About this Journal Submit a Manuscript Table of Contents
BioMed Research International
Volume 2013 (2013), Article ID 467869, 9 pages
http://dx.doi.org/10.1155/2013/467869
Review Article

Hepatitis C Virus NS3 Inhibitors: Current and Future Perspectives

Radioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

Received 29 April 2013; Accepted 8 September 2013

Academic Editor: Fumio Imazeki

Copyright © 2013 Kazi Abdus Salam and Nobuyoshi Akimitsu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. S. M. Feinstone, A. Z. Kapikian, R. H. Purcell, H. J. Alter, and P. V. Holland, “Transfusion associated hepatitis not due to viral hepatitis type A or B,” The New England Journal of Medicine, vol. 292, no. 15, pp. 767–770, 1975. View at Scopus
  2. Q.-L. Choo, G. Kuo, A. J. Weiner, L. R. Overby, D. W. Bradley, and M. Houghton, “Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome,” Science, vol. 244, no. 4902, pp. 359–362, 1989. View at Scopus
  3. L. Gravitz, “Introduction: a smouldering public-health crisis,” Nature, vol. 474, no. 7350, pp. S2–S4, 2011. View at Publisher · View at Google Scholar · View at Scopus
  4. D. Lavanchy, “Evolving epidemiology of hepatitis C virus,” Clinical Microbiology and Infection, vol. 17, no. 2, pp. 107–115, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. A. Takamizawa, C. Mori, I. Fuke et al., “Structure and organization of the hepatitis C virus genome isolated from human carriers,” Journal of Virology, vol. 65, no. 3, pp. 1105–1113, 1991. View at Scopus
  6. T. Nakano, G. M. G. Lau, G. M. L. Lau, M. Sugiyama, and M. Mizokami, “An updated analysis of hepatitis C virus genotypes and subtypes based on the complete coding region,” Liver International, vol. 32, no. 2, pp. 339–345, 2012. View at Publisher · View at Google Scholar · View at Scopus
  7. D. Moradpour, F. Penin, and C. M. Rice, “Replication of hepatitis C virus,” Nature Reviews Microbiology, vol. 5, no. 6, pp. 453–463, 2007. View at Publisher · View at Google Scholar · View at Scopus
  8. C. M. T. Spahn, J. S. Kieft, R. A. Grassucci et al., “Hepatitis C virus IRES RNA-induced changes in the conformation of the 40S ribosomal subunit,” Science, vol. 291, no. 5510, pp. 1959–1962, 2001. View at Publisher · View at Google Scholar · View at Scopus
  9. H. Ji, C. S. Fraser, Y. Yu, J. Leary, and J. A. Doudna, “Coordinated assembly of human translation initiation complexes by the hepatitis C virus internal ribosome entry site RNA,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 49, pp. 16990–16995, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. G. A. Otto and J. D. Puglisi, “The pathway of HCV IRES-mediated translation initiation,” Cell, vol. 119, no. 3, pp. 369–380, 2004. View at Publisher · View at Google Scholar · View at Scopus
  11. C. M. Rice, “New insights into HCV replication: potential antiviral targets,” Topics in Antiviral Medicine, vol. 19, no. 3, pp. 117–120, 2011. View at Scopus
  12. S. D. C. Griffin, L. P. Beales, D. S. Clarke et al., “The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine,” FEBS Letters, vol. 535, no. 1–3, pp. 34–38, 2003. View at Publisher · View at Google Scholar · View at Scopus
  13. D. Pavlovic, D. C. A. Neville, O. Argaud et al., “The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 10, pp. 6104–6108, 2003. View at Publisher · View at Google Scholar · View at Scopus
  14. A. D. Branch, D. D. Stump, J. A. Gutierrez, F. Eng, and J. L. Walewski, “The hepatitis C virus alternate reading frame (ARF) and its family of novel products: the alternate reading frame protein/F-protein, the double-frameshift protein, and others,” Seminars in Liver Disease, vol. 25, no. 1, pp. 105–117, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. F. Penin, J. Dubuisson, F. A. Rey, D. Moradpour, and J. Pawlotsky, “Structural biology of hepatitis C virus,” Hepatology, vol. 39, no. 1, pp. 5–19, 2004. View at Publisher · View at Google Scholar · View at Scopus
  16. C. Tai, W. Chi, D. Chen, and L. Hwang, “The helicase activity associated with hepatitis C virus nonstructural protein 3 (NS3),” Journal of Virology, vol. 70, no. 12, pp. 8477–8484, 1996. View at Scopus
  17. M. Gu and C. M. Rice, “Three conformational snapshots of the hepatitis C virus NS3 helicase reveal a ratchet translocation mechanism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 2, pp. 521–528, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. D. N. Frick, R. S. Rypma, A. M. I. Lam, and B. Gu, “The nonstructural protein 3 protease/helicase requires an intact protease domain to unwind duplex RNA efficiently,” The Journal of Biological Chemistry, vol. 279, no. 2, pp. 1269–1280, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. P. S. Pang, E. Jankowsky, P. J. Planet, and A. M. Pyle, “The hepatitis C viral NS3 protein is a processive DNA helicase with cofactor enhanced RNA unwinding,” The EMBO Journal, vol. 21, no. 5, pp. 1168–1176, 2002. View at Publisher · View at Google Scholar · View at Scopus
  20. S. Behrens, L. Tomei, and R. de Francesco, “Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus,” The EMBO Journal, vol. 15, no. 1, pp. 12–22, 1996. View at Scopus
  21. Y. Tanji, T. Kaneko, S. Satoh, and K. Shimotohno, “Phosphorylation of hepatitis C virus-encoded nonstructural protein NS5A,” Journal of Virology, vol. 69, no. 7, pp. 3980–3986, 1995. View at Scopus
  22. L. Huang, J. Hwang, S. D. Sharma et al., “Hepatitis C virus nonstructural protein 5A (NS5A) is an RNA-binding protein,” The Journal of Biological Chemistry, vol. 280, no. 43, pp. 36417–36428, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. T. Shimakami, M. Hijikata, H. Luo et al., “Effect of interaction between hepatitis C virus NS5A and NS5B on hepatitis C virus RNA replication with the hepatitis C virus replicon,” Journal of Virology, vol. 78, no. 6, pp. 2738–2748, 2004. View at Publisher · View at Google Scholar · View at Scopus
  24. S. Reiss, I. Rebhan, P. Backes 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 and Microbe, vol. 9, no. 1, pp. 32–45, 2011. View at Publisher · View at Google Scholar · View at Scopus
  25. A. W. Tai and S. Salloum, “The role of the phosphatidylinositol 4-kinase PI4KA in hepatitis C virus-induced host membrane rearrangement,” PLoS ONE, vol. 6, no. 10, Article ID e26300, 2011. View at Publisher · View at Google Scholar · View at Scopus
  26. T. L. Tellinghuisen, K. L. Foss, and J. Treadaway, “Regulation of hepatitis C virion production via phosphorylation of the NS5A protein,” PLoS Pathogens, vol. 4, no. 3, Article ID e1000032, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. N. Appel, M. Zayas, S. Miller et al., “Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly,” PLoS Pathogens, vol. 4, no. 3, Article ID e1000035, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. D. Egger, B. Wölk, R. Gosert et al., “Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex,” Journal of Virology, vol. 76, no. 12, pp. 5974–5984, 2002. View at Publisher · View at Google Scholar · View at Scopus
  29. K. V. Konan, T. H. Giddings Jr., M. Ikeda, K. Li, S. M. Lemon, and K. Kirkegaard, “Nonstructural protein precursor NS4A/B from hepatitis C virus alters function and ultrastructure of host secretory apparatus,” Journal of Virology, vol. 77, no. 14, pp. 7843–7855, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. C. Failla, L. Tomei, and R. de Francesco, “Both NS3 and NS4A are required for proteolytic processing of hepatitis C virus nonstructural proteins,” Journal of Virology, vol. 68, no. 6, pp. 3753–3760, 1994. View at Scopus
  31. F. Poordad and D. Dieterich, “Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents,” Journal of Viral Hepatitis, vol. 19, no. 7, pp. 449–464, 2012.
  32. M. W. Fried, M. L. Shiffman, K. R. Reddy et al., “Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection,” The New England Journal of Medicine, vol. 347, no. 13, pp. 975–982, 2002. View at Publisher · View at Google Scholar · View at Scopus
  33. A. J. Muir, J. D. Bornstein, and P. G. Killenberg, “Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites,” The New England Journal of Medicine, vol. 350, no. 22, pp. 2265–2271, 2004. View at Publisher · View at Google Scholar · View at Scopus
  34. M. L. Shiffman, F. Suter, B. R. Bacon et al., “Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3,” The New England Journal of Medicine, vol. 357, no. 2, pp. 124–134, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. M. Rodriguez-Torres, L. J. Jeffers, M. Y. Sheikh et al., “Peginterferon alfa-2a and ribavirin in latino and non-latino whites with hepatitis C,” The New England Journal of Medicine, vol. 360, no. 3, pp. 257–267, 2009. View at Publisher · View at Google Scholar · View at Scopus
  36. R. Ray, “Progress toward development of a hepatitis C vaccine with broad shoulders,” Science Translational Medicine, vol. 3, no. 94, Article ID 94ps33, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. M. G. Ghany, D. B. Strader, D. L. Thomas, and L. B. Seeff, “Diagnosis, management, and treatment of hepatitis C: an update,” Hepatology, vol. 49, no. 4, pp. 1335–1374, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. European Association for the Study of the Liver, “EASL clinical practice guidelines: management of hepatitis C virus infection,” Journal of Hepatology, vol. 55, no. 2, pp. 245–264, 2011.
  39. Editors of the Drafting Committee for Hepatitis Management Guidelines: the Japan Society of Hepatology, “Guidelines for the management of hepatitis C virus infection,” Hepatology Research, vol. 43, no. 1, pp. 1–34, 2013.
  40. T. Kanda, F. Imazeki, and O. Yokosuka, “New antiviral therapies for chronic hepatitis C,” Hepatology International, vol. 4, no. 3, pp. 548–561, 2010. View at Publisher · View at Google Scholar · View at Scopus
  41. E. Lawitz, F. Poordad, K. V. Kowdley et al., “A phase 2a trial of 12-week interferon-free therapy with two direct-acting antivirals (ABT-450/r, ABT-072) and ribavirin in IL28B C/C patients with chronic hepatitis C genotype 1,” Journal of Hepatology, vol. 59, no. 1, pp. 18–23, 2013.
  42. S. Tanwar, P. M. Trembling, and G. M. Dusheiko, “TMC435 for the treatment of chronic hepatitis C,” Expert Opinion on Investigational Drugs, vol. 21, no. 8, pp. 1193–1209, 2012.
  43. S. Zeuzem, T. Asselah, P. Angus et al., “Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection,” Gastroenterology, vol. 141, no. 6, pp. 2047–2055, 2011. View at Publisher · View at Google Scholar · View at Scopus
  44. C. Cooper, “Hepatitis C treatment highlights from the 2011 American Association for the Study of Liver Disease meeting,” Clinical Infectious Diseases, vol. 55, no. 3, pp. 418–425.
  45. A. S. Lok, D. F. Gardiner, E. Lawitz et al., “Preliminary study of two antiviral agents for hepatitis C genotype 1,” The New England Journal of Medicine, vol. 366, no. 3, pp. 216–224, 2012. View at Publisher · View at Google Scholar · View at Scopus
  46. K. Chayama, S. Takahashi, J. Toyota et al., “Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders,” Hepatology, vol. 55, no. 3, pp. 742–748, 2012. View at Publisher · View at Google Scholar · View at Scopus
  47. A. A. Kolykhalov, K. Mihalik, S. M. Feinstone, and C. M. Rice, “Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo,” Journal of Virology, vol. 74, no. 4, pp. 2046–2051, 2000. View at Publisher · View at Google Scholar · View at Scopus
  48. A. M. I. Lam and D. N. Frick, “Hepatitis C virus subgenomic replicon requires an active NS3 RNA helicase,” Journal of Virology, vol. 80, no. 1, pp. 404–411, 2006. View at Publisher · View at Google Scholar · View at Scopus
  49. P. Borowski, J. Deinert, S. Schalinski et al., “Halogenated benzimidazoles and benzotriazoles as inhibitors of the NTPase/helicase activities of hepatitis C and related viruses,” European Journal of Biochemistry, vol. 270, no. 8, pp. 1645–1653, 2003. View at Publisher · View at Google Scholar · View at Scopus
  50. J. Paeshuyse, I. Vliegen, L. Coelmont et al., “Comparative in vitro anti-hepatitis C virus activities of a selected series of polymerase, protease, and helicase inhibitors,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 9, pp. 3433–3437, 2008. View at Publisher · View at Google Scholar · View at Scopus
  51. C. Chen, C. Chiou, G. S. Chen et al., “Structure-based discovery of triphenylmethane derivatives as inhibitors of hepatitis C virus helicase,” Journal of Medicinal Chemistry, vol. 52, no. 9, pp. 2716–2723, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. N. Zhang, H. Chen, V. Koch et al., “Ring-expanded (“fat”) nucleoside and nucleotide analogues exhibit potent in vitro activity against Flaviviridae NTPases/helicases, including those of the West Nile virus, hepatitis C virus, and Japanese encephalitis virus,” Journal of Medicinal Chemistry, vol. 46, no. 19, pp. 4149–4164, 2003. View at Publisher · View at Google Scholar · View at Scopus
  53. R. K. Ujjinamatada, A. Baier, P. Borowski, and R. S. Hosmane, “An analogue of AICAR with dual inhibitory activity against WNV and HCV NTPase/helicase: synthesis and in vitro screening of 4-carbamoyl-5-(4,6-diamino-2,5-dihydro-1,3,5-triazin-2-yl)imidazole-1- β-d-ribofuranoside,” Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 8, pp. 2285–2288, 2007. View at Publisher · View at Google Scholar · View at Scopus
  54. G. Maga, S. Gemma, C. Fattorusso et al., “Specific targeting of hepatitis C virus NS3 RNA helicase. Discovery of the potent and selective competitive nucleotide-mimicking inhibitor QU663,” Biochemistry, vol. 44, no. 28, pp. 9637–9644, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. P. Borowski, M. V. Heising, I. B. Miranda, C. Liao, J. Choe, and A. Baier, “Viral NS3 helicase activity is inhibited by peptides reproducing the Arg-rich conserved motif of the enzyme (motif VI),” Biochemical Pharmacology, vol. 76, no. 1, pp. 28–38, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. A. M. Boguszewska-Chachulska, M. Krawczyk, A. Najda et al., “Searching for a new anti-HCV therapy: synthesis and properties of tropolone derivatives,” Biochemical and Biophysical Research Communications, vol. 341, no. 2, pp. 641–647, 2006. View at Publisher · View at Google Scholar · View at Scopus
  57. P. Borowski, M. Lang, A. Haag, and A. Baier, “Tropolone and its derivatives as inhibitors of the helicase activity of hepatitis C virus nucleotide triphosphatase/helicase,” Antiviral Chemistry and Chemotherapy, vol. 18, no. 2, pp. 103–109, 2007. View at Scopus
  58. A. Stankiewicz-Drogon, L. G. Palchykovska, V. G. Kostina, I. V. Alexeeva, A. D. Shved, and A. M. Boguszewska-Chachulska, “New acridone-4-carboxylic acid derivatives as potential inhibitors of hepatitis C virus infection,” Bioorganic and Medicinal Chemistry, vol. 16, no. 19, pp. 8846–8852, 2008. View at Publisher · View at Google Scholar · View at Scopus
  59. A. Stankiewicz-Drogoń, B. Dörner, T. Erker, and A. M. Boguszewska-Chachulska, “Synthesis of new acridone derivatives, inhibitors of NS3 helicase, which efficiently and specifically inhibit subgenomic HCV replication,” Journal of Medicinal Chemistry, vol. 53, no. 8, pp. 3117–3126, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. G. Manfroni, J. Paeshuyse, S. Massari et al., “Inhibition of subgenomic hepatitis C virus RNA replication by acridone derivatives: identification of an NS3 helicase inhibitor,” Journal of Medicinal Chemistry, vol. 52, no. 10, pp. 3354–3365, 2009. View at Publisher · View at Google Scholar · View at Scopus
  61. C. A. Belon, Y. D. High, T. Lin, F. Pauwels, and D. N. Frick, “Mechanism and specificity of a symmetrical benzimidazolephenylcarboxamide helicase inhibitor,” Biochemistry, vol. 49, no. 9, pp. 1822–1832, 2010. View at Publisher · View at Google Scholar · View at Scopus
  62. A. Najda-Bernatowicz, M. Krawczyk, A. Stankiewicz-Drogoń, M. Bretner, and A. M. Boguszewska-Chachulska, “Studies on the anti-hepatitis C virus activity of newly synthesized tropolone derivatives: identification of NS3 helicase inhibitors that specifically inhibit subgenomic HCV replication,” Bioorganic and Medicinal Chemistry, vol. 18, no. 14, pp. 5129–5136, 2010. View at Publisher · View at Google Scholar · View at Scopus
  63. S. Gemma, S. Butini, G. Campiani et al., “Discovery of potent nucleotide-mimicking competitive inhibitors of hepatitis C virus NS3 helicase,” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 9, pp. 2776–2779, 2011. View at Publisher · View at Google Scholar · View at Scopus
  64. K. A. Salam, A. Furuta, N. Noda et al., “Inhibition of hepatitis C virus NS3 helicase by manoalide,” Journal of Natural Products, vol. 75, no. 4, pp. 650–654, 2012.
  65. K. Li, K. J. Frankowski, C. A. Belon et al., “Optimization of potent hepatitis C virus NS3 helicase inhibitors isolated from the yellow dyes thioflavine S and primuline,” Journal of Medicinal Chemistry, vol. 55, no. 7, pp. 3319–3330, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. A. Yamashita, K. A. Salam, A. Furuta et al., “Inhibition of hepatitis C virus replication and viral helicase by ethyl acetate extract of the marine feather star Alloeocomatella polycladia,” Marine Drugs, vol. 10, no. 4, pp. 744–761, 2012. View at Publisher · View at Google Scholar · View at Scopus
  67. S. Mukherjee, A. M. Hanson, W. R. Shadrick et al., “Identification and analysis of hepatitis C virus NS3 helicase inhibitors using nucleic acid binding assays,” Nucleic Acids Research, vol. 40, no. 17, pp. 8607–8621, 2012.
  68. Y. Fujimoto, K. A. Salam, A. Furuta et al., “Inhibition of both protease and helicase activities of hepatitis C virus NS3 by an ethyl acetate extract of marine sponge Amphimedon sp.,” PLos ONE, vol. 7, no. 11, Article ID e48685, 2012.
  69. K. A. Salam, A. Furuta, N. Noda et al., “Psammaplin A inhibits hepatitis C virus NS3 helicase,” Journal of Natural Medicines, vol. 67, no. 4, pp. 765–772, 2013.
  70. A. Furuta, K. A. Salam, N. Akimitsu et al., “Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase,” Journal of Enzyme Inhibition and Medicinal Chemistry. In press.
  71. T. J. Liang and M. G. Ghany, “Current and future therapies for hepatitis C virus infection,” The New England Journal of Medicine, vol. 368, no. 20, pp. 1907–1917, 2013.