The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors

PLoS Pathogens

Volumn 8, Issue 7, 2012, Pages 22-

  Romano, Keith P ^a   Ali, Akbar ^a   Aydin, Cihan ^a   Soumana, Djade ^a   Özen, Ayşegül ^a   Deveau, Laura M ^a   Silver, Casey ^a   Cao, Hong ^a   Newton, Alicia ^b   Petropoulos, Christos J ^b   Huang, Wei ^b   Schiffer, Celia A ^a  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^b MONOGRAM BIOSCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DANOPREVIR; MK 5172; NONSTRUCTURAL PROTEIN 3; NONSTRUCTURAL PROTEIN 4A; PROTEINASE; PROTEINASE INHIBITOR; TELAPREVIR; UNCLASSIFIED DRUG; VANIPREVIR; ANTIVIRUS AGENT; DRUG DERIVATIVE; INDOLE DERIVATIVE; LACTAM; MK-7009; N (3 AMINO 1 (CYCLOBUTYLMETHYL) 2,3 DIOXOPROPYL) 3 (2 ((((1,1 DIMETHYLETHYL)AMINO)CARBONYL)AMINO) 3,3 DIMETHYL 1 OXOBUTYL) 6,6 DIMETHYL 3 AZABICYCLO(3.1.0)HEXAN 2 CARBOXAMIDE; N-(3-AMINO-1-(CYCLOBUTYLMETHYL)-2,3-DIOXOPROPYL)-3-(2-((((1,1-DIMETHYLETHYL)AMINO)CARBONYL)AMINO)-3,3-DIMETHYL-1-OXOBUTYL)-6,6-DIMETHYL-3-AZABICYCLO(3.1.0)HEXAN-2-CARBOXAMIDE; NS3 PROTEIN, HEPATITIS C VIRUS; OLIGOPEPTIDE; PROLINE; SULFONAMIDE; VIRUS PROTEIN;

ARTICLE; CONFORMATION; CRYSTAL STRUCTURE; DRUG SENSITIVITY; ENZYME ASSAY; HEPATITIS C; HEPATITIS C VIRUS; MUTATION; NONHUMAN; WILD TYPE; ANTIVIRAL RESISTANCE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; DRUG EFFECT; GENETICS; HUMAN; METABOLISM; PROTEIN TERTIARY STRUCTURE; STRUCTURE ACTIVITY RELATION; VIROLOGY;

HEPATITIS C VIRUS;

ANTIVIRAL AGENTS; DRUG RESISTANCE, VIRAL; HEPACIVIRUS; HEPATITIS C; HUMANS; INDOLES; LACTAMS; MODELS, MOLECULAR; OLIGOPEPTIDES; PROLINE; PROTEASE INHIBITORS; PROTEIN STRUCTURE, TERTIARY; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; VIRAL NONSTRUCTURAL PROTEINS;

EID: 84864602817     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1002832     Document Type: Article

References (65)

1. Shepard CW, Finelli L, Alter MJ, (2005) Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 5: 558-567.
2. Lavanchy D, (2009) The global burden of hepatitis C. Liver Int 29: 74-81.
3. Simmonds P, Bukh J, Combet C, Deléage G, Enomoto N, et al. (2005) Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 42: 962-973.
4. Liang TJ, Heller T, (2004) Pathogenesis of hepatitis C-associated hepatocellular carcinoma. Gastroenterology 127: S62-S71.
5. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB, (2011) An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 54: 1433-1444.
6. McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, et al. (2009) Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 360: 1827-1838.
7. Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, 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: 705-716.
8. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, et al. (2011) Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364: 2405-2416.
9. Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, et al. (2009) Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 360: 1839-1850.
10. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, et al. (2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364: 1195-1206.
11. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, et al. (2009) Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461: 399-401.
12. Fried MW, (2002) Side effects of therapy of hepatitis C and their management. Hepatology 36: S237-S244.
13. Kolykhalov AA, Mihalik K, Feinstone SM, Rice CM, (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.
14. Li K, Foy E, Ferreon JC, Nakamura M, Ferreon AC, et al. (2005) 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 102: 2992-2997.
15. Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, et al. (2003) Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300: 1145-1148.
16. Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, et al. (2003) An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426: 186-189.
17. Hinrichsen H, Benhamou Y, Wedemeyer H, Reiser M, Sentjens RE, et al. (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.
18. Vanwolleghem T, Meuleman P, Libbrecht L, Roskams T, De Vos R, et al. (2007) Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse. Gastroenterology 133: 1144-1155.
19. Malcolm BA, Liu R, Lahser F, Agrawal S, Belanger B, et al. (2006) SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother 50: 1013-1020.
20. Perni RB, Almquist SJ, Byrn RA, Chandorkar G, Chaturvedi PR, et al. (2006) Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother 50: 899-909.
21. Kwong AD, Kauffman RS, Hurter P, Mueller P, (2011) Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat Biotech 29: 993-1003.
22. McPhee F, (2010) Identification and preclinical profile of the novel HCV NS3 protease inhibitor BMS-650032. J Hepatol 52: S296.
23. White PW, Llinàs-Brunet M, Amad Ma, Bethell RC, Bolger G, 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: 4611-4618.
24. Seiwert SD, Andrews SW, Jiang Y, Serebryany V, Tan H, et al. (2008) Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227). Antimicrob Agents Chemother 52: 4432-4441.
25. Lin T-I, Lenz O, Fanning G, Verbinnen T, Delouvroy F, et al. (2009) In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrob Agents Chemother 53: 1377-1385.
26. Liverton NJ, Carroll SS, DiMuzio J, Fandozzi C, Graham DJ, et al. (2010) MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease. Antimicrob Agents Chemother 54: 305-311.
27. Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, et al. (2012) Discovery of MK-5172, a macrocyclic hepatitis C virus NS3/4a protease inhibitor. ACS Med Chem Lett DOI:10.1021/ml300017p.
28. Adiwijaya BS, Hare B, Caron PR, Randle JC, Neumann AU, et al. (2009) Rapid decrease of wild-type hepatitis C virus on telaprevir treatment. Antivir Ther 14: 591-595.
29. Manns MP, Bourlière M, Benhamou Y, Pol S, Bonacini M, 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: 1114-1122.
30. Lim SR, Qin X, Susser S, Nicholas JB, Lange C, et al. (2012) Virologic escape during danoprevir (ITMN-191/RG7227) monotherapy is hepatitis C virus subtype dependent and associated with R155K substitution. Antimicrob Agents Chemother 56: 271-279.
31. Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, et al. (2006) Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 131: 997-1002.
32. Manns M, Reesink H, Berg T, Dusheiko G, Flisiak R, et al. (2011) Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial. Antivir Ther 16: 1021-1033.
33. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, et al. (2011) Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 364: 1207-1217.
34. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, et al. (2011) Telaprevir for retreatment of HCV infection. N Engl J Med 364: 2417-2428.
35. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, et al. (1998) Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282: 103-107.
36. Rong L, Dahari H, Ribeiro RM, Perelson AS, (2010) Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2: 30ra32.
37. Sarrazin C, Zeuzem S, (2010) Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 138: 447-462.
38. Kieffer TL, Kwong AD, Picchio GR, (2010) Viral resistance to specifically targeted antiviral therapies for hepatitis C (STAT-Cs). J Antimicrob Chemother 65: 202-212.
39. Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N, et al. (2007) Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 46: 631-639.
40. Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Muh U, et al. (2007) Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 132: 1767-1777.
41. Susser S, Welsch C, Wang Y, Zettler M, Domingues FS, et al. (2009) Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology 50: 1709-1718.
42. Manns MP, Gane E, Rodriguez-Torres M, Stoehr A, Yeh CT, et al. (2009) MK-7009 significantly improves rapid viral response (RVR) in combination with pegylated interferon alfa-2a and ribavirin in patients with chronic hepatitis c (CHC) genotype 1 infection. J Hepatol 50: S384.
43. Romano KP, Ali A, Royer WE, Schiffer CA, (2010) Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding. Proc Natl Acad Sci U S A 107: 20986-20991.
44. He Y, King MS, Kempf DJ, Lu L, Lim HB, et al. (2008) Relative replication capacity and selective advantage profiles of protease inhibitor-resistant hepatitis C virus (HCV) NS3 protease mutants in the HCV genotype 1b replicon system. Antimicrob Agents Chemother 52: 1101-1110.
45. Cummings MD, Lindberg J, Lin TI, de Kock H, Lenz O, et al. (2010) Induced-fit binding of the macrocyclic noncovalent inhibitor TMC435 to its HCV NS3/NS4A protease target. Angew Chem Int Ed Engl 49: 1652-1655.
46. Bae A, Sun S-C, Qi X, Chen X, Ku K, et al. (2010) Susceptibility of treatment-naive hepatitis C Virus (HCV) clinical isolates to HCV protease inhibitors. Antimicrob Agents Chemother 54: 5288-5297.
47. Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, et al. (2010) In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother 54: 1878-1887.
48. Zhou Y, Muh U, Hanzelka BL, Bartels DJ, Wei Y, et al. (2007) Phenotypic and structural analyses of hepatitis C virus NS3 protease Arg155 variants: sensitivity to telaprevir (VX-950) and interferon alpha. J Biol Chem 282: 22619-22628.
49. Gottwein JM, Scheel TKH, Jensen TB, Ghanem L, Bukh J, (2011) Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses. Gastroenterology 141: 1067-1079.
50. McCauley JA, McIntyre CJ, Rudd MT, Nguyen KT, Romano JJ, et al. (2010) Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor. J Med Chem 53: 2443-2463.
51. Wittekind M, Weinheirner S, Zhang Y, Goldfarb V, (2002) Modified forms of hepatitis C NS3 protease for facilitating inhibitor screening and structural studies of protease:inhibitor complexes. US Patent pp. 6333186.
52. Taremi SS, Beyer B, Maher M, Yao N, Prosise W, et al. (1998) Construction, expression, and characterization of a novel fully activated recombinant single-chain hepatitis C virus protease. Protein Sci 7: 2143-2149.
53. Drummond AJ, Ashton B, Buxton S, Cheung M, Cooper A, et al. (2011) Geneious v5.4. Available fromhttp://www.geneious.com/.
54. Sarkar G, Sommer SS, (1990) The "megaprimer" method of site-directed mutagenesis. Biotechniques 8: 404-407.
55. Gallinari P, Brennan D, Nardi C, Brunetti M, Tomei L, et al. (1998) Multiple enzymatic activities associated with recombinant NS3 protein of hepatitis C virus. J Virol 72: 6758-6769.
56. Otwinowski Z, Minor W, (1997) Processing of X-ray Diffraction Data Collected in Oscillation Mode. In: Carter JRMS CW, editors. Methods in Enzymology pp. 307-326 Volume 276: Macromolecular Crystallography, part A.
57. McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, et al. (2007) Phaser crystallographic software. J Appl Crystallogr 40: 658-674.
58. Collaborative Computational Project N (1994) The CCP4 Suite: Programs for Protein Crystallography. Acta Crystallographica 50: 760-763.
59. Davis IW, Leaver-Fay A, Chen VB, Block JN, Kapral GJ, et al. (2007) MolProbity: all-atom contacts and structure validation for proteins and nucleic acids. Nucleic Acids Res 35: W375-W383.
60. Brunger AT, (1992) Free R value: a novel statistical quantity for assessing the accuracy of crystal structures. Nature 355: 472-475.
61. Emsley P, Cowtan K, (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60: 2126-2132.
62. Adams PD, Afonine PV, Bunkoczi G, Chen VB, Davis IW, et al. (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 66: 213-221.
63. DeLano WL, (2008) The PyMOL Molecular Graphics System San Carlos, CA DeLano Scientific LLC.
64. Yao N, Reichert P, Taremi SS, Prosise WW, Weber PC, (1999) Molecular views of viral polyprotein processing revealed by the crystal structure of the hepatitis C virus bifunctional protease-helicase. Structure 7: 1353-1363.
65. Nalam MN, Ali A, Altman MD, Reddy GS, Chellappan S, et al. (2010) Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance. J Virol 84: 5368-5378.