Mechanism of inhibition for BMS-791325, a novel non-nucleoside inhibitor of hepatitis C virus NS5B polymerase

Journal of Biological Chemistry

Volumn 289, Issue 48, 2014, Pages 33456-33468

  Rigat, Karen L ^a   Lu, Hao ^a   Wang, Ying Kai ^a   Argyrou, Argyrides ^a,b   Fanslau, Caroline ^a   Beno, Brett ^a   Wang, Yi ^a,c   Marcinkeviciene, Jovita ^a,d   Ding, Min ^a   Gentles, Robert G ^a   Gao, Min ^a   Abell, Lynn M ^a   Roberts, Susan B ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b GLAXOSMITHKLINE   (United Kingdom)

^c EZBiolab   (United States)

^d NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRAL AGENTS; DISSOCIATION; PATIENT MONITORING; PATIENT TREATMENT; RNA; SYNTHESIS (CHEMICAL); VIRUSES;

ACTIVE REPLICATION; BIOPHYSICAL STUDIES; COMPLEX FORMATIONS; DYNAMIC INTERACTION; EXPERIMENTAL EVIDENCE; HEPATITIS C VIRUS NS5B POLYMERASE; INHIBITION PROFILE; RNA-DEPENDENT RNA POLYMERASE;

POLYMERS;

BECLABUVIR; LEUCINE; NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR; NONSTRUCTURAL PROTEIN 5B; PROLINE; RNA; SERINE; 8-CYCLOHEXYL-N-((DIMETHYLAMINO)SULFONYL)-1,1A,2,12B-TETRAHYDRO-11-METHOXY-1A-((3-METHYL-3,8-DIAZABICYCLO(3.2.1)OCT-8-YL)CARBONYL)CYCLOPROP(D)INDOLO(2,1-A)(2)BENZAZEPINE-5-CARBOXAMIDE; ANTIVIRUS AGENT; BENZAZEPINE DERIVATIVE; INDOLE DERIVATIVE; NS-5 PROTEIN, HEPATITIS C VIRUS; PROTEIN BINDING; RNA DIRECTED RNA POLYMERASE; VIRUS PROTEIN; VIRUS RNA;

ARTICLE; BINDING KINETICS; COMPLEX FORMATION; DISSOCIATION; DRUG POTENCY; DRUG PROTEIN BINDING; GENETIC VARIABILITY; HEPATITIS C VIRUS; NONHUMAN; PROTEIN SYNTHESIS INHIBITION; RNA SYNTHESIS; VIRUS REPLICATION; WILD TYPE; AMINO ACID SUBSTITUTION; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; CHEMISTRY; ENZYMOLOGY; HEPACIVIRUS; HEPATITIS C; HUMAN; METABOLISM; MISSENSE MUTATION;

HEPATITIS C VIRUS;

AMINO ACID SUBSTITUTION; ANTIVIRAL AGENTS; BENZAZEPINES; HEPACIVIRUS; HEPATITIS C; HUMANS; INDOLES; MUTATION, MISSENSE; PROTEIN BINDING; RNA REPLICASE; RNA, VIRAL; VIRAL NONSTRUCTURAL PROTEINS;

EID: 84912102990     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.613653     Document Type: Article

References (54)

1. World Health Organization (2012) Prevention and Control of Viral Hepatitis Infection: Framework for Global Action. World Health Organization, Geneva
2. Ditah, I., Ditah, F., Devaki, P., Ewelukwa, O., Ditah, C., Njei, B., Luma, H. N., and Charlton, M. (2014) The changing epidemiology of hepatitis C virus infection in the United States: National Health and Nutrition Examination Survey 2001 through 2010. J. Hepatol. 60, 691-698
3. El-Serag, H. B. (2007) Epidemiology of hepatocellular carcinoma in U.S.A. Hepatol. Res. 37, S88-S94
4. Averhoff, F. M., Glass, N., and Holtzman, D. (2012) Global burden of hepatitis C: considerations for healthcare providers in the United States. Clin. Infect. Dis. 55, S10-S15
5. Ly, K. N., Xing, J., Klevens, R. M., Jiles, R. B., Ward, J. W., and Holmberg, S. D. (2012) The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann. Intern. Med. 156, 271-278
6. Ward, J. W., Rein, D. B., and Smith, B. D. (2012) Data to guide the "test and treat era" of hepatitis C. Gastroenterology 143, 887-889
7. Sims, K. D., Lemm, J., Eley, T., Liu, M., Berglind A, Sherman, D., Lawitz, E., Vutikullird, A. B., Tebas, P., Gao, M., Pasquinelli, C., and Grasela, D. M. (2014) A randomized, single ascending dose study of BMS-791325, a hepatitis C virus NS5B polymerase inhibitor, in genotype 1 infection. Antimicrob. Agents Chemother. 58, 3496-3503
8. Tatum, H., Thuluvath, P., Lawitz, E., Martorell, C., Cohen, S. M., Rustgi, V., Ravendhran, N., Ghalib, R., Hanson, J., Zamparo, J., Zhao, J., Treitel, M., and Hughes, E. (2013) Safety and efficacy of BMS-791325, a non-nucleoside NS5B polymerase inhibitor, combined with peginterferon α-2a and ribavirin in treatment-naive patients infected with hepatitis C virus genotype 1. J. Hepatol. 58, Suppl. 1, S182, Poster 1126
9. Everson, G. T., Sims, K. D., Rodriguez-Torres, M., Hézode, C., Lawitz, E., Bourlière, M., Loustaud-Ratti, V., Rustgi, V., Schwartz, H., Tatum, H., Marcellin, P., Pol, S., Thuluvath, P. J., Eley, T., Wang, X., Huang, S. P., McPhee, F., Wind-Rotolo, M., Chung, E., Pasquinelli, C., Grasela, D. M., and Gardiner, D. F. (2014) Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naïve patients with HCV genotype 1 infection. Gastroenterology 146, 420-429
10. Gentles, R. G., Ding, M., Bender, J. A., Bergstrom, C. P., Grant-Young, K., Hewawasam, P., Hudyma, T., Martin, S., Nickel, A., Regueiro-Ren, A., Tu, Y., Yang, Z., Yeung, K.S., Zheng, X., Chao, S., Sun, J. H., Beno, B. R., Camac, D. M., Chang, C. H., Gao, M., Morin, P. E., Sheriff, S., Tredup, J., Wan, J., Witmer, M. R., Xie, D., Hanumegowda, U., Knipe, J., Mosure, K., Santone, K. S., Parker, D. D., Zhuo, X., Lemm, J., Liu, M., Pelosi, L., Rigat, K., Voss, S., Wang, Y., Wang, Y. K., Colonno, R. J., Gao, M., Roberts, S. B., Gao, Q., Ng, A., Meanwell, N. A., and Kadow, J. F. (2014) Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase. J. Med. Chem. 57, 1855-1879
11. Lemm, J. A., Liu, M., Gentles, R. G., Ding, M., Voss, S., Pelosi, L. A., Wang, Y.-K., Rigat, K. L., Mosure, K. W., Bender, J. A., Knipe, J. O., Colonno, R., Meanwell, N. A., Kadow, J. F., Santone, K. S., Roberts, S. B., and Gao, M. (2014) Preclinical characterization of BMS-791325, an allosteric inhibitor of human hepatitis C virus NS5B polymerase. Antimicrob. Agents Chemother. 58, 3485-3495
12. Ago, H., Adachi, T., Yoshida, A., Yamamoto, M., Habuka, N., Yatsunami, K., and Miyano, M. (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Structure 7, 1417-1426
13. Lesburg, C. A., Cable, M. B., Ferrari, E., Hong, Z., Mannarino, A. F., and Weber, P. C. (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
14. Bressanelli, S., Tomei, L., Roussel, A., Incitti, I., Vitale, R. L., Mathieu, M., De Francesco, R., and Rey, F. A. (1999) Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Proc. Natl. Acad. Sci. U.S.A. 96, 13034-13039
15. Biswal, B. K., Cherney, M. M., Wang, M., Chan, L., Yannopoulos, C. G., Bilimoria, D., Nicolas, O., Bedard, J., and James, M. N. (2005) Crystal Structures of the RNA-dependent RNA polymerase genotype 2a of hepatitis C virus reveal two conformations and suggest mechanisms of inhibition by non-nucleoside inhibitors. J. Biol. Chem. 280, 18202-18210
16. McKercher, G., Beaulieu, P. L., Lamarre, D., LaPlante, S., Lefebvre, S., Pellerin, C., Thauvette, L., and Kukolj, G. (2004) Binding site characterization and resistance to a class of non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase. Nucleic Acids Res. 32, 422-431
17. Di Marco, S., Volpari, C., Tomei, L., Altamura, S., Harper, S., Narjes, F., Koch, U., Rowley, M., De Francesco, R., Migliaccio, G., and Carfí, A. (2005) Interdomain communication in hepatitis C virus polymerase abolished by small molecule inhibitors bound to a novel allosteric site. J. Biol. Chem. 280, 29765-29770
18. Tomei, L., Altamura, S., Bartholomew, L., Biroccio, A., Ceccacci, A., Pacini, L., Narjes, F., Gennari, N., Bisbocci, M., Incitti, I., Orsatti, L., Harper, S., Stansfield, I., Rowley, M., De Francesco, R., and Migliaccio, G. (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
19. Erhardt, A., Deterding, K., Benhamou, Y., Reiser, M., Forns, X., Pol, S., Calleja, J. L., Ross, S., Spangenberg, H. C., Garcia-Samaniego, J., Fuchs, M., Enríquez, J., Wiegand, J., Stern, J., Wu, K., Kukolj, G., Marquis, M., Beaulieu, P., Nehmiz, G., Steffgen, J., and BILB 1941 Study Group (2009) Safety, pharmacokinetics and antiviral effect of BILB 1941, a novel hepatitis C virus RNA polymerase inhibitor, after 5 days oral treatment. Antivir. Ther. 14, 23-32
20. Narjes, F., Crescenzi, B., Ferrara, M., Habermann, J., Colarusso, S., Ferreira, M. del R., Stansfield, I., Mackay, A. C., Conte, I., Ercolani, C., Zaramella, S., Palumbi, M. C., Meuleman, P., Leroux-Roels, G., Giuliano, C., Fiore, F., Di Marco, S., Baiocco, P., Koch, U., Migliaccio, G., Altamura, S., Laufer, R., De Francesco, R., and Rowley, M. (2011) Discovery of (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6Hindolo [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, 289-301
21. Brainard, D. M., Anderson, M. S., Petry, A., Van Dyck, K., de Lepeleire, I., Sneddon, C., Cummings, C. E., Nachbar, R. B., Barnard, R. J., Sun, P., Panorchan, P., Sanderson, J. B., Udezue, E., Wagner, F., Iwamoto, M., Chodakewitz, J., and Wagner, J. A. (2009) Safety and antiviral activity of NS5B polymerase inhibitor MK-3281, in treatment-naive genotype 1A, 1B and 3 HCV-infected patients. Hepatology 50, Suppl. 4, Poster 1568
22. Vendeville, S., Lin, T-I., Hu, L., Tahri, A., McGowan, D., Cummings, M. D., Amssoms, K., Canard, M., Last, S., Van den Steen, I., Devogelaere, B., Rouan, M. C., Vijgen, L., Berke, J. M., Dehertogh, P., Fransen, E., Cleiren, E., van der Helm, L., Fanning, G., Van Emelen, K., Nyanguile, O., Simmen, K., and Raboisson, P. (2012) Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055. Bioorg. Med. Chem. Lett. 22, 4437-4443
23. Devogelaere, B., Berke, J. M., Vijgen, L., Dehertogh, P., Fransen, E., Cleiren, E., van der Helm, L., Nyanguile, O., Tahri, A., Amssoms, K., Lenz, O., Cummings, M. D., Clayton, R. F., Vendeville, S., Raboisson, P., Simmen, K. A., Fanning, G. C., and Lin, T. I. (2012) TMC647055, a potent non-nucleoside hepatitis C virus NS5B polymerase inhibitor with cross-genotypic coverage. Antimicrob. Agents Chemother. 56, 4676-4684
24. National Institutes of Health (2012) A study to evaluate the safety, tolerability, and effectiveness of a 12-week combination therapy of TMC647055 and TMC435 with and without GSK23336805 with a pharmacokinetic enhancer with and without ribavirin in patients infected with chronic genotype 1 hepatitis C virus. ClinicalTrials.gov ID NCT01724086
25. Larrey, D., Lohse, A. W., de Ledinghen, V., Trepo, C., Gerlach, T., Zarski, J. P., Tran, A., Mathurin, P., Thimme, R., Arastéh, K., Trautwein, C., Cerny, A., Dikopoulos, N., Schuchmann, M., Heim, M. H., Gerken, G., Stern, J. O., Wu, K., Abdallah, N., Girlich, B., Scherer, J., Berger, F., Marquis, M., Kukolj, G., Böcher, W., and Steffgen, J. (2012) Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon α 2a and ribavirin. J. Hepatol. 57, 39-46
26. Larrey, D., Lohse, A. W., Trepo, C., Bronowicki, J. P., Arastéh, K., Bourliè re, M., Calleja, J. L., Stern, J. O., Nehmiz, G., Abdallah, N., Berger, K. L., Marquis, M., Steffgen, J., Kukolj, G., and BI 207127 Study Group (2013) Antiviral effect, safety, and pharmacokinetics of 5 days' oral administration of deleobuvir (BI 207127), an investigational HCV RNA polymerase inhibitor, in patients with chronic hepatitis C. Antimicrob. Agents Chemother. 57, 4727-4735
27. Zeuzem, S., Soriano, V., Asselah, T., Bronowicki, J. P., Lohse, A. W., Müllhaupt, B., Schuchmann, M., Bourlière, M., Buti, M., Roberts, S. K., Gane, E. J., Stern, J. O., Vinisko, R., Kukolj, G., Gallivan, J. P., Böcher, W. O., and Mensa, F. J. (2013) Faldaprevir and deleobuvir for HCV genotype 1 infection. N. Engl. J. Med. 369, 630-639
28. National Institutes of Health (2012) Phase 3 study of BI 207127 in combination with faldaprevir and ribavirin for treatment of patients with hepatitis C infection, including patients who are not eligible to receive peginterferon: HCVerso2. ClinicalTrials.gov ID NCT01728324
29. Zheng, X., Hudyma, T. W., Martin, S. W., Bergstrom, C., Ding, M., He, F., Romine, J., Poss, M. A., Kadow, J. F., Chang, C. H., Wan, J., Witmer, M. R., Morin, P., Camac, D. M., Sheriff, S., Beno, B. R., Rigat, K. L., Wang, Y. K., Fridell, R., Lemm, J., Qiu, D., Liu, M., Voss, S., Pelosi, L., Roberts, S. B., Gao, M., Knipe, J., and Gentles, R. G. (2011) Syntheses and initial evaluation of a series of indolo-fused heterocyclic inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus. Bioorg. Med. Chem. Lett. 21, 2925-2929
30. DeLano, W. L. (2012) The PyMOL Molecular Graphics System, version 1.5.0.4, Schrödinger, LLC, New York
31. Wang, Y.-K., Rigat, K. L., Roberts, S. B., and Gao, M. (2006) A homogeneous, solid-phase assay for hepatitis C virus RNA-dependent RNA polymerase. Anal. Biochem. 359, 106-111
32. Wang, Y.-K., Rigat, K. L., Sun, J. H., Gao, M., and Roberts, S. B. (2008)RNA template-directed inhibition of hepatitis C virus RNA polymerase. Arch. Biochem. Biophys. 470, 146-152
33. Morrison J. F. (1969) Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors. Biochim. Biophys. Acta 185, 269-286
34. Luo, G., Hamatake, R. K., Mathis, D. M., Racela, J., Rigat, K. L., Lemm, J., and Colonno, R. J. (2000) De novo initiation of RNA synthesis by the RNA-dependent RNA polymerase (NS5B) of hepatitis C virus. J. Virol. 74, 851-863
35. Ranjith-Kumar, C. T., Gutshall, L., Kim, M. J., Sarisky, R. T., and Kao, C. C. (2002) Requirements for de novo initiation of RNA synthesis by recombinant flaviviral RNA-dependent RNA polymerases. J. Virol. 76, 12526-12536
36. Zhong, W., Ferrari, E., and Lesburg, C. A., Maag, D., Ghosh, S. K., Cameron, C. E., Lau, J. Y., and Hong, Z. (2000) Template/primer requirements and single nucleotide incorporation by hepatitis C virus nonstructural protein 5B polymerase. J. Virol. 74, 9134-9143
37. Hong, Z., Cameron, C. E., Walker, M. P., Castro, C., Yao, N., Lau, J. Y., and Zhong, W. (2001) A novel mechanism to ensure terminal initiation by hepatitis C virus NS5B polymerase. Virology 285, 6-11
38. Mosley, R. T., Edwards, T. E., Murakami, E., Lam, A. M., Grice, R. L., Du, J., Sofia, M. J., Furman, P. A., and Otto, M. J. (2012) Structure of hepatitis C virus polymerase in complex with primer-template RNA. J. Virol. 86, 6503-6511
39. Bambara, R. A., Fay, P. J., and Mallaber, L. M. (1995) Methods of analyzing processivity. Methods Enzymol. 262, 270-280
40. Migliaccio, G., Tomassini, J. E., Carroll, S. S., Tomei, L., Altamura, S., Bhat, B., Bartholomew, L., Bosserman, M. R., Ceccacci, A., Colwell, L. F., Cortese, R., De Francesco, R., Eldrup, A. B., Getty, K. L., Hou, X. S., LaFemina, R. L., Ludmerer, S. W., MacCoss, M., McMasters, D. R., Stahlhut, M. W., Olsen, D. B., Hazuda, D. J., and Flores, O. A. (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
41. Labonté, P., Axelrod, V., Agarwal, A., Aulabaugh, A., Amin, A., and Mak, P. (2002) Modulation of hepatitis C virus RNA-dependent RNA polymerase activity by structure-based site-directed mutagenesis. J. Biol. Chem. 277, 38838-38846
42. Rigat, K. L., Wang, Y., Hudyma, T. W., Ding, M., Zheng, X., Gentles, R. G., Beno, B. R., Gao, M., and Roberts, S. B. (2010) Ligand-induced changes in hepatitis C virus NS5B polymerase structure. Antiviral Res. 88, 197-206
43. Schmitt, H.-M., Brecht, A., Piehler, J., and Gauglitz, G. (1997) An integrated system for optical biomolecular interaction analysis. Biosensors and Bioelectronics 12, 809-816
44. Miyata Y., Li, X., Lee, H.-F., Jinwal, U. K., Srinivasan, S. R., Seguin, S. P., Young, Z. T., Brodsky, J. L., Dickey, C. A., Sun, D., and Gestwicki, J. E. (2013) Synthesis and initial evaluation of YM-08, a blood-brain barrier permeable derivative of the heat shock protein 70 (Hsp70) inhibitor MKT-077, which reduces Tau levels. ACS Chem. Neurosci. 4, 930-939
45. Sofia, M. J., Chang, W., Furman, P. A., Mosley, R. T., and Ross, B. S. (2012) Nucleoside, nucleotide, and non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA-polymerase. J. Med. Chem. 55, 2481-2531
46. Copeland, R. A. (2010) The dynamics of drug-target interactions: drug-target residence time and its impact on efficacy and safety. Expert Opin. Drug Discov. 5, 305-310
47. Dahl, G., and Akerud, T. (2013) Pharmacokinetics and the drug-target residence time concept. Drug Discov. Today 18, 697-707
48. Chinnaswamy, S., Yarbrough, I., Palaninathan, S., Kumar, C. T., Vijayaraghavan, V., Demeler, B., Lemon, S. M., Sacchettini, J. C., and Kao, C. C. (2008) A locking mechanism regulates RNA synthesis and host protein interaction by the hepatitis C virus polymerase. J. Biol. Chem. 283, 20535-20546
49. Chinnaswamy, S., Murali, A., Cai, H., Yi, G., Palaninathan, S., and Kao, C. C. (2010) Conformations of the monomeric hepatitis C virus RNA-dependent RNA polymerase. Virus Adaptation and Treatment 2, 21-39
50. LaPlante, S. R., Gillard, J. R., Jakalian, A., Aubry, N., Coulombe, R., Brochu, C., Tsantrizos, Y. S., Poirier, M., Kukolj, G., and Beaulieu, P. L. (2010) Importance of ligand bioactive conformation in the discovery of potent indole-diamide inhibitors of the hepatitis C virus NS5B. J. Am. Chem. Soc. 132, 15204-15212
51. Ranjith-Kumar, C. T., and Kao, C. C. (2006) Recombinant viral RdRps can initiate RNA synthesis from circular template. RNA 12, 303-312
52. Santoso, Y., Joyce, C. M., Potapova, O., Le Reste, L., Hohlbein, J., Torella, J. P., Grindley, N. D. F., and Kapanidis, A. N. (2010) Conformational transitions inDNApolymerase I revealed by single-molecule FRET. Proc. Natl. Acad. Sci. U.S.A. 107, 715-720
53. Rothwell, P. J., and Waksman, G. (2007) A pre-equilibrium before nucleotide binding limits fingers subdomain closure by Klentaq. J. Biol. Chem. 282, 28884-28892
54. Karam, P., Powdrill, M. H., Liu, H.-W., Vasquez, C., Mah, W., Bernatchez, J., Götte, M., and Cosa, G. (2014) Dynamics of hepatitis C virus (HCV) RNA-dependent RNA polymerase NS5B in complex with RNA. J. Biol. Chem. 289, 14399-14411