Mutations conferring resistance to a hepatitis C virus (HCV) RNA-dependent RNA polymerase inhibitor alone or in combination with an HCV serine protease inhibitor in vitro

Antimicrobial Agents and Chemotherapy

Volumn 49, Issue 10, 2005, Pages 4305-4314

  Mo, Hongmei ^a,b   Lu, Liangjun ^a   Pilot Matias, Tami ^a   Pithawalla, Ron ^a   Mondal, Rubina ^a   Masse, Sherie ^a   Dekhtyar, Tatyana ^a   Ng, Teresa ^a   Koev, Gennadiy ^a   Stoll, Vincent ^a   Stewart, Kent D ^a   Pratt, John ^a   Donner, Pam ^a   Rockway, Todd ^a   Maring, Clarence ^a   Molla, Akhteruzzaman ^a  

^a ABBOTT LABORATORIES   (United States)

^b Building AP52 N ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

A 782759; CILUPREVIR; ENZYME INHIBITOR; NEOMYCIN; NUCLEOSIDE DERIVATIVE; RECOMBINANT ALPHA INTERFERON; RNA DIRECTED RNA POLYMERASE INHIBITOR; SERINE PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; VIRUS RNA;

ARTICLE; CONTROLLED STUDY; DRUG POTENCY; DRUG SELECTIVITY; GENE MUTATION; HEPATITIS C; HEPATITIS C VIRUS; IN VITRO STUDY; MOLECULAR CLONING; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; REPLICON; RNA TRANSCRIPTION; VIRUS REPLICATION;

BINDING SITES; CELL LINE; DRUG RESISTANCE, VIRAL; ENZYME INHIBITORS; HEPACIVIRUS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; MUTATION; PROTEIN BINDING; REPLICON; RNA REPLICASE; RNA, VIRAL; SERINE PROTEINASE INHIBITORS;

EID: 25844466713     PISSN: 00664804     EISSN: None     Source Type: Journal    
DOI: 10.1128/AAC.49.10.4305-4314.2005     Document Type: Article

References (59)

1. Bartenschlager, R. 1999. The NS3/4A proteinase of the hepatitis C virus: unravelling structure and function of an unusual enzyme and a prime target for antiviral therapy. J. Viral Hepat. 6:165-181.
2. Bartenschlager, R., L. Ahlborn-Laake, J. Mous, and H. Jacobsen. 1994. Kinetic and structural analyses of hepatitis C virus polyprotein processing. J. Virol. 68:5045-5055.
3. Beaulieu, P. 2004. Allosteric inhibitors of the hepatitis C virus NS5B polymerase: towards novel anti-HCV therapies, abstr. 1. Abstr. 29th Nat. Med. Chem. Symp. American Chemical Society and University of Wisconsin-Madison, Madison, Wis.
4. Behrens, S. E., L. Tomei, and R. De Francesco. 1996. Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. EMBO J. 15:12-22.
5. Carroll, S. S., J. E. Tomassini, M. Bosserman, K. Getty, M. W. Stahlhut, A. B. Eldrup, B. Bhat, D. Hall, A. L. Simcoe, R. LaFemina, C. A. Rutkowski, B. Wolanski, Z. Yang, G. Migliaccio, R. De Francesco, L. C. Kuo, M. MacCoss, and D. B. Olsen. 2003. Inhibition of hepatitis C virus RNA replication by 2′-modified nucleoside analogs. J. Biol. Chem. 278:11979-11984.
6. Chan, L., O. Pereira, T. J. Reddy, S. K. Das, C. Poisson, M. Courchesne, M. Proulx, A. Siddiqui, C. G. Yannopoulos, N. Nguyen-Ba, C. Roy, D. Nasturica, C. Moinet, R. Bethell, M. Hamel, L. L'Heureux, M. David, O. Nicolas, P. Courtemanche-Asselin, S. Brunette, D. Bilimoria, and J. Bedard. 2004. Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 2. Tertiary amides. Bioorg. Med. Chem. Lett. 14:797-800.
7. Cheeseman, S. H., D. Havlir, M. M. McLaughlin, T. C. Greenough, J. L. Sullivan, D. Hall, S. E. Hattox, S. A. Spector, D. S. Stein, M. Myers, et al. 1995. Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 8:141-151.
8. Coulombe, R., P. L. Beaulieu, E. Jolicoeur, G. Kukolj, S. Laplante, and M. A. Poupart. 18 Nov. Hepatititis C virus NS5B polymerase inhibitor binding pocket. Int. Patent Appl. WO 2004099241 A1.
9. Davis, G. L. 1999. Combination therapy with interferon alfa and ribavirin as retreatment of interferon relapse in chronic hepatitis C. Semin. Liver Dis. 19(Suppl. 1):49-55.
10. Davis, G. L. 1999. Combination treatment with interferon and ribavirin for chronic hepatitis C. Clin. Liver Dis. 3:811-826.
11. Davis, G. L., R. Esteban-Mur, V. Rustgi, J. Hoefs, S. C. Gordon, C. Trepo, M. L. Shiffman, S. Zeuzem, A. Craxi, M. H. Ling, J. Albrecht, et al. 1998. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N. Engl. J. Med. 339:1493-1499.
12. De Francesco, R., L. Tomei, S. Altamura, V. Summa, and G. Migliaccio. 2003. Approaching a new era for hepatitis C virus therapy: inhibitors of the NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase. Antivir. Res. 58:1-16.
13. Dhanak, D., K. J. Duffy, V. K. Johnston, J. Lin-Goerke, M. Darcy, A. N. Shaw, B. Gu, C. Silverman, A. T. Gates, M. R. Nonnemacher, D. L. Earnshaw, D. J. Casper, A. Kaura, A. Baker, C. Greenwood, L. L. Gutshall, D. Maley, A. DelVecchio, R. Macarron, G. A. Hofmann, Z. Alnoah, H. Y. Cheng, G. Chan, S. Khandekar, R. M. Keenan, and R. T. Sarisky. 2002. Identification and biological characterization of heterocyclic inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. J. Biol. Chem. 277:38322-38327.
14. Di Bisceglie, A. M., and J. H. Hoofnagle. 2002. Optimal therapy of hepatitis C. Hepatology 36:S121-S127.
15. Duffy, K. J. 2004. The discovery of benzo(1,2,4) thiadiazine as non-nucleoside hepatitis C virus NS5B polymerase inhibitors, abstr. 2. Abstr. 29th Nat. Med. Chem. Symp. American Chemical Society and University of Wisconsin-Madison, Madison, Wis.
16. Eldrup, A. B., M. Prhavc, J. Brooks, B. Bhat, T. P. Prakash, Q. Song, S. Bera, N. Bhat, P. Dande, P. D. Cook, C. F. Bennett, S. S. Carroll, R. G. Ball, M. Bosserman, C. Burlein, L. F. Colwell, J. F. Fay, O. A. Flores, K. Getty, R. L. LaFemina, J. Leone, M. MacCoss, D. R. McMasters, J. E. Tomassini, D. Von Langen, B. Wolanski, and D. B. Olsen. 2004. Structure-activity relationship of heterobase-modified 2′-C-methyl ribonucleosides as inhibitors of hepatitis C virus RNA replication. J. Med. Chem. 47:5284-5297.
17. Frecer, V., M. Kabelac, P. De Nardi, S. Pricl, and S. Miertus. 2004. Structure-based design of inhibitors of NS3 serine protease of hepatitis C virus. J. Mol. Graph Model. 22:209-220.
18. Fried, M. W., M. L. Shiffman, K. R. Reddy, C. Smith, G. Marinos, F. L. Goncales, Jr., D. Haussinger, M. Diago, G. Carosi, D. Dhumeaux, A. Craxi, A. Lin, J. Hoffman, and J. Yu. 2002. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med. 347:975-982.
19. Godofsky, E. 2004. Phase I/II dose escalation trial assessing tolerance, pharmacokinetics, and antiviral activity of NM283, a novel antiviral treatment for hepatitis C, abstr. 407. Abstr. Dig. Dis. Week 2004. Medscape, New Orleans, La.
20. Gopalsamy, A., K. Lim, G. Ciszewski, K. Park, J. W. Ellingboe, J. Bloom, S. Insaf, J. Upeslacis, T. S. Mansour, G. Krishnamurthy, M. Damarla, Y. Pyatski, D. Ho, A. Y. Howe, M. Orlowski, B. Feld, and J. O'Connell. 2004. Discovery of pyrano[3,4-b]indoles as potent and selective HCV NS5B polymerase inhibitors. J. Med. Chem. 47:6603-6608.
21. Grakoui, A., D. W. McCourt, C. Wychowski, S. M. Feinstone, and C. M. Rice. 1993. Characterization of the hepatitis C virus-encoded serine proteinase: determination of proteinase-dependent polyprotein cleavage sites. J. Virol. 67:2832-2843.
22. Gu, B., V. K. Johnston, L. L. Gutshall, T. T. Nguyen, R. R. Gontarek, M. G. Darcy, R. Tedesco, D. Dhanak, K. J. Duffy, C. C. Kao, and R. T. Sarisky. 2003. Arresting initiation of hepatitis C virus RNA synthesis using heterocyclic derivatives. J. Biol. Chem. 278:16602-16607.
23. Hinrichsen, H., Y. Benhamou, H. Wedemeyer, M. Reiser, R. E. Sentjens, J. L. Calleja, X. Forns, A. Erhardt, J. Cronlein, R. L. Chaves, C. L. Yong, G. Nehmiz, and G. G. Steinmann. 2004. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology 127:1347-1355.
24. Huang, H., R. Chopra, G. L. Verdine, and S. C. Harrison. 1998. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 282:1669-1675.
25. Johnston, V. K., D. Maley, R. C. Gagnon, C. W. Grassmann, S. E. Behrens, and R. T. Sarisky. 2003. Kinetic profile of a heterocyclic HCV replicon RNA synthesis inhibitor. Biochem. Biophys. Res. Commun. 311:672-677.
26. Kolykhalov, A. A., K. Mihalik, S. M. Feinstone, and C. M. Rice. 2000. Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo. J. Virol. 74:2046-2051.
27. Lesburg, C. A., M. B. Cable, E. Ferrari, Z. Hong, A. F. Mannarino, and P. C. Weber. 1999. Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat. Struct. Biol. 6:937-943.
28. Lin, C., K. Lin, Y. P. Luong, B. G. Rao, Y. Y. Wei, D. L. Brennan, J. R. Fulghum, H. M. Hsiao, S. Ma, J. P. Maxwell, K. M. Cottrell, R. B. Perni, C. A. Gates, and A. D. Kwong. 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. 279:17508-17514.
29. Lindenbach, B. D., and C. M. Rice. 2003. Evasive maneuvers by hepatitis C virus. Hepatology 38:769-771.
30. Llinas-Brunet, M., M. D. Bailey, G. Bolger, C. Brochu, A. M. Faucher, J. M. Ferland, M. Garneau, E. Ghiro, V. Gorys, C. Grand-Maitre, T. Halmos, N. Lapeyre-Paquette, F. Liard, M. Poirier, M. Rheaume, Y. S. Tsantrizos, and D. Lamarre. 2004. Structure-activity study on a novel series of macrocyclic inhibitors of the hepatitis C virus NS3 protease leading to the discovery of BILN 2061. J. Med. Chem. 47:1605-1608.
31. Lohmann, V., F. Korner, U. Herian, and R. Bartenschlager. 1997. Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity. J. Virol. 71:8416-8428.
32. Lohmann, V., A. Roos, F. Korner, J. O. Koch, and R. Bartenschlager. 1998. Biochemical and kinetic analyses of NS5B RNA-dependent RNA polymerase of the hepatitis C virus. Virology 249:108-118.
33. Love, R. A., H. E. Parge, X. Yu, M. J. Hickey, W. Diehl, J. Gao, H. Wriggers, A. Ekker, L. Wang, J. A. Thomson, P. S. Dragovich, and S. A. Fuhrman. 2003. Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C virus NS5B RNA polymerase enzyme. J. Virol. 77:7575-7581.
34. Lu, L., T. J. Pilot-Matias, K. D. Stewart, J. T. Randolph, R. Pithawalla, W. He, P. P. Huang, L. L. Klein, H. Mo, and A. Molla. 2004. Mutations conferring resistance to a potent hepatitis C virus serine protease inhibitor in vitro. Antimicrob. Agents Chemother. 48:2260-2266.
35. McHutchison, J. G., S. C. Gordon, E. R. Schiff, M. L. Shiffman, W. M. Lee, V. K. Rustgi, Z. D. Goodman, M. H. Ling, S. Cort, J. K. Albrecht, et al. 1998. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N. Engl. J. Med. 339:1485-1492.
36. Migliaccio, G., J. E. Tomassini, S. S. Carroll, L. Tomei, S. Altamura, B. Bhat, L. Bartholomew, M. R. Bosserman, A. Ceccacci, L. F. Colwell, R. Cortese, R. De Francesco, A. B. Eldrup, K. L. Getty, X. S. Hou, R. L. LaFemina, S. W. Ludmerer, M. MacCoss, D. R. McMasters, M. W. Stahlhut, D. B. Olsen, D. J. Hazuda, and O. A. Flores. 2003. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J. Biol. Chem. 278:49164-49170.
37. Mo, H., L. Lu, T. Dekhtyar, K. D. Stewart, E. Sun, D. J. Kempf, and A. Molla. 2003. Characterization of resistant HIV variants generated by in vitro passage with lopinavir/ritonavir. Antivir. Res. 59:173-180.
38. Molla, A., M. Korneyeva, Q. Gao, S. Vasavanonda, P. J. Schipper, H. M. Mo, M. Markowitz, T. Chernyavskiy, P. Niu, N. Lyons, A. Hsu, G. R. Granneman, D. D. Ho, C. A. Boucher, J. M. Leonard, D. W. Norbeck, and D. J. Kempf. 1996. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat. Med. 2:760-766.
39. Nguyen, T. T., A. T. Gates, L. L. Gutshall, V. K. Johnston, B. Gu, K. J. Duffy, and R. T. Sarisky. 2003. Resistance profile of a hepatitis C virus RNA-dependent RNA polymerase benzothiadiazine inhibitor. Antimicrob. Agents Chemother. 47:3525-3530.
40. Ni, Z. J., and A. S. Wagman. 2004. Progress and development of small molecule HCV antivirals. Curr. Opin. Drug Discov. Devel. 7:446-459.
41. Olsen, D. B., A. B. Eldrup, L. Bartholomew, B. Bhat, M. R. Bosserman, A. Ceccacci, L. F. Colwell, J. F. Fay, O. A. Flores, K. L. Getty, J. A. Grobler, R. L. LaFemina, E. J. Markel, G. Migliaccio, M. Prhavc, M. W. Stahlhut, J. E. Tomassini, M. MacCoss, D. J. Hazuda, and S. S. Carroll. 2004. A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrob. Agents Chemother. 48:3944-3953.
42. Pace, P., E. Nizi, B. Pacini, S. Pesci, V. Matassa, R. De Francesco, S. Altamura, and V. Summa. 2004. The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase. Bioorg. Med. Chem. Lett. 14:3257-3261.
43. Pause, A., G. Kukolj, M. Bailey, M. Brault, F. Do, T. Halmos, L. Lagace, R. Maurice, M. Marquis, G. McKercher, C. Pellerin, L. Pilote, D. Thibeault, and D. Lamarre. 2003. An NS3 serine protease inhibitor abrogates replication of subgenomic hepatitis C virus RNA. J. Biol. Chem. 278:20374-20380.
44. Pauwels, R., J. Balzarini, M. Baba, R. Snoeck, D. Schols, P. Herdewijn, J. Desmyter, and E. De Clercq. 1988. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods 20:309-321.
45. Pratt, J. K., D. Beno, P. Donner, W. Jiang, W. Kati, D. J. Kempf, G. Koev, D. Liu, Y. Liu, C. Maring, S. Masse, T. Middleton, H. Mo, A. Molla, D. Montgomery, and Q. Xie. 2004. N-1-AZA-4-hydroxyquinolone benzothiadianes: inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase exhibiting replication potency and favorable rat pharmacokinetics, abstr. 1224a. Abstr. 55th Ann. Meet. Am. Assoc. Study Liver Dis.
46. Ramratnam, B., S. Bonhoeffer, J. Binley, A. Hurley, L. Zhang, J. E. Mittler, M. Markowitz, J. P. Moore, A. S. Perelson, and D. D. Ho. 1999. Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis. Lancet 354:1782-1785.
47. Sarisky, R. T. 2004. Non-nucleoside inhibitors of the HCV polymerase. J. Antimicrob Chemother. 54:14-16.
48. Shulman, N., and M. Winters. 2003. A review of HIV-1 resistance to the nucleoside and nucleotide inhibitors. Curr. Drug Targets Infect. Disord. 3:273-281.
49. Sommadossi, J. P., and P. Lacolla. 29 Nov. 2001. Methods and compositions for treating hepatitis C virus. Int. patent appl. WO 0190121 A2.
50. Stansfield, I., S. Avolio, S. Colarusso, N. Gennari, F. Narjes, B. Pacini, S. Ponzi, and S. Harper. 2004. Active site inhibitors of HCV NS5B polymerase. The development and pharmacophore of 2-thienyl-5,6- dihydroxypyrimidine-4-carboxylic acid. Bioorg. Med. Chem. Lett. 14:5085-5088.
51. Summa, V., A. Petrocchi, P. Pace, V. G. Matassa, R. De Francesco, S. Altamura, L. Tomei, U. Koch, and P. Neuner. 2004. Discovery of α,γ-diketo acids as potent selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase. J. Med. Chem. 47:14-17.
52. Tomei, L., S. Altamura, L. Bartholomew, A. Biroccio, A. Ceccacci, L. Pacini, F. Narjes, N. Gennari, M. Bisbocci, I. Incitti, L. Orsatti, S. Harper, I. Stansfield, M. Rowley, R. De Francesco, and G. Migliaccio. 2003. Mechanism of action and antiviral activity of benzimidazole-based allosteric inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. J. Virol. 77:13225-13231.
53. Tomei, L., S. Altamura, L. Bartholomew, M. Bisbocci, C. Bailey, M. Bosserman, A. Cellucci, E. Forte, I. Incitti, L. Orsatti, U. Koch, R. De Francesco, D. B. Olsen, S. S. Carroll, and G. Migliaccio. 2004. Characterization of the inhibition of hepatitis C virus RNA replication by nonnucleosides. J. Virol. 78:938-946.
54. Trozzi, C., L. Bartholomew, A. Ceccacci, G. Biasiol, L. Pacini, S. Altamura, F. Narjes, E. Muraglia, G. Paonessa, U. Koch, R. De Francesco, C. Steinkuhler, and G. Migliaccio. 2003. In vitro selection and characterization of hepatitis C virus serine protease variants resistant to an active-site peptide inhibitor. J. Virol. 77:3669-3679.
55. Tsantrizos, Y. S. 2004. The design of a potent inhibitor of the hepatitis C virus NS3 protease: BILN 2061-from the NMR tube to the clinic. Biopolymers 76:309-323.
56. Tsantrizos, Y. S., G. Bolger, P. Bonneau, D. R. Cameron, N. Goudreau, G. Kukolj, S. R. LaPlante, M. Llinas-Brunet, H. Nar, and D. Lamarre. 2003. Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection. Angew. Chem. Int. Ed. Engl. 42:1356-1360.
57. Wang, M., K. K. Ng, M. M. Cherney, L. Chan, C. G. Yannopoulos, J. Bedard, N. Morin, N. Nguyen-Ba, M. H. Alaoui-Ismaili, R. C. Bethell, and M. N. James. 2003. Non-nucleoside analogue inhibitors bind to an allosteric site on HCV NS5B polymerase. Crystal structures and mechanism of inhibition. J. Biol. Chem. 278:9489-9495.
58. Yi, M., F. Bodola, and S. M. Lemon. 2002. Subgenomic hepatitis C virus replicons inducing expression of a secreted enzymatic reporter protein. Virology 304:197-210.
59. Yip, Y., F. Victor, J. Lamar, R. Johnson, Q. M. Wang, D. Barket, J. Glass, L. Jin, L. Liu, D. Venable, M. Wakulchik, C. Xie, B. Heinz, E. Villarreal, J. Colacino, N. Yumibe, M. Tebbe, J. Munroe, and S. H. Chen. 2004. Discovery of a novel bicycloproline P2 bearing peptidyl alpha-ketoamide LY514962 as HCV protease inhibitor. Bioorg. Med. Chem. Lett. 14:251-256.