Molecular dynamics simulations and structure-based rational design lead to allosteric HCV NS5B polymerase thumb pocket 2 inhibitor with picomolar cellular replicon potency

Journal of Medicinal Chemistry

Volumn 57, Issue 5, 2014, Pages 1932-1943

  Hucke, Oliver ^a,b   Coulombe, René ^a   Bonneau, Pierre ^a   Bertrand Laperle, Mégan ^a   Brochu, Christian ^a   Gillard, James ^a   Joly, Marc André ^a   Landry, Serge ^a   Lepage, Olivier ^a   Llinàs Brunet, Montse ^a   Pesant, Marc ^a   Poirier, Martin ^a   Poirier, Maude ^a   McKercher, Ginette ^a   Marquis, Martin ^a   Kukolj, George ^a   Beaulieu, Pierre L ^a   Stammers, Timothy A ^a  

^a BOEHRINGER INGELHEIM CANADA LTD   (Canada)

^b BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; CARBONYL DERIVATIVE; NS5B THUMB POCKET 2 ALLOSTERIC INHIBITOR; PROTEIN; PROTEINASE INHIBITOR; QUINAZOLINONE DERIVATIVE; UNCLASSIFIED DRUG;

ALLOSTERISM; ARTICLE; CELL MEMBRANE PERMEABILITY; CHEMICAL INTERACTION; DRUG POTENCY; GENOTYPE; HEPATITIS C VIRUS; HUMAN; HYDROGEN BOND; LIGAND BINDING; MOLECULAR DYNAMICS; MOLECULAR WEIGHT; REPLICON; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ALLOSTERIC REGULATION; ANTIVIRAL AGENTS; CELL LINE; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; HEPACIVIRUS; MOLECULAR DYNAMICS SIMULATION; REPLICON; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

EID: 84896290583     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm4004522     Document Type: Article

References (44)

1. Lavanchy, D. Evolving epidemiology of hepatitis C virus Clin. Microbiol. Infect. 2011, 17, 107-115
2. Bosetti, C.; Levi, F.; Lucchini, F.; Zatonski, W. A.; Negri, E.; La, V. C. Worldwide mortality from cirrhosis: an update to 2002 J. Hepatol. 2007, 46, 827-839
3. Wise, M.; Bialek, S.; Finelli, L.; Bell, B. P.; Sorvillo, F. Changing trends in hepatitis C-related mortality in the United States, 1995-2004 Hepatology 2008, 47, 1128-1135
4. Davila, J. A.; Morgan, R. O.; Shaib, Y.; McGlynn, K. A.; El-Serag, H. B. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study Gastroenterology 2004, 127, 1372-1380
5. National Institutes of Health consensus development conference statement: management of hepatitis C 2002 (June 10-12, 2002). Gastroenterology 2002, 123, 2082-2099.
6. Manns, M. P.; Foster, G. R.; Rockstroh, J. K.; Zeuzem, S.; Zoulim, F.; Houghton, M. The way forward in HCV treatment: finding the right path Nature Rev. Drug Discovery 2007, 6, 991-1000
7. Björnsson, E.; Verbaan, H.; Oksanen, A.; Frydén, A.; Johansson, J.; Friberg, S.; DalgaÌŠrd, O.; Kalaitzakis, E. Health-related quality of life in patients with different stages of liver disease induced by hepatitis C Scand. J. Gastroenterol. 2009, 44, 878-887
8. Hinrichsen, H.; Benhamou, Y.; Wedemeyer, H.; Reiser, M.; Sentjens, R. E.; Calleja, J. L.; Forns, X.; Erhardt, A.; Cronlein, J.; Chaves, R. L.; Yong, C. L.; Nehmiz, G.; Steinmann, G. G. Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients Gastroenterology 2004, 127, 1347-1355
9. Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Bos, M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A. M.; Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagace, L.; LaPlante, S. R.; Narjes, H.; Poupart, M. A.; Rancourt, J.; Sentjens, R. E.; St. George, R.; Simoneau, B.; Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong, C. L.; Llinas-Brunet, M. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus Nature 2003, 426, 186-189
10. Berman, K.; Kwo, P. Y. Boceprevir, an NS3 protease inhibitor of HCV Clin. Liver Dis. 2009, 13, 429-439
11. Gentile, I.; Carleo, M. A.; Borgia, F.; Castaldo, G.; Borgia, G. The efficacy and safety of telaprevir-a new protease inhibitor against hepatitis C virus Expert Opin. Invest. Drugs 2010, 19, 151-159
12. Kwong, A. D.; Kauffman, R. S.; Hurter, P.; Mueller, P. Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus Nature Biotechnol. 2011, 29, 993-1003
13. Asselah, T.; Marcellin, P. New direct-acting antivirals' combination for the treatment of chronic hepatitis C Liver Int. 2011, 31 (Suppl 1) 68-77
14. Tanwar, S.; Trembling, P. M.; Dusheiko, G. M. TMC435 for the treatment of chronic hepatitis C Expert Opin. Invest. Drugs 2012, 21, 1193-1209
15. Lenz, O.; Vijgen, L.; Berke, J. M.; Cummings, M. D.; Fevery, B.; Peeters, M.; Smedt, G. D.; Moreno, C.; Picchio, G. Virologic response and characterization of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202) J. Hepatol. 2013, 58, 445-451
16. White, P. W.; Llinas-Brunet, M.; Amad, M.; Bethell, R. C.; Bolger, G.; Cordingley, M. G.; Duan, J.; Garneau, M.; Lagace, L.; Thibeault, D.; Kukolj, G. Preclinical characterization of BI 201335, a C-terminal carboxylic acid inhibitor of the hepatitis C virus NS3-NS4A protease Antimicrob. Agents Chemother. 2010, 54, 4611-4618
17. Lemke, C. T.; Goudreau, N.; Zhao, S.; Hucke, O.; Thibeault, D.; Llinas-Brunet, M.; White, P. W. Combined X-ray, NMR, and kinetic analyses reveal uncommon binding characteristics of the hepatitis C virus NS3-NS4A protease inhibitor BI 201335 J. Biol. Chem. 2011, 286, 11434-11443
18. Poordad, F.; Cohen, D. E.; Nelson, D. R.; Zeuzem, S.; Everson, G. T.; Kwo, P. Y.; Foster, G. R.; Sulkowski, M. S.; Xie, W.; Pilot-Matias, T.; Liossis, G.; Larsen, L. M.; Khatri, A.; Podsadecki, T. J.; Bernstein, B. Exploratory study of oral combination antiviral therapy for hepatitis C N. Engl. J. Med. 2013, 368, 45-53 Presented at the 63rd Annual Meeting of the American Association for the Study of the Liver Diseases (AASLD) November 9-13th, Boston, MA, late-breaker abstract LB-1
19. Zeuzem, S.; Asselah, T.; Angus, P.; Zarski, J.-P.; Larrey, D.; Müllhaupt, B.; Gane, E.; Schuchmann, M.; Lohse, A.; Pol, S.; Bronowicki, J.-P.; Roberts, S.; Arasteh, K.; Zoulim, F.; Heim, M.; Stern, J. O.; Kukolj, G.; Nehmiz, G.; Haefner, C.; Boecher, W. O. Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection Gastroenterology 2011, 141, 2047
20. Zeuzem, S.; Gane, E.; Roberts, S.; Mensa, F. J. Gastroent. Hepatol. 2012, 27 (Suppl 4) 182
21. Ago, H.; Adachi, T.; Yoshida, A.; Yamamoto, M.; Habuka, N.; Yatsunami, K.; Miyano, M. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus Structure 1999, 7, 1417-1426
22. Bressanelli, S.; Tomei, L.; Roussel, A.; Incitti, I.; Vitale, R. L.; Mathieu, M.; De Francesco, R.; Rey, F. A. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 13034-13039
23. Love, R. A.; Yu, X.; Diehl, W.; Hickey, M. J.; Parge, H. E.; Gao, J.; Fuhrman, S. Hepatitis c virus (hcv) ns5b RNA polymerase and mutants thereof. Patent EP 12566628, 2002.
24. Love, R. A.; Parge, H. E.; Yu, X.; Hickey, M. J.; Diehl, W.; Gao, J.; Wriggers, H.; Ekker, A.; Wang, L.; Thomson, J. A.; Dragovich, P. S.; Fuhrman, S. A. Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C virus NS5B RNA polymerase enzyme J. Virol. 2003, 77, 7575
25. Wang, M.; Ng, K. K.; Cherney, M. M.; Chan, L.; Yannopoulos, C. G.; Bedard, J.; Morin, N.; Nguyen-Ba, N.; Alaoui-Ismaili, M. H.; Bethell, R. C.; James, M. N. Non-nucleoside analogue inhibitors bind to an allosteric site on HCV NS5B polymerase. Crystal structures and mechanism of inhibition J. Biol. Chem. 2003, 278, 9489-9495
26. Beaulieu, P. L. Recent advances in the development of NS5B polymerase inhibitors for the treatment of hepatitis C virus infection Expert Opin. Ther. Pat 2009, 19, 145-164
27. Haudecoeur, R.; Peuchmaur, M.; Ahmed-Belkacem, A.; Pawlotsky, J. M.; Boumendjel, A. Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research. Med. Res. Rev. 2012, DOI: 10.1002/med.21271.
28. Beaulieu, P. L. In Successful Strategies for the Discovery of Antiviral Drugs; Desai, M. C.,; Meanwell, N. A., Eds.; RSC Publishing: Cambridge, UK, 2013, (in press).
29. Stammers, T. A.; Coulombe, R.; Rancourt, J.; Thavonekham, B.; Fazal, G.; Goulet, S.; Jakalian, A.; Wernic, D.; Tsantrizos, Y.; Poupart, M.-A.; Bös, M.; McKercher, G.; Thauvette, L.; Kukolj, G.; Beaulieu, P. L. Discovery of a Novel Series of Non-Nucleoside Thumb Pocket 2 HCV NS5B Polymerase Inhibitors. Submitted for publication.
30. Beaulieu, P. L.; Coulombe, R.; Duan, J.; Fazal, G.; Godbout, C.; Hucke, O.; Jakalian, A.; Joly, M.-A.; Lepage, O.; Llinàs-Brunet, M.; Naud, J.; Poirier, M.; Rioux, N.; Thavonekham, B.; Kukolj, G.; Timothy, A. Stammers. Structure-Based Design of Novel HCV NS5B Thumb Pocket 2 Allosteric Inhibitors with Submicromolar gt1 Replicon Potency: Discovery of a Quinazolinone Chemotype. Bioorg. Med. Chem. Lett., 2013, 23, DOI: 10.1016/j.bmcl.2013.05.037.
31. Beaulieu, P. L.; Fazal, G.; Goulet, S.; Kukolj, G.; Poirier, M.; Tsantrizos, Y.; Jolicoeur, E.; Gillard, J.; Poupart, M.-A.; Rancourt, J. Viral Polymerase Inhibitors. WO Patent WO 03/010141, 2003.
32. Llinàs-Brunet, M.; Bailey, M. D.; Goudreau, N.; Bhardwaj, P. K.; Bordeleau, J.; Bös, M.; Bousquet, Y.; Cordingely, M. G.; Duan, J.; Forgione, P.; Garneau, M.; Ghiro, E.; Gorys, V.; Goulet, S.; Halmos, T.; Kawai, S. H.; Naud, J.; Poupart, M. -A.; White, P. W. J. Med. Chem. 2010, 53, 6466-6476
33. Vaillancourt, F. H.; Pilote, L.; Cartier, M.; Lippens, J.; Liuzzi, M.; Bethell, R. C.; Cordingley, M. G.; Kukolj, G. Virology 2009, 387, 5-10
34. Gao, M.; Nettles, R. E.; Belema, M.; Snyder, L. B.; Nguyen, V. N.; Fridell, R. A.; Serrano-Wu, M. H.; Langley, D. R.; Sun, J. H.; O'Boyle, D. R.; Lemm, J. A.; Wang, C.; Knipe, J. O.; Chien, C.; Colonno, R. J.; Grasela, D. M.; Meanwell, N. A.; Hamann, L. G. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect Nature 2010, 465, 96-100
35. Belda, O.; Targett-Adams, P. Small molecule inhibitors of the hepatitis C virus-encoded NS5A protein Virus Res. 2012, 170, 1-14
36. McClure, M. S.; Glover, B.; McSorley, E.; Millar, A.; Osterhout, M. H.; Roschangar, F. Regioselective Palladium-Catalyzed Arylation of 2-Furaldehyde Org. Lett. 2001, 3, 1677-1680
37. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Palladium-Catalyzed Arylation of Azole Compounds with Aryl Halides in the Presence of Alkali Metal Carbonates and the Use of Copper Iodide in the Reaction Bull. Chem. Soc. Jpn. 1998, 71, 467-473
38. Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-catalyzed cross-coupling reaction of alkoxydiboron with haloarenes: a direct procedure for arylboronic esters J. Org. Chem. 1995, 60, 7508-7510
39. McKercher, G.; Beaulieu, P. L.; Lamarre, D.; LaPlante, S.; Lefebvre, S.; Pellerin, C.; Thauvette, L.; Kukolj, G. Specific inhibitors of HCV polymerase identified using an NS5B with lower affinity for template/primer substrate Nucleic Acids Res. 2004, 32, 422-431
40. LaPlante, S. R.; Gillard, J. R.; Jakalian, A.; Aubry, N.; Coulombe, R.; Brochu, C.; Tsantrizos, Y. S.; Poirier, M.; Kukolj, G.; Beaulieu, P. L. Importance of ligand bioactive conformation in the discovery of potent indole-diamide inhibitors of the hepatitis C virus NS5B J. Am. Chem. Soc. 2010, 132, 15204-15212
41. Case, D. A.; Darden, T. A.; Cheatham, T. E., III; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Merz, K. M.; Wang, B.; Pearlman, D. A.; Crowley, M.; Brozell, S.; Tsui, V.; Gohlke, H.; Mongan, J.; Hornak, V.; Cui, G.; Beroza, P.; Schafmeister, C.; Caldwell, J. W.; Ross, W. S.; Kollman, P. A., AMBER 8; University of California: San Francisco, 2004.
42. Duan, Y.; Wu, C.; Chowdhury, S.; Lee, M. C.; Xiong, G.; Zhang, W.; Yang, R.; Cieplak, P.; Luo, R.; Lee, T. A Point-Charge Force Field for Molecular Mechanics Simulations of Proteins J. Comput. Chem. 2003, 24, 1999-2012
43. Jakalian, A.; Bush, B. L.; Jack, D. B.; Bayly, C. I. Fast, Efficient Generation of High-Quality Atomic Charges. AM1-BCC Model: I. Method J. Comput. Chem. 2000, 21, 132-146
44. Wang, J.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D. A. Development and testing of a general Amber force field J. Comput. Chem. 2004, 25, 1157-1174