNA synthesis by beta-D-2′-deoxy-2′-fluoro-2′-C-methylcytidine: a specific inhibitor of hepatitis C virus replication. Antivir Chem Chemother 17:79–87PubMedGoogle Scholar
  157. Sulkowski M, Rodriguez-Torres M, Lawitz E et al (2012a) High sustained virologic response rate in treatment-naïve HCV genotype 1a and 1b patients treated for 12 weeks with an interferon-free all-oral quad regimen: interim results. J Hepatol 56:S560Google Scholar
  158. Sulkowski MS, Gardiner DF, Rodriguez-Torres M et al (2012b) High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naïve patients chronically infected with HCV genotype 1, 2, or 3. In: Abstracts LB-2 of the 63rd annual meeting of the american association for the study of liver diseases, Boston, Massachusetts, 9–13 Nov 2012Google Scholar
  159. Summa V, Ludmerer SW, McCauley JA et al (2012) MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 56:4161–4167PubMedCrossRefGoogle Scholar
  160. Susser S, Welsch C, Wang Y et al (2009) Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology 50:1709–1718PubMedCrossRefGoogle Scholar
  161. Tanwandee T, Luscombe CA, Ewart G et al (2011) Antiviral activity and tolerability of BIT225 plus pegylated interferon alpha 2a or 2b and weight-based ribavirin for 28 days in HCV treatment-naïve monoinfected patients. Glob Antiviral J 7(1):64 HEP DART 2011Google Scholar
  162. Targett-Adams P, Graham EJ, Middleton J et al (2011) Small molecules targeting hepatitis C virus-encoded NS5A cause subcellular redistribution of their target: insights into compound modes of action. J Virol 85:6353–6368PubMedCrossRefGoogle Scholar
  163. Tellinghuisen TL, Marcotrigiano J, Rice CM (2005) Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature 435:374–379PubMedCrossRefGoogle Scholar
  164. Thompson P, Patel R, Steffy K, Appleman J (2009) Preclinical studies of ANA598 combined with other Anti-HCV agents demonstrate potential of combination treatment. J Hepatol 50:S37CrossRefGoogle Scholar
  165. Tomei L, Failla C, Santolini E et al (1993) NS3 is a serine protease required for processing of hepatitis C virus polyprotein. J Virol 67:4017–4026PubMedGoogle Scholar
  166. Tomei L, Altamura S, Bartholomew L 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 77:13225–13231PubMedCrossRefGoogle Scholar
  167. Tomei L, Altamura S, Bartholomew L et al (2004) Characterization of the inhibition of hepatitis C virus RNA replication by nonnucleosides. J Virol 78:938–946PubMedCrossRefGoogle Scholar
  168. Trozzi C, Bartholomew L, Ceccacci A et al (2003) In vitro selection and characterization of hepatitis C virus serine protease variants resistant to an active-site peptide inhibitor. J Virol 77:3669–3679PubMedCrossRefGoogle Scholar
  169. Vernachio JH, Bleiman B, Bryant KD et al (2011) INX-08189, a phosphoramidate prodrug of 6-O-methyl-2′-C-methyl guanosine, is a potent inhibitor of hepatitis C virus replication with excellent pharmacokinetic and pharmacodynamic properties. Antimicrob Agents Chemother 55:1843–1851PubMedCrossRefGoogle Scholar
  170. von Wagner M, Hofmann WP, Teuber G et al (2008) Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection. Hepatology 48:1404–1411CrossRefGoogle Scholar
  171. Wagaw S, Ravn M, Engstrom K et al (2009) Process for making macrocyclic oximyl hepatitis C protease inhibitors. WO/2009/073780Google Scholar
  172. Wagner F, Thompson R, Kantaridis C et al (2011) Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir in genotype 1-infected patients. Hepatology 54:50–59PubMedCrossRefGoogle Scholar
  173. Wang M, Ng KK, Cherney MM 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 278:9489–9495PubMedCrossRefGoogle Scholar
  174. White PW, Llinas-Brunet M, Amad M et al (2010) Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease. Antimicrob Agents Chemother 54:4611–4618PubMedCrossRefGoogle Scholar
  175. Yan Y, Li Y, Munshi S et al (1998) Complex of NS3 protease and NS4A peptide of BK strain hepatitis C virus: a 2.2 A resolution structure in a hexagonal crystal form. Protein Sci 7:837–847PubMedCrossRefGoogle Scholar
  176. Yang G, Wiles J, Patel D et al (2012) Preclinical characteristics of of ACH-3102: a novel HCV NS5A inhibitor with imporved potency against genotype-1a virus and variants resistant to 1st generation of NS5A inhibitors. J Hepatol 56(2):S330CrossRefGoogle Scholar
  177. Yi G, Deval J, Fan B et al (2012) Biochemical study of the comparative inhibition of hepatitis C virus RNA polymerase by VX-222 and filibuvir. Antimicrob Agents Chemother 56:830–837PubMedCrossRefGoogle Scholar
  178. Zeuzem S, Buggisch P, Agarwal K et al (2012a) The protease inhibitor, GS-9256, and non-nucleoside polymerase inhibitor tegobuvir alone, with ribavirin, or pegylated interferon plus ribavirin in hepatitis C. Hepatology 55:749–758PubMedCrossRefGoogle Scholar
  179. Zeuzem S, Soriano A, Asselah T et al (2012b) Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor BI 201335 and the non-nucleoside NS5B inhibitor BI 207127 ± ribavirin (R): final results of SOUND-C2 and predictors of response. In: Abstracts 232 of the 63rd annual meeting of the american association for the study of liver diseases, Boston, Massachusetts, 9–13 Nov 2012Google Scholar
  180. Zhou XJ, Pietropaolo K, Chen J et al (2011) Safety and pharmacokinetics of IDX184, a liver-targeted nucleotide polymerase inhibitor of hepatitis C virus, in healthy subjects. Antimicrob Agents Chemother 55:76–81PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Leen Delang
    • 1
  • Johan Neyts
    • 1
  • Inge Vliegen
    • 1
  • Sergio Abrignani
    • 2
  • Petra Neddermann
    • 2
  • Raffaele De Francesco
    • 2
  1. 1.Rega Institute for Medical ResearchKU LeuvenLeuvenBelgium
  2. 2.Istituto Nazionale Genetica Molecolare (INGM)MilanItaly

Personalised recommendations