The Discovery and Development of Daclatasvir: An Inhibitor of the Hepatitis C Virus NS5A Replication Complex

  • Nicholas A. MeanwellEmail author
  • Makonen Belema
Part of the Topics in Medicinal Chemistry book series (TMC, volume 32)


The discovery of the hepatitis C virus (HCV) NS5A replication inhibitor daclatasvir (1) had its origins in a phenotypic screening lead. However, during the optimization campaign, it was observed that some members of the chemotype underwent a radical dimerization under the assay conditions. This redirected the effort to focus on palindromic molecules, a species subsequently shown to complement the dimeric nature of the NS5A protein. The most challenging aspect of the discovery program was extending antiviral activity to encompass GT-1a virus which was accomplished only after the development of extensive structure-activity relationships. In clinical trials, oral administration of daclatasvir (1) produced a profound effect on viral load with onset that was more rapid than had been seen previously with either NS3 protease or NS5B polymerase inhibitors. A groundbreaking clinical trial that combined daclatasvir (1) with the protease inhibitor asunaprevir (52) established that a chronic HCV infection could be cured with small molecule therapy in the absence of immune stimulation, setting the stage for approval of this regimen for the treatment of GT-1b-infected subjects by the Japanese health authorities on July 4, 2014.


Asunaprevir Beclabuvir Daclatasvir Dimerization Hepatitis C virus NS5A inhibitor, NS3 protease inhibitor Sofosbuvir Synergy 


Compliance with Ethical Standards

Conflict of Interest The authors are employees of Bristol-Myers Squibb and own company stock.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Belema M, Meanwell NA (2014) Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect. J Med Chem 57:5057–5071PubMedGoogle Scholar
  2. 2.
    Belema M, Schnittman SM, Meanwell NA (2016) Case history: the discovery of the first hepatitis C virus NS5A replication complex inhibitor daclatasvir (Daklinza™). Med Chem Rev 51:375–397Google Scholar
  3. 3.
    Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun J-H, O’Boyle DR II, Lemm JA, Wang C, Knipe JO, Chien C, Colonno RJ, Grasela DM, Meanwell NA, Hamann LG (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465:96–100Google Scholar
  4. 4.
    Belema M, Nguyen VN, Bachand C, Deon DH, Goodrich JT, James CA, Lavoie R, Lopez OD, Martel A, Romine JL, Ruediger EH, Snyder LB, St. Laurent DR, Yang F, Zhu J, Wong HS, Langley DR, Adams SP, Cantor GH, Chimalakonda A, Fura A, Johnson BM, Knipe JO, Parker DD, Santone KS, Fridell RA, Lemm JA, O’Boyle DR II, Colonno RJ, Gao M, Meanwell NA, Hamann LG (2014) Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir. J Med Chem 57:2013–2032PubMedGoogle Scholar
  5. 5.
    Belema M, Lopez OD, Bender JA, Romine JL, Laurent DR, Langley DR, Lemm JA, O’Boyle DRII, Sun J-H, Wang C, Fridell RA, Meanwell NA (2014) The discovery and development of hepatitis C virus NS5A replication complex inhibitors. J Med Chem 57:1643–1672PubMedGoogle Scholar
  6. 6.
    O’Boyle DR II, Nower PT, Lemm JA, Valera L, Sun J-H, Rigat K, Colonno R, Gao M (2005) Development of a cell-based high-throughput specificity screen using a hepatitis C virus-bovine viral diarrhea virus dual replicon assay. Antimicrob Agents Chemother 49:1346–1353PubMedPubMedCentralGoogle Scholar
  7. 7.
    Lohmann V, Körner F, Koch JO, Herian U, Theilmann L, Bartenschlager R (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110–113PubMedPubMedCentralGoogle Scholar
  8. 8.
    Bartenschlager R (2002) Hepatitis C virus replicons: potential role for drug development. Nat Rev Drug Discov 1:911–916PubMedGoogle Scholar
  9. 9.
    Bartenschlager R (2005) The hepatitis C virus replicon system: from basic research to clinical application. J Hepatol 43:210–216PubMedGoogle Scholar
  10. 10.
    Taylor DR (2013) Evolution of cell culture systems for HCV. Antivir Ther 18:523–530PubMedGoogle Scholar
  11. 11.
    Lohmann V, Bartenschlager R (2014) On the history of hepatitis C virus cell culture systems. J Med Chem 57:1627–1642PubMedGoogle Scholar
  12. 12.
    Lemm JA, O’Boyle DR II, Liu M, Nower PT, Colonno R, Deshpande MS, Snyder LB, Martin SW, St. Laurent DR, Serrano-Wu MH, Romine JL, Meanwell NA, Gao M (2010) Identification of hepatitis C virus NS5A inhibitors. J Virol 84:482–491PubMedPubMedCentralGoogle Scholar
  13. 13.
    Verma A, Saraf SK (2008) 4-Thiazolidinone – A biologically active scaffold. Eur J Med Chem 43:897–905PubMedGoogle Scholar
  14. 14.
    Sarkis M, Tran D-N, Dasso Lang MC, Garbay C, Braud E (2014) Convenient synthesis of 5-arylidene-2-imino-4-thiazolidinone derivatives using microwave irradiation. Synlett 25:1257–1262Google Scholar
  15. 15.
    Romine JL, St. Laurent DR, Leet JE, Martin SW, Serrano-Wu MH, Yang F, Gao M, O’Boyle DR II, Lemm JA, Sun J-H, Nower PT, Huang X, Deshpande MS, Meanwell NA, Snyder LB (2011) Inhibitors of HCV NS5A: from iminothiazolidinones to symmetrical stilbenes. ACS Med Chem Lett 2:224–229PubMedPubMedCentralGoogle Scholar
  16. 16.
    Macdonald A, Harris M (2004) Hepatitis C virus NS5A: tales of a promiscuous protein. J Gen Virol 85:2485–2502PubMedPubMedCentralGoogle Scholar
  17. 17.
    Pawlotsky J-M, Germanidis G (1999) The non-structural 5A protein of hepatitis C virus. J Viral Hepat 6:343–356PubMedGoogle Scholar
  18. 18.
    Ross-Thriepland D, Harris M (2015) Hepatitis C virus NS5A: enigmatic but still promiscuous 10 years on! J Gen Virol 96:727–738PubMedGoogle Scholar
  19. 19.
    De Francesco R, Neddermann P, Tomei L, Steinkühler C, Gallinari P, Folgori A (2000) Biochemical and immunologic properties of the nonstructural proteins of the hepatitis C virus: implications for development of antiviral agents and vaccines. Semin Liver Dis 20:69–83PubMedGoogle Scholar
  20. 20.
    Bukh J, Pietschmann T, Lohmann V, Krieger N, Faulk K, Engle RE, Govindarajan S, Shapiro M, St. Claire M, Bartenschlager R (2002) Mutations that permit efficient replication of hepatitis C virus RNA in Huh-7 cells prevent productive replication in chimpanzees. Proc Natl Acad Sci U S A 99:14416–14421PubMedPubMedCentralGoogle Scholar
  21. 21.
    St Laurent DR, Gao Q, Wu D, Serrano-Wu MH (2004) Regioselective synthesis of 3-(heteroaryl)-iminothiazolindin-4-ones. Tetrahedron Lett 45:1907–1910Google Scholar
  22. 22.
    Lemm JA, Leet JE, O’Boyle DR II, Romine JL, Huang XS, Schroeder DR, Alberts J, Cantone JL, Sun J-H, Nower PT, Martin SW, Serrano-Wu MH, Meanwell NA, Snyder LB, Gao M (2011) Discovery of potent hepatitis C virus NS5A inhibitors with dimeric structures. Antimicrob Agents Chemother 55:3795–3802PubMedPubMedCentralGoogle Scholar
  23. 23.
    Leet JE, Belcastro JV, Dowling CJ, Nemeth GA, Weller HN (2015) HPLC biogram analysis: a powerful tool used for hit confirmation in early drug discovery. J Biomol Screen 20:681–687PubMedGoogle Scholar
  24. 24.
    Viehe HG, Janousek Z, Merenyi R, Stella L (1985) The captodative effect. Acc Chem Res 18:148–154Google Scholar
  25. 25.
    Ingold KU, Pratt DA (2014) Advances in radical-trapping antioxidant chemistry in the twenty-first century: a kinetics and mechanisms perspective. Chem Rev 114:9022–9046PubMedGoogle Scholar
  26. 26.
    Tellinghuisen TL, Marcotrigiano J, Rice CM (2005) Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature 435:374–379PubMedPubMedCentralGoogle Scholar
  27. 27.
    Love RA, Brodsky O, Hickey MJ, Wells PA, Cronin CN (2009) Crystal structure of a novel dimeric form of NS5A domain I protein from hepatitis C virus. J Virol 83:4395–4403PubMedPubMedCentralGoogle Scholar
  28. 28.
    Lambert SM, Langley DR, Garnett JA, Hedgethorne K, Meanwell NA, Matthews SJ (2014) The crystal structure of NS5A domain 1 from genotype 1a reveals new clues to the mechanism of action for dimeric HCV inhibitors. Protein Sci 23:723–734PubMedPubMedCentralGoogle Scholar
  29. 29.
    Lim PJ, Chatterju U, Cordek D, Sharma SD, Garcia-Rivera JA, Cameron CE, Lin K, Targett-Adams P, Gallay PA (2012) Correlation between NS5A dimerization and HCV replication. J Biol Chem 287:30861–30873PubMedPubMedCentralGoogle Scholar
  30. 30.
    Huang L, Hwang J, Sharma SD, Hargittai MRS, Chen Y, Arnold JJ, Raney KD, Cameron CE (2005) Hepatitis C virus nonstructural protein 5A (NS5A) is an RNA-binding protein. J Biol Chem 280:36417–36428PubMedGoogle Scholar
  31. 31.
    Hwang J, Huang L, Cordek DG, Vaughan R, Reynolds SL, Kihara G, Raney KD, Kao CC, Cameron CE (2010) Hepatitis C virus nonstructural protein 5A: biochemical characterization of a novel structural class of RNA-binding proteins. J Virol 84:12480–12491PubMedPubMedCentralGoogle Scholar
  32. 32.
    Foster TL, Belyaeva T, Stonehouse NJ, Pearson AR, Harris M (2010) All three domains of the hepatitis C virus nonstructural NS5A protein contribute to RNA binding. J Virol 84:9267–9277PubMedPubMedCentralGoogle Scholar
  33. 33.
    Lopez OD, Nguyen VN, St Laurent DR, Belema M, Serrano-Wu MH, Goodrich JT, Yang F, Qiu Y, Ripka AS, Nower PT, Valera L, Liu M, O’Boyle DR II, Sun J-H, Fridell RA, Lemm JA, Gao M, Good AC, Meanwell NA, Snyder LB (2013) HCV NS5A replication complex inhibitors. Part 3: discovery of potent analogs with distinct core topologies. Bioorg Med Chem Lett 23:779–784PubMedGoogle Scholar
  34. 34.
    St Laurent DR, Serrano-Wu MH, Belema M, Ding M, Fang H, Gao M, Goodrich JT, Krause RG, Lemm JA, Liu M, Lopez OD, Nguyen VN, Nower PT, O’Boyle DR II, Pearce BC, Romine JL, Valera L, Sun J-H, Wang Y-K, Yang F, Yang X, Meanwell NA, Snyder LB (2014) HCV NS5A replication complex inhibitors. Part 4: optimization for genotype 1a replicon inhibitory activity. J Med Chem 57:1976–1994PubMedGoogle Scholar
  35. 35.
    Belema M, Nguyen VN, St Laurent DR, Lopez OD, Qiu Y, Good AC, Nower PT, Valera L, O’Boyle DR II, Sun J-H, Fridell RA, Lemm JA, Gao M, Knipe JO, Meanwell NA, Snyder LB (2013) HCV NS5A replication complex inhibitors. Part 5: discovery of potent and pan-genotypic HCV NS5A replication complex inhibitors. Bioorg Med Chem Lett 23:4428–4435PubMedGoogle Scholar
  36. 36.
    Belema M, Nguyen VN, Romine JL, St Laurent DR, Lopez OD, Goodrich J, Nower PT, O’Boyle DR II, Lemm JA, Fridell RA, Gao M, Fang H, Krause RG, Wang Y-K, Oliver AJ, Good AC, Knipe JO, Meanwell NA, Snyder LB (2014) Hepatitis C virus NS5A replication complex inhibitors. Part 6: the discovery of a novel and highly potent biarylimidazole chemotype with inhibitory activity toward genotype 1a and 1b replicons. J Med Chem 57:1995–2012PubMedGoogle Scholar
  37. 37.
    Fridell RA, Qiu D, Wang C, Valera L, Gao M (2010) Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system. Antimicrob Agents Chemother 54:3641–3650PubMedPubMedCentralGoogle Scholar
  38. 38.
    Wang C, Jia L, Huang H, Qiu D, Valera L, Huang X, Sun J-H, Nower PT, O’Boyle DR II, Gao M, Fridell RA (2012) In vitro activity of BMS-790052 on hepatitis C virus genotype 4 NS5A. Antimicrob Agents Chemother 56:1588–1590PubMedPubMedCentralGoogle Scholar
  39. 39.
    Wang C, Valera L, Jia L, Kirk MJ, Gao M, Fridell RA (2013) In vitro activity of daclatasvir on hepatitis C virus genotype 3 NS5A. Antimicrob Agents Chemother 57:611–613PubMedPubMedCentralGoogle Scholar
  40. 40.
    Wang C, Jia L, O’Boyle DR, Sun J-H, Rigat K, Valera L, Nower P, Huang X, Kienzle B, Roberts S, Gao M, Fridell RA (2014) Comparison of daclatasvir resistance barriers on NS5A from hepatitis C virus genotypes 1 to 6: implications for cross-genotype activity. Antimicrob Agents Chemother 58:5155–5163PubMedPubMedCentralGoogle Scholar
  41. 41.
    Wakenhut F, Tran TD, Pickford C, Shaw S, Westby M, Smith-Burchnell C, Watson L, Paradowski M, Milbank J, Stonehouse D, Cheung K, Wybrow R, Daverio F, Crook S, Statham K, Leese D, Stead D, Adam F, Hay D, Roberts LR, Chiva J-Y, Nichols C, David C, Blakemore D, Goetz GH, Che Y, Gardner I, Dayal S, Pike A, Webster R, Pryde DC (2014) The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile – part 2. ChemMedChem 9:1387–1396PubMedGoogle Scholar
  42. 42.
    Szabo G (2006) Hepatitis C virus NS5A protein – a master regulator? Gastroenterology 130:996–999Google Scholar
  43. 43.
    Najarro P, Mathews N, Cockerill S (2006) NS5A inhibitors. In: Tan S-L (ed) Hepatitis C viruses. Horizon Bioscience, Wymondham, pp 271–292Google Scholar
  44. 44.
    Schmitz U, Tan S-L (2008) NS5A – from obscurity to new target for HCV therapy. Recent Pat Antiinfect Drug Discov 3:77–92PubMedGoogle Scholar
  45. 45.
    Cordek DG, Bechtel JT, Maynard AT, Kazmierski WM, Cameron CE (2011) Targeting the NS5A protein of HCV: an emerging option. Drugs Future 36:691–711PubMedPubMedCentralGoogle Scholar
  46. 46.
    Belda O, Targett-Adams P (2012) Small molecule inhibitors of the hepatitis C virus-encoded NS5A protein. Virus Res 170:1–14PubMedGoogle Scholar
  47. 47.
    Debes JD, Smith CI (2012) NS5A: a new target for antiviral drugs in the treatment of hepatitis C virus infection. Hepatology 56:797–799PubMedGoogle Scholar
  48. 48.
    Gao M, O’Boyle DR II, Roberts S (2016) HCV NS5A replication complex inhibitors. Curr Opin Pharmacol 30:151–157PubMedGoogle Scholar
  49. 49.
    Guedj J, Dahari H, Rong L, Sansone ND, Nettles RE, Cotler SJ, Layden TJ, Uprichard SL, Perelson AS (2013) 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 110:3991–3996PubMedPubMedCentralGoogle Scholar
  50. 50.
    McGivern DR, Masaki T, Williford S, Ingravallo P, Feng Z, Lahser F, Asante-Appiah E, Neddermann P, De Francesco R, Howe AY, Lemon SM (2014) Kinetic analyses reveal potent and early blockade of hepatitis C virus assembly by NS5A inhibitors. Gastroenterology 147:453–462PubMedPubMedCentralGoogle Scholar
  51. 51.
    Nettles RE, Gao M, Bifano M, Chung E, Persson A, Marbury TC, Goldwater R, DeMicco MP, Rodriguez-Torres M, Vutikullird A, Fuentes E, Lawitz E, Lopez-Talavera JC, Grasela DM (2011) Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1. Hepatology 54:1956–1965PubMedGoogle Scholar
  52. 52.
    Tellinghuisen TL, Rice CM (2002) Interaction between hepatitis C virus and host cell factors. Curr Opin Microbiol 5:419–427PubMedGoogle Scholar
  53. 53.
    Kwofie SK, Schaefer U, Sundararajan VS, Bajic VB, Christoffels A (2011) HCVpro: hepatitis C virus protein interaction database. Infect Genet Evol 11:1971–1977PubMedGoogle Scholar
  54. 54.
    Tripathi LP, Kambara H, Chen Y-A, Nishimura Y, Moriishi K, Okamoto T, Morita E, Abe T, Mori T, Matsuura Y, Mizuguchi K (2013) Understanding the biological context of NS5A-host interactions in HCV infection: a network-based approach. J Proteome Res 12:2537–2551PubMedGoogle Scholar
  55. 55.
    Upadhyay A, Dixit U, Manvar D, Chaturvedi N, Pandey VN (2013) Affinity capture and identification of host cell factors associated with hepatitis C virus (+) strand subgenomic RNA. Mol Cell Proteomics 12:1539–1552PubMedPubMedCentralGoogle Scholar
  56. 56.
    Dolan PT, Zhang C, Khadka S, Arumugaswami V, Vangeloff AD, Heaton NS, Sahasrabudhe S, Randall G, Sun R, LaCount DJ (2013) Identification and comparative analysis of hepatitis C virus-host cell protein interactions. Mol Biosyst 9:3199–3209PubMedPubMedCentralGoogle Scholar
  57. 57.
    Colpitts CC, Lupberger J, Doerig C, Baumert TF (2015) Host cell kinases and the hepatitis C virus lifecycle. Biochim Biophys Acta 1854(10 Part B):1657–1662PubMedGoogle Scholar
  58. 58.
    Ascher DB, Wielens J, Nero TL, Doughty L, Morton CJ, Parker MW (2014) Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA. Nat Sci Rep.
  59. 59.
    Kwon HJ, Xing W, Chan K, Niedziela-Majka A, Brendza KM, Kirschberg T, Kato D, Link JO, Cheng G, Liu X, Sakowicz R (2015) Direct binding of ledipasvir to HCV NS5A: mechanism of resistance to an HCV antiviral agent. PLoS One. PubMedPubMedCentralGoogle Scholar
  60. 60.
    Sun J-H, O’Boyle DR II, Fridell RA, Langley DR, Wang C, Roberts SB, Nower P, Johnson BM, Moulin F, Nophsker MJ, Wang Y-K, Liu M, Rigat K, Tu Y, Hewawasam P, Kadow J, Meanwell NA, Cockett M, Lemm JA, Kramer M, Belema M, Gao M (2015) Resensitizing daclatasvir-resistance hepatitis C variants by allosteric modulation of NS5A. Nature 527:245–248PubMedGoogle Scholar
  61. 61.
    O’Boyle DR II, Nower PT, Gao M, Fridell R, Wang C, Hewawasam P, Lopez O, Tu Y, Meanwell NA, Belema M, Roberts SB, Cockett M, Sun J-H (2016) Synergistic activity of combined NS5A inhibitors. Antimicrob Agents Chemother 60:1573–1583PubMedCentralGoogle Scholar
  62. 62.
    Nettles JH, Stanton RA, Broyde J, Amblard F, Zhang H, Zhou L, Shi J, McBrayer TR, Whitaker T, Coats SJ, Kohler JJ, Schinazi RF (2014) Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition. J Med Chem 57:10031–10043PubMedPubMedCentralGoogle Scholar
  63. 63.
    Issur M, Goette M (2014) Resistance patterns associated with HCV NS5A inhibitors provide limited insight into drug binding. Viruses 6:4227–4241PubMedPubMedCentralGoogle Scholar
  64. 64.
    Barakat KH, Anwar-Mohamed A, Tuszynski JA, Robins MJ, Tyrrell DL, Houghton M (2015) A refined model of the HCV NS5A protein bound to daclatasvir explains drug-resistant mutations and activity against divergent genotypes. J Chem Inf Model 55:362–373PubMedGoogle Scholar
  65. 65.
    Ahmed M, Pal A, Houghton M, Barakat K (2016) A comprehensive computational analysis for the binding modes of hepatitis C virus NS5A inhibitors: the question of symmetry. ACS Infect Dis 2:872–881PubMedGoogle Scholar
  66. 66.
    Badillo A, Receveur-Brechot V, Sarrazin S, Cantrelle FX, Delolme F, Fogeron M-L, Molle J, Montserret R, Bockmann A, Bartenschlager R, Lohmann V, Lippens G, Ricard-Blum S, Hanoulle X, Penin F (2017) Overall structural model of NS5A protein from hepatitis C virus and modulation by mutations conferring resistance of virus replication to cyclosporin A. Biochemistry 56:3029–3048PubMedGoogle Scholar
  67. 67.
    Ahmed A, Felmlee DJ (2015) Mechanisms of hepatitis C viral resistance to direct acting antivirals. Viruses 7:6716–6729PubMedPubMedCentralGoogle Scholar
  68. 68.
    Appel N, Schaller T, Penin F, Bartenschlager R (2006) From structure to function: new insights into hepatitis C virus RNA replication. J Biol Chem 281:9833–9836PubMedGoogle Scholar
  69. 69.
    Moon SL, Barnhart MD, Wilusz J (2012) Inhibition and avoidance of mRNA degradation by RNA viruses. Curr Opin Microbiol 15:500–505PubMedPubMedCentralGoogle Scholar
  70. 70.
    Molleston JM, Cherry S (2017) Attacked from all sides: RNA decay in antiviral defense. Viruses 9:2. CrossRefPubMedCentralGoogle Scholar
  71. 71.
    Targett-Adams P, Graham EJ, Middleton J, Palmer A, Shaw SM, Lavender H, Brain P, Tran TD, Jones LH, Wakenhut F, Stammen B, Pryde D, Pickford C, Westby M (2011) Small molecules targeting hepatitis C virus-encoded NS5A cause subcellular redistribution of their target: insights into compound modes of action. J Virol 85:6353–6368PubMedPubMedCentralGoogle Scholar
  72. 72.
    Qiu D, Lemm JA, O’Boyle DR II, Sun JH, Nower P, Nguyen V, Hamann LG, Snyder LB, Deon DH, Ruediger E, Meanwell NA, Belema M, Gao M, Fridell RA (2011) The effect of NS5A inhibitors on NS5A phosphorylation, polyprotein processing and localization. J Gen Virol 92:2502–2511PubMedGoogle Scholar
  73. 73.
    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 (2014) Daclatasvir-like inhibitors of NS5A block early biogenesis of hepatitis C virus-induced membranous replication factories, independent of RNA replication. Gastroenterology 147:1094–1105PubMedPubMedCentralGoogle Scholar
  74. 74.
    Boson B, Denolly S, Turlure F, Chamot C, Dreuz M, Cosset F-L (2017) Daclatasvir prevents hepatitis C virus infectivity by blocking transfer of the viral genome to assembly sites. Gastroenterology 152:895–907PubMedGoogle Scholar
  75. 75.
    Lee C, Ma H, Hang JQ, Leveque V, Sklan EH, Elazar M, Klumpp K, Glenn JS (2011) The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein. Virology 414:10–18PubMedPubMedCentralGoogle Scholar
  76. 76.
    Chatterji U, Bobardt M, Tai A, Wood M, Gallay PA (2015) Cyclophilin and NS5A inhibitors, but not other anti-hepatitis C virus (HCV) agents, preclude HCV-mediated formation of double-membrane-vesicle viral factories. Antimicrob Agents Chemother 59:2496–2507PubMedPubMedCentralGoogle Scholar
  77. 77.
    Jiang H, Zeng J, Li W, Bifano M, Gu H, Titsch C, Easter J, Burrell R, Kandoussi H, Aubry A-F, Arnold ME (2012) Practical and efficient strategy for evaluating oral absolute bioavailability with an intravenous microdose of a stable isotopically-labeled drug using a selected reaction monitoring mass spectrometry assay. Anal Chem 84:10031–10037PubMedGoogle Scholar
  78. 78.
    McCormack PL (2015) Daclatasvir: a review of its use in adult patients with chronic hepatitis C virus infection. Drugs 75:515–524PubMedGoogle Scholar
  79. 79.
    Gandhi Y, Eley T, Fura A, Li W, Bertz RJ, Garimella T (2018) Daclatasvir: a review of preclinical and clinical pharmacokinetics. Clin Pharmacokinet 57:911–928. PubMedGoogle Scholar
  80. 80.
    Keating GM (2016) Daclatasvir: a review in chronic hepatitis C. Drugs 76:1381–1391PubMedGoogle Scholar
  81. 81.
    Powdrill MH, Tchesnokov EP, Kozak RA, Russell RS, Martin R, Svarovskaia ES, Mo H, Kouyos RD, Götte M (2011) Contribution of a mutational bias in hepatitis C virus replication to the genetic barrier in the development of drug resistance. Proc Natl Acad Sci U S A 108:20509–20513PubMedPubMedCentralGoogle Scholar
  82. 82.
    Wyles DL (2013) Antiviral resistance and the future landscape of hepatitis C virus infection therapy. J Infect Dis 207(S1):S33–S39PubMedGoogle Scholar
  83. 83.
    Wyles DL, Gutierrez JA (2014) Importance of HCV genotype 1 subtypes for drug resistance and response to therapy. J Viral Hepat 21:229–240PubMedPubMedCentralGoogle Scholar
  84. 84.
    Fridell RA, Wang C, Sun J-H, O’Boyle DR II, Nower P, Valera L, Qiu D, Roberts S, Huang X, Kienzle B, Bifano M, Nettles RE, Gao M (2011) 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 54:1924–1935PubMedGoogle Scholar
  85. 85.
    Wang C, Huang H, Valera L, Sun J-H, O’Boyle DR II, Nower PT, Jia L, Qiu D, Huang X, Altaf A, Gao M, Fridell RA (2012) Hepatitis C virus RNA elimination and development of resistance in replicon cells treated with BMS-790052. Antimicrob Agents Chemother 56:1350–1358PubMedPubMedCentralGoogle Scholar
  86. 86.
    Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS (1998) Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy. Science 282:103–107PubMedGoogle Scholar
  87. 87.
    Perelson AS, Herrmann E, Micol F, Zeuzem S (2005) New kinetic models for the hepatitis C virus. Hepatology 42:749–754PubMedGoogle Scholar
  88. 88.
    Shudo E, Ribeiro RM, Perelson AS (2009) Modeling HCV kinetics under therapy using PK and PD information. Expert Opin Drug Metab Toxicol 5:321–332PubMedPubMedCentralGoogle Scholar
  89. 89.
    Rong L, Perelson AS (2010) Treatment of hepatitis C virus infection with interferon and small molecule direct antivirals: viral kinetics and modeling. Crit Rev Immunol 30:131–148PubMedPubMedCentralGoogle Scholar
  90. 90.
    Ribeiro RM, Li H, Wang S, Stoddard MB, Learn GH, Korber BT, Bhattacharya T, Guedj J, Parrish EH, Hahn BH, Shaw GM, Perelson AS (2012) Quantifying the diversification of hepatitis C virus (HCV) during primary infection: estimates of the in vivo mutation rate. PLoS Pathog 8(8):e1002881. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Chatterjee A, Guedj J, Perelson AS (2012) Mathematical modeling of HCV infection: what can it teach us in the era of direct-acting antiviral agents? Antivir Ther 17:1171–1182PubMedPubMedCentralGoogle Scholar
  92. 92.
    Hézode C, Hirschfield GM, Ghesquiere W, Sievert W, Rodriguez-Torres M, Shafran SD, Thuluvath PJ, Tatum HA, Waked I, Esmat GE, Lawitz EJ, Rustgi VK, Pol S, Weis N, Pockros PJ, Bourlière M, Serfaty L, Vierling JM, Fried MW, Weiland O, Brunetto MR, Everson GT, Zeuzem S, Kwo PY, Sulkowski M, Bräu N, Hernandez D, McPhee F, Wind-Rotolo M, Liu Z, Noviello S, Hughes EA, Yin PD, Schnittman S (2015) Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study. Gut 64:948–956PubMedGoogle Scholar
  93. 93.
    Dore GJ, Lawitz E, Hézode C, Shafran SD, Ramji A, Tatum HA, Taliani G, Tran A, Brunetto MR, Zaltron S, Strasser SI, Weis N, Ghesquiere W, Lee SS, Larrey D, Pol S, Harley H, George J, Fung SK, de Lédinghen V, Hagens P, McPhee F, Hernandez D, Cohen D, Cooney E, Noviello S, Hughes E (2015) Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection. Gastroenterology 148:355–366PubMedGoogle Scholar
  94. 94.
    Sulkowski MS, Fessel WJ, Lazzarin A, Berenguer J, Zakharova N, Cheinquer H, Cote P, Dieterich D, Gadano A, Matthews G, Molina J-M, Moreno C, Pineda JA, Pulido F, Rivero A, Rockstroh J, Hernandez D, McPhee F, Eley T, Mendez P, Liu Z, Hughes E, Noviello S, Ackerman P (2017) Efficacy and safety of daclatasvir plus pegylated-interferon alfa 2a and ribavirin in previously untreated HCV subjects coinfected with HIV and HCV genotype-1: a phase III, open-label study. Hepatol Int 11:188–198PubMedGoogle Scholar
  95. 95.
    Suzuki F, Toyota J, Ikeda K, Chayama K, Mochida S, Hayashi N, Ishikawa H, Miyagoshi H, Hu W, McPhee F, Hughes EA, Kumada H (2014) A randomized trial of daclatasvir with peginterferon alfa-2b and ribavirin for HCV genotype 1 infection. Antivir Ther 19:491–499PubMedGoogle Scholar
  96. 96.
    Izumi N, Yokosuka O, Kawada N, Osaki Y, Yamamoto K, Sata M, Ishikawa H, Ueki T, Hu W, McPhee F, Hughes EA, Kumada H (2014) Daclatasvir combined with peginterferon alfa-2a and ribavirin in Japanese patients infected with hepatitis C genotype 1. Antivir Ther 19:501–510PubMedGoogle Scholar
  97. 97.
    Scola PM, Sun L-Q, Wang AX, Chen J, Sin N, Venables BL, Sit S-Y, Chen Y, Cocuzza A, Bilder DM, D’Andrea SV, Zheng B, Hewawasam P, Tu Y, Friborg J, Falk P, Hernandez D, Levine S, Chen C, Yu F, Sheaffer AK, Zhai G, Barry D, Knipe JO, Han Y-H, Schartman R, Donoso M, Mosure K, Sinz MW, Zvyaga T, Good AC, Rajamani R, Kish K, Tredup J, Klei HE, Gao Q, Mueller L, Colonno RJ, Grasela DM, Adams SP, Loy J, Levesque PC, Sun H, Shi H, Sun L, Warner W, Li D, Zhu J, Meanwell NA, McPhee F (2015) The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection. J Med Chem 57:1730–1752Google Scholar
  98. 98.
    McPhee F, Sheaffer AK, Friborg J, Hernandez D, Falk P, Zhai G, Levine S, Chaniewski S, Yu F, Barry D, Chen C, Lee MS, Mosure K, Sun L-Q, Sinz M, Meanwell NA, Colonno RJ, Knipe J, Scola P (2012) Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032). Antimicrob Agents Chemother 56:5387–5396PubMedPubMedCentralGoogle Scholar
  99. 99.
    Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, Rustgi V, McPhee F, Wind-Rotolo M, Persson A, Zhu K, Dimitrova DI, Eley T, Guo T, Grasela DM, Pasquinelli C (2012) Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 366:216–224PubMedPubMedCentralGoogle Scholar
  100. 100.
    Chung RT (2012) A watershed moment in the treatment of hepatitis C. N Engl J Med 366:273–275PubMedGoogle Scholar
  101. 101.
    McPhee F, Friborg J, Levine S, Chen C, Falk P, Yu F, Hernandez D, Lee MS, Chaniewski S, Sheaffer AK, Pasquinelli C (2012) Resistance analysis of the hepatitis C virus NS3 protease inhibitor asunaprevir. Antimicrob Agents Chemother 56:3670–3681PubMedPubMedCentralGoogle Scholar
  102. 102.
    Lok AS, Gardiner DF, Hézode C, Lawitz EJ, Bourlière M, Everson GT, Marcellin P, Rodriguez-Torres M, Pol S, Serfaty L, Eley T, Huang S-P, Li J, Wind-Rotolo M, Yu F, McPhee F, Grasela DM, Pasquinelli C (2014) Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatol 60:490–499PubMedGoogle Scholar
  103. 103.
    Toyoda H, Kumada T, Takaguchi K, Shimada N, Tanaka J (2014) Changes in hepatitis C virus genotype distribution in Japan. Epidemiol Infect 142:2624–2628PubMedGoogle Scholar
  104. 104.
    Chung H, Ueda T, Kudo M (2010) Changing trends in hepatitis C infection over the past 50 years in Japan. Intervirology 53:39–43PubMedGoogle Scholar
  105. 105.
    Chayama K, Takahashi S, Toyota J, Karino Y, Ikeda K, Ishikawa H, Watanabe H, McPhee F, Hughes E, Kumada H (2012) Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology 55:742–748PubMedGoogle Scholar
  106. 106.
    Wang HL, Lu X, Yang X, Xu N (2017) Effectiveness and safety of daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: systematic review and meta-analysis. J Gastroenterol Hepatol 32:45–52PubMedGoogle Scholar
  107. 107.
    Poole RM (2014) Daclatasvir + asunaprevir: first global approval. Drugs 74:1559–1571PubMedGoogle Scholar
  108. 108.
    Karino Y, Toyota J, Ikeda K, Suzuki F, Chayama K, Kawakami Y, Ishikawa H, Watanabe H, Hernandez D, Yu F, McPhee F, Kumada H (2013) Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct acting antivirals daclatasvir and asunaprevir. J Hepatol 58:646–654PubMedGoogle Scholar
  109. 109.
    Suzuki Y, Ikeda K, Suzuki F, Toyota J, Karino Y, Chayama K, Kawakami Y, Ishikawa H, Watanabe J, Hu W, Eley T, McPhee F, Hughes E, Kumada H (2013) Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J Hepatol 58:655–662PubMedGoogle Scholar
  110. 110.
    Kumada H, Suzuki Y, Ikeda K, Toyota J, Karino Y, Chayama K, Kawakami Y, Ido A, Yamamoto K, Takaguchi K, Izumi N, Koike K, Takehara T, Kawada N, Sata M, Miyagoshi H, Eley T, McPhee F, Damokosh A, Ishikawa H, Hughes E (2014) Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 59:2083–2091PubMedPubMedCentralGoogle Scholar
  111. 111.
    McPhee F, Suzuki Y, Toyota J, Karino Y, Chayama K, Kawakami Y, Yu ML, Ahn SH, Ishikawa H, Bhore R, Zhou N, Hernandez D, Mendez P, Kumada H (2015) High sustained virologic response to daclatasvir plus asunaprevir in elderly and cirrhotic patients with hepatitis C virus genotype 1b without baseline NS5A polymorphisms. Adv Ther 32:637–649PubMedPubMedCentralGoogle Scholar
  112. 112.
    Kanda T, Yasui S, Nakamura M, Suzuki E, Arai M, Haga Y, Sasaki R, Wu S, Nakamoto S, Imazeki F, Yokosuka O (2016) Daclatasvir plus asunaprevir treatment for real-world HCV genotype 1-infected patients in Japan. Int J Med Sci 13:418–423PubMedPubMedCentralGoogle Scholar
  113. 113.
    Kumada H, Suzuki F, Suzuki Y, Toyota J, Karino Y, Chayama K, Kawakami Y, Fujiyama S, Ito T, Itoh Y, Tamura E, Ueki T, Ishikawa H, Hu W, McPhee F, Linaberry M, Hughes E (2016) Randomized comparison of daclatasvir+asunaprevir versus telaprevir+peginterferon/ribavirin in Japanese hepatitis C virus patients. J Gastroenterol Hepatol 31:14–22PubMedGoogle Scholar
  114. 114.
    Akuta N, Sezaki H, Suzuki F, Kawamura Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Suzuki Y, Arase Y, Ikeda K, Kumada H (2017) Favorable efficacy of daclatasvir plus asunaprevir in treatment of elderly Japanese patients infected with HCV genotype 1b aged 70 and older. J Med Virol 89:91–98PubMedGoogle Scholar
  115. 115.
    Toyoda H, Kumada T, Tada T, Shimada N, Takaguchi K, Senoh T, Tsuji K, Tachi Y, Hiraoka A, Ishikawa T, Shima T, Okanoue T (2017) Efficacy and tolerability of an IFN-free regimen with DCV/ASV for elderly patients infected with HCV genotype 1B. J Hepatol 66:521–527PubMedGoogle Scholar
  116. 116.
    Sezaki H, Suzuki F, Hosaka T, Akuta N, Fujiyama S, Kawamura Y, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Kumada H (2017) The efficacy and safety of dual oral therapy with daclatasvir and asunaprevir for genotype 1b in Japanese real-life settings. Liver Int 37:1325–1333PubMedGoogle Scholar
  117. 117.
    Hayes CN, Imamura M, Chayama K (2017) The practical management of chronic hepatitis C infection in Japan – dual therapy of daclatasvir + asunaprevir. Expert Rev Gastroenterol Hepatol 11:103–113PubMedGoogle Scholar
  118. 118.
    Adler H, Lambert JS (2014) Daclatasvir for the treatment of hepatitis C virus infection. Expert Rev Gastroenterol Hepatol 8:725–738PubMedGoogle Scholar
  119. 119.
    Gamal N, Gitto S, Andreone P (2016) Efficacy and safety of daclatasvir in hepatitis C: an overview. J Clin Transl Hepatol 4:336–344PubMedPubMedCentralGoogle Scholar
  120. 120.
    Gentles RG, Ding M, Bender JA, Bergstrom CP, 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 BR, Camac DM, Chang C-H, Gao M, Morin PE, Sheriff S, Tredup J, Wan J, Witmer MR, Xie D, Hanumegowda U, Knipe J, Mosure K, Santone KS, Parker DD, Zhuo X, Lemm J, Liu M, Pelosi L, Rigat K, Voss S, Wang Y, Wang Y-K, Colonno RJ, Gao M, Roberts SB, Gao Q, Ng A, Meanwell NA, Kadow JF (2014) Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase. J Med Chem 57:1855–1879PubMedGoogle Scholar
  121. 121.
    Poordad F, Sievert W, Mollison L, Bennett M, Tse E, Brau N, Levin J, Sepe T, Lee SS, Angus P, Conway B, Pol S, Boyer N, Bronowicki J-P, Jacobson I, Muir AJ, Reddy KR, Tam E, Ortiz-Lasanta G, de Ledinghen V, Sulkowski M, Boparai N, McPhee F, Hughes E, Swenson ES, Yin PD, UNITY-1 Study Group (2013) Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients with HCV genotype 1 infection. J Am Med Assoc 313:1728–1735Google Scholar
  122. 122.
    Muir AJ, Poordad F, Lalezari J, Everson G, Dore GJ, Herring R, Sheikh A, Kwo P, Hézode C, Pockros PJ, Tran A, Yozviak J, Reau N, Ramji A, Stuart K, Thompson AJ, Vierling J, Freilich B, Cooper J, Ghesquiere W, Yang R, McPhee F, Hughes EA, Swenson ES, Yin PD (2015) Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis. J Am Med Assoc 313:1736–1744Google Scholar
  123. 123.
    Hassanein T, Sims KD, Bennett M, Gitlin N, Lawitz E, Nguyen T, Webster L, Younossi Z, Schwartz H, Thuluvath PJ, Zhou H, Rege B, McPhee F, Zhou N, Wind-Rotolo M, Chung E, Griffies A, Grasela DM, Gardiner DF (2015) A randomized trial of daclatasvir in combination with asunaprevir and beclabuvir in patients with chronic hepatitis C virus genotype 4 infection. J Hepatol 62:1204–1206PubMedGoogle Scholar
  124. 124.
    Toyota J, Karino Y, Suzuki F, Ikeda F, Ido A, Tanaka K, Takaguchi K, Naganuma A, Tomita E, Chayama K, Fujiyama S, Inada Y, Yoshiji H, Watanabe H, Ishikawa H, Hu W, McPhee F, Linaberry M, Yin PD, Swenson ES, Kumada H (2017) Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection. J Gastroenterol 52:385–395PubMedGoogle Scholar
  125. 125.
    Kao JH, Yu ML, Peng CY, Heo J, Chu CJ, Chang TT, Lee YJ, Hu TH, Yoon KT, Paik SW, Lim YS, Ahn SH, Isakov V, McPhee F, Hu W, Swenson ES, Yin PD, Treitel M (2017) Daclatasvir/asunaprevir/beclabuvir, all-oral, fixed-dose combination for patients with chronic hepatitis C virus genotype 1. J Gastroenterol Hepatol 32:1998–2005PubMedGoogle Scholar
  126. 126.
    Ahmed AM, Doheim MF, Mattar OM, Sherif NA, Truong DH, Le Hoa PT, Hirayama K, Huy NT (2018) Beclabuvir in combination with asunaprevir and daclatasvir for hepatitis C virus genotype 1 infection: a systematic review and meta-analysis. J Med Virol 90:907–918. PubMedGoogle Scholar
  127. 127.
    Poordad F, Schiff ER, Vierling JM, Landis C, Fontana RJ, Yang R, McPhee F, Hughes EA, Noviello S, Swenson ES (2016) Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology 63:1493–1505PubMedPubMedCentralGoogle Scholar
  128. 128.
    Wyles DL, Ruane PJ, Sulkowski MS, Dieterich D, Luetkemeyer A, Morgan TR, Sherman KE, Dretler R, Fishbein D, Gathe JC, Henn S, Hinestrosa F, Huynh C, McDonald C, Mills A, Overton ET, Ramgopal M, Rashbaum B, Ray G, Scarsella A, Yozviak J, Mcphee F, Liu Z, Hughes E, Yin PD, Noviello S, Ackerman P (2015) Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 373:714–725PubMedPubMedCentralGoogle Scholar
  129. 129.
    Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, Freilicj BF, Younes ZH, Harlan W, Ghalib R, Oguchi G, Thuluvath PJ, Ortiz-Lasanta G, Rabinovitz M, Berstein D, Bennett M, Hawkins T, Ravendhran N, Sheikh A, Varunok P, Kowdley KV, Hennicken D, McPhee F, Rana K, Hughes EA (2015) All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 61:1127–1135PubMedPubMedCentralGoogle Scholar
  130. 130.
    Welzel TM, Petersen J, Herzer K, Ferenci P, Gschwantler M, Wedemeyer H, Berg T, Spengler U, Weiland O, van der Valk M, Rockstroh J, Peck-Radosavljevic M, Zhao Y, Jumenez-Exposito MJ, Zeuzem S (2016) Daclatasvir plus sofobuvir, with and without ribavirin, achieved high sustained virological response rates in patients with HCV infection and advanced liver disease in a real-world cohort. Gut 65:1861–1870PubMedPubMedCentralGoogle Scholar
  131. 131.
    Reddy KP, Pol S, Thuluvath PJ, Kumada H, Toyota J, Chayama K, Levin J, Lawitz EJ, Gadano A, Ghesquiere W, Gerken G, Brunetto MR, Peng C-Y, Silva M, Strasser SI, Heo J, McPhee F, Liu Z, Yang R, Linaberry M, Noviello S (2018) Long-term follow-up of clinical trial patients treated for chronic HCV infection with daclatasvir-based regimens. Liver Int 38:821–833. PubMedPubMedCentralGoogle Scholar
  132. 132.
    Li G, De Clercq E (2017) Current therapy for chronic hepatitis C: the role of direct-acting antivirals. Antivir Res 142:83–122PubMedGoogle Scholar
  133. 133.
    Sulkowski MS, Flamm S, Kayali Z, Lawitz EJ, Kwo P, McPhee F, Torbeyns A, Hughes EA, Swenson ES, Yin PD, Linaberry M (2017) Short-duration treatment for chronic hepatitis C virus with daclatasvir, asunaprevir, beclabuvir and sofosbuvir (FOURward study). Liver Int 37:836–842PubMedGoogle Scholar
  134. 134.
    Gentile I, Borgia F, Coppola N, Buonomo AR, Castaldo G, Borgia G (2014) Daclatasvir: the first of a new class of drugs targeted against hepatitis C virus NS5A. Curr Med Chem 21:1391–1404PubMedGoogle Scholar
  135. 135.
    Swinney DC, Anthony J (2011) How were new medicines discovered? Nat Rev Drug Discov 10:507–519PubMedGoogle Scholar
  136. 136.
    Macarron R, Banks MN, Bojanic D, Burns DJ, Cirovic DA, Garyantes T, Green DVS, Hertzberg RP, Janzen WP, Paslay JW, Schopfer U, Sittampalam GS (2011) Impact of high-throughput screening on biomedical research. Nat Rev Drug Discov 10:189–195Google Scholar
  137. 137.
    Green N, Ott RD, Isaacs RJ, Fang H (2008) Cell-based assays to identify inhibitors of viral disease. Expert Opin Drug Discov 3:671–676PubMedPubMedCentralGoogle Scholar
  138. 138.
    Keller TH, Shi P-Y, Wang Q-Y (2011) Anti-infectives: can cellular screening deliver? Curr Opin Chem Biol 15:529–533PubMedGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Discovery ChemistryBristol-Myers Squibb Research and DevelopmentPrincetonUSA
  2. 2.Department of Discovery Chemistry and Molecular TechnologiesBristol-Myers Squibb Research and DevelopmentPrincetonUSA

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