Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition

Journal of Medicinal Chemistry

Volumn 57, Issue 23, 2014, Pages 10031-10043

  Nettles, James H ^a,b   Stanton, Richard A ^a,b   Broyde, Joshua ^a   Amblard, Franck ^a   Zhang, Hongwang ^a   Zhou, Longhu ^a   Shi, Junxing ^c   McBrayer, Tamara R ^b,c   Whitaker, Tony ^c   Coats, Steven J ^c   Kohler, James J ^a,b   Schinazi, Raymond F ^a,b  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VETERANS AFFAIRS MEDICAL CENTER   (United States)

^c RFS Pharma LLC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DACLATASVIR; FAT DROPLET; NONSTRUCTURAL PROTEIN 5A; PROLINE; ANTIVIRUS AGENT; BMS-790052; IMIDAZOLE DERIVATIVE; NS-5 PROTEIN, HEPATITIS C VIRUS; VIRUS PROTEIN;

ANTIVIRAL ACTIVITY; ARTICLE; COMPLEX FORMATION; DRUG POTENCY; DRUG RECEPTOR BINDING; HEPATITIS C VIRUS; MOLECULAR DOCKING; PHARMACOPHORE; PROTEIN CONFORMATION; PROTEIN PROTEIN INTERACTION; RECEPTOR POTENTIAL; STRUCTURE ACTIVITY RELATION; VIRION; AMINO ACID SEQUENCE; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; HEPACIVIRUS; METABOLISM; SEQUENCE ALIGNMENT; VIRUS REPLICATION;

AMINO ACID SEQUENCE; ANTIVIRAL AGENTS; HEPACIVIRUS; IMIDAZOLES; MOLECULAR DOCKING SIMULATION; SEQUENCE ALIGNMENT; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

EID: 84918549836     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm501291c     Document Type: Article

References (49)

1. Word Health Organization. Hepatitis C. http://www.who.int/mediacentre/factsheets/fs164/en/ (accessed May 16, 2014).
2. Kohler, J. J.; Nettles, J. H.; Amblard, F.; Hurwitz, S. J.; Bassit, L.; Stanton, R. A.; Ehteshami, M.; Schinazi, R. F. Approaches to hepatitis C treatment and cure using NS5A inhibitors Infect. Drug Resist. 2014, 7, 41-56
3. Belema, M.; Nguyen, V. N.; Bachand, C.; Deon, D. H.; Goodrich, J. T.; James, C. A.; Lavoie, R.; Lopez, O. D.; Martel, A.; Romine, J. L.; Ruediger, E. H.; Snyder, L. B.; Laurent, D. R.; Yang, F.; Zhu, J.; Wong, H. S.; Langley, D. R.; Adams, S. P.; Cantor, G. H.; Chimalakonda, A.; Fura, A.; Johnson, B. M.; Knipe, J. O.; Parker, D. D.; Santone, K. S.; Fridell, R. A.; Lemm, J. A.; O'Boyle, D. R., 2nd; Colonno, R. J.; Gao, M.; Meanwell, N. A.; Hamann, L. G. Hepatitis C virus NS5A replication complex inhibitors: the discovery of Daclatasvir J. Med. Chem. 2014, 57, 2013-2032
4. Fridell, R. A.; Wang, C.; Sun, J. H.; O'Boyle, D. R., 2nd; Nower, P.; Valera, L.; Qiu, D.; Roberts, S.; Huang, X.; Kienzle, B.; Bifano, M.; Nettles, R. E.; Gao, M. Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in humans: in vitro and in vivo correlations Hepatology 2011, 54, 1924-1935
5. 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., 2nd; 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
6. Targett-Adams, P.; Graham, E. J.; Middleton, J.; Palmer, A.; Shaw, S. M.; Lavender, H.; Brain, P.; Tran, T. D.; Jones, L. H.; Wakenhut, F.; Stammen, B.; Pryde, D.; Pickford, C.; Westby, M. Small molecules targeting hepatitis C virus-encoded NS5A cause subcellular redistribution of their target: insights into compound modes of action J. Virol. 2011, 85, 6353-6368
7. Penin, F.; Brass, V.; Appel, N.; Ramboarina, S.; Montserret, R.; Ficheux, D.; Blum, H. E.; Bartenschlager, R.; Moradpour, D. Structure and function of the membrane anchor domain of hepatitis C virus nonstructural protein 5A J. Biol. Chem. 2004, 279, 40835-40843
8. Macdonald, A.; Harris, M. Hepatitis C virus NS5A: tales of a promiscuous protein J. Gen. Virol. 2004, 85, 2485-2502
9. Guedj, J.; Dahari, H.; Uprichard, S. L.; Perelson, A. S. The hepatitis C virus NS5A inhibitor daclatasvir has a dual mode of action and leads to a new virus half-life estimate Expert Rev. Gastroenterol. Hepatol. 2013, 7, 397-399
10. Guedj, J.; Dahari, H.; Rong, L.; Sansone, N. D.; Nettles, R. E.; Cotler, S. J.; Layden, T. J.; Uprichard, S. L.; Perelson, A. S. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 3991-3996
11. Berger, C.; Romero-Brey, I.; Radujkovic, D.; Terreux, R.; Zayas, M.; Paul, D.; Harak, C.; Hoppe, S.; Gao, M.; Penin, F.; Lohmann, V.; Bartenschlager, R. Daclatasvir-like inhibitors of NS5A block early biogenesis of HCV-induced membranous replication factories, independent of RNA replication Gastroenterology 2014, 147, 1094-1105
12. Belema, M.; Lopez, O. D.; Bender, J. A.; Romine, J. L., St; Laurent, D. R.; Langley, D. R.; Lemm, J. A.; O'Boyle, D. R., 2nd; Sun, J. H.; Wang, C.; Fridell, R. A.; Meanwell, N. A. Discovery and development of hepatitis C virus NS5A replication complex inhibitors J. Med. Chem. 2014, 57, 1643-1672
13. Wang, C.; Sun, J. H.; O'Boyle, D. R., 2nd; Nower, P.; Valera, L.; Roberts, S.; Fridell, R. A.; Gao, M. Persistence of resistant variants in hepatitis C virus-infected patients treated with the NS5A replication complex inhibitor daclatasvir Antimicrob. Agents Chemother. 2013, 57, 2054-2065
14. Link, J. O.; Taylor, J. G.; Xu, L.; Mitchell, M.; Guo, H.; Liu, H.; Kato, D.; Kirschberg, T.; Sun, J.; Squires, N.; Parrish, J.; Keller, T.; Yang, Z. Y.; Yang, C.; Matles, M.; Wang, Y.; Wang, K.; Cheng, G.; Tian, Y.; Mogalian, E.; Mondou, E.; Cornpropst, M.; Perry, J.; Desai, M. C. Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection J. Med. Chem. 2014, 57, 2033-2046
15. Kazmierski, W. M.; Maynard, A.; Duan, M.; Baskaran, S.; Botyanszki, J.; Crosby, R.; Dickerson, S.; Tallant, M.; Grimes, R.; Hamatake, R.; Leivers, M.; Roberts, C. D.; Walker, J. Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound J. Med. Chem. 2014, 57, 2058-2073
16. Degoey, D. A.; Randolph, J. T.; Liu, D.; Pratt, J.; Hutchins, C.; Donner, P.; Krueger, A. C.; Matulenko, M.; Patel, S.; Motter, C. E.; Nelson, L.; Keddy, R.; Tufano, M.; Caspi, D. D.; Krishnan, P.; Mistry, N.; Koev, G.; Reisch, T. J.; Mondal, R.; Pilot-Matias, T.; Gao, Y.; Beno, D. W.; Maring, C. J.; Molla, A.; Dumas, E.; Campbell, A.; Williams, L.; Collins, C.; Wagner, R.; Kati, W. M. Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A J. Med. Chem. 2014, 57, 2047-2057
17. Belema, M.; Meanwell, N. A. Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect J. Med. Chem. 2014, 57, 5057-5071
18. Lambert, S. M.; Langley, D. R.; Garnett, J. A.; Angell, R.; Hedgethorne, K.; Meanwell, N. A.; Matthews, S. J. The crystal structure of NS5A domain 1 from genotype 1a reveals new clues to the mechanism of action for dimeric HCV inhibitors Protein Sci. 2014, 23, 723-734
19. Barakat, K. H.; Anwar-Mohamed, A.; Tuszynski, J. A.; Robins, M. J.; Tyrrell, D. L.; Houghton, M. A refined model of the HCV NS5A protein bound to daclatasvir explains drug-resistant mutations and activity against divergent genotypes J. Chem. Inf. Model. 2014, 10.1021/ci400631n
20. O'Boyle, D. R., II; Sun, J. H.; Nower, P. T.; Lemm, J. A.; Fridell, R. A.; Wang, C.; Romine, J. L.; Belema, M.; Nguyen, V. N.; Laurent, D. R.; Serrano-Wu, M.; Snyder, L. B.; Meanwell, N. A.; Langley, D. R.; Gao, M. Characterizations of HCV NS5A replication complex inhibitors Virology 2013, 444, 343-354
21. Ascher, D. B.; Wielens, J.; Nero, T. L.; Doughty, L.; Morton, C. J.; Parker, M. W. Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA Sci. Rep. 2014, 4, 4765
22. Bartenschlager, R.; Lohmann, V.; Penin, F. The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection Nat. Rev. Microbiol. 2013, 11, 482-496
23. Ross-Thriepland, D.; Amako, Y.; Harris, M. The C terminus of NS5A domain II is a key determinant of hepatitis C virus genome replication, but is not required for virion assembly and release J. Gen. Virol. 2013, 94, 1009-1018
24. Hughes, M.; Griffin, S.; Harris, M. Domain III of NS5A contributes to both RNA replication and assembly of hepatitis C virus particles J. Gen. Virol. 2009, 90, 1329-1334
25. Tellinghuisen, T. L.; Marcotrigiano, J.; Rice, C. M. Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase Nature 2005, 435, 374-379
26. Tellinghuisen, T. L.; Marcotrigiano, J.; Gorbalenya, A. E.; Rice, C. M. The NS5A protein of hepatitis C virus is a zinc metalloprotein J. Biol. Chem. 2004, 279, 48576-48587
27. Love, R. A.; Brodsky, O.; Hickey, M. J.; Wells, P. A.; Cronin, C. N. Crystal structure of a novel dimeric form of NS5A domain I protein from hepatitis C virus J. Virol. 2009, 83, 4395-4403
28. Elazar, M.; Cheong, K. H.; Liu, P.; Greenberg, H. B.; Rice, C. M.; Glenn, J. S. Amphipathic helix-dependent localization of NS5A mediates hepatitis C virus RNA replication J. Virol. 2003, 77, 6055-6061
29. Brass, V.; Bieck, E.; Montserret, R.; Wolk, B.; Hellings, J. A.; Blum, H. E.; Penin, F.; Moradpour, D. An amino-terminal amphipathic alpha-helix mediates membrane association of the hepatitis C virus nonstructural protein 5A J. Biol. Chem. 2002, 277, 8130-8139
30. Kay, B. K.; Williamson, M. P.; Sudol, M. The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains FASEB J. 2000, 14, 231-241
31. Amblard, F.; Zhang, H.; Zhou, L.; Shi, J.; Bobeck, D. R.; Nettles, J. H.; Chavre, S.; McBrayer, T. R.; Tharnish, P.; Whitaker, T.; Coats, S. J.; Schinazi, R. F. Synthesis and evaluation of non-dimeric HCV NS5A inhibitors Bioorg. Med. Chem. Lett. 2013, 23, 2031-2034
32. Zhang, H.; Zhou, L.; Amblard, F.; Shi, J.; Bobeck, D. R.; Tao, S.; McBrayer, T. R.; Tharnish, P. M.; Whitaker, T.; Coats, S. J.; Schinazi, R. F. Synthesis and evaluation of novel potent HCV NS5A inhibitors Bioorg. Med. Chem. Lett. 2012, 22, 4864-4868
33. Shi, J.; Zhou, L.; Amblard, F.; Bobeck, D. R.; Zhang, H.; Liu, P.; Bondada, L.; McBrayer, T. R.; Tharnish, P. M.; Whitaker, T.; Coats, S. J.; Schinazi, R. F. Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors Bioorg. Med. Chem. Lett. 2012, 22, 3488-3491
34. Sali, A.; Blundell, T. L. Comparative protein modelling by satisfaction of spatial restraints J. Mol. Biol. 1993, 234, 779-815
35. Koharudin, L. M.; Furey, W.; Liu, H.; Liu, Y. J.; Gronenborn, A. M. The phox domain of sorting nexin 5 lacks phosphatidylinositol 3-phosphate (PtdIns(3)P) specificity and preferentially binds to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) J. Biol. Chem. 2009, 284, 23697-23707
36. Villar, V. A.; Armando, I.; Sanada, H.; Frazer, L. C.; Russo, C. M.; Notario, P. M.; Lee, H.; Comisky, L.; Russell, H. A.; Yang, Y.; Jurgens, J. A.; Jose, P. A.; Jones, J. E. Novel role of sorting nexin 5 in renal D(1) dopamine receptor trafficking and function: implications for hypertension FASEB J. 2013, 27, 1808-1819
37. Chang, W.; Mosley, R. T.; Bansal, S.; Keilman, M.; Lam, A. M.; Furman, P. A.; Otto, M. J.; Sofia, M. J. Inhibition of hepatitis C virus NS5A by fluoro-olefin based gamma-turn mimetics Bioorg. Med. Chem. Lett. 2012, 22, 2938-2942
38. Warren, G. L.; Andrews, C. W.; Capelli, A. M.; Clarke, B.; LaLonde, J.; Lambert, M. H.; Lindvall, M.; Nevins, N.; Semus, S. F.; Senger, S.; Tedesco, G.; Wall, I. D.; Woolven, J. M.; Peishoff, C. E.; Head, M. S. A critical assessment of docking programs and scoring functions J. Med. Chem. 2006, 49, 5912-5931
39. Yoshikawa, Y.; Oishi, S.; Kubo, T.; Tanahara, N.; Fujii, N.; Furuya, T. Optimized method of G-protein-coupled receptor homology modeling: its application to the discovery of novel CXCR7 ligands J. Med. Chem. 2013, 56, 4236-4251
40. McGivern, D.; Masaki, T.; Williford, S.; Ingravallo, P.; Feng, Z.; Lahser, F.; Asante-Appiah, E.; Neddermann, P.; De Francesco, R.; Howe, A.; Lemon, S. Kinetic analyses reveal potent and early blockade of hepatitis C virus assembly by NS5A inhibitors Gastroenterology 2014, 147, 453-462
41. Stumpfe, D.; Hu, Y.; Dimova, D.; Bajorath, J. Recent progress in understanding activity cliffs and their utility in medicinal chemistry J. Med. Chem. 2014, 57, 18-28
42. Wong, K. A.; Worth, A.; Martin, R.; Svarovskaia, E.; Brainard, D. M.; Lawitz, E.; Miller, M. D.; Mo, H. Characterization of hepatitis C virus resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885 Antimicrob. Agents Chemother. 2013, 57, 6333-6340
43. Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank Nucleic Acids Res. 2000, 28, 235-242
44. Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF Chimera-a visualization system for exploratory research and analysis J. Comput. Chem. 2004, 25, 1605-1612
45. Tieleman, D. P.; Sansom, M. S.; Berendsen, H. J. Alamethicin helices in a bilayer and in solution: molecular dynamics simulations Biophys. J. 1999, 76, 40-49
46. Trott, O.; Olson, A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading J. Comput. Chem. 2010, 31, 455-461
47. Nettles, J. H.; Jenkins, J. L.; Bender, A.; Deng, Z.; Davies, J. W.; Glick, M. Bridging chemical and biological space: "target fishing" using 2D and 3D molecular descriptors J. Med. Chem. 2006, 49, 6802-6810
48. Nettles, J. H.; Jenkins, J. L.; Williams, C.; Clark, A. M.; Bender, A.; Deng, Z.; Davies, J. W.; Glick, M. Flexible 3D pharmacophores as descriptors of dynamic biological space J. Mol. Graphics Modell. 2007, 26, 622-633
49. Hari, M.; Loganzo, F.; Annable, T.; Tan, X. Z.; Musto, S.; Morilla, D. B.; Nettles, J. H.; Snyder, J. P.; Greenberger, L. M. Paclitaxel-resistant cells have a mutation in the paclitaxel-binding region of beta-tubulin (AsP(26)Glu) and less stable microtubules Mol. Cancer Ther. 2006, 5, 270-278