Advertisement

NS5A as a Target for HCV Drug Discovery

  • Donald R. O’BoyleII
  • Min GaoEmail author
Chapter
  • 28 Downloads
Part of the Topics in Medicinal Chemistry book series (TMC, volume 32)

Abstract

Discovery and development of HCV inhibitors is one of the most successful stories in the history of antiviral research. After more than 30 years of effort by academic and pharmaceutical researchers, HCV infection is a curable disease. In fact, HCV is the first chronic infectious disease to be cured with combinations of direct antiviral agents. Among these antiviral agents, NS5A inhibitors are the most potent. The unprecedented low pM potency, pan-genotype coverage, and well-tolerated clinical profile have made NS5A inhibitors an essential component of all interferon-/ribavirin-free regimens in currently approved HCV therapies. Since NS5A has no known enzymatic activity and is not a traditional antiviral target, this review focuses on the challenges and concerns that arose during the discovery of this class of inhibitor, the mode of action/inhibition, and the value of NS5A inhibitors in the treatment of HCV infection.

Keywords

Combination therapy Daclatasvir Genotype coverage NS5A inhibitors Resistance Synergistic effect 

Notes

Acknowledgments

We thank Drs David Langley for providing Fig. 1 and Susan Roberts for critical review and editing the manuscript.

Compliance with Ethical Standards

Conflict of Interest: Dr. Gao worked for Bristol Myers Squibb.

Ethical Approval: This chapter does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Macdonald A, Harris M (2004) Hepatitis C virus NS5A: tales of a promiscuous protein. J Gen Virol 85:2485–2502PubMedPubMedCentralGoogle Scholar
  2. 2.
    He Y, Staschke KA, Tan SL (2006) HCV NS5A: a multifunctional regulator of cellular pathways and virus replication. In: Tan SL (ed) Hepatitis C virus genome and molecular biology. Horizon Bioscience, Norfolk, pp 267–292 Chapter 9Google Scholar
  3. 3.
    Brass V, Bieck E, Montserret R, Wolk B, Hellings JA, Blum HE, Penin F, Moradpour D (2002) An amino-terminal amphipathic a-helix mediates membrane association of the hepatitis C virus nonstructural protein 5A. J Biol Chem 277:8130–8139PubMedGoogle Scholar
  4. 4.
    Penin F, Brass V, Appel N et al (2004) Structure and function of the membrane anchor domain of hepatitis C virus nonstructural protein 5A. J Biol Chem 279(39):40835–40843PubMedGoogle Scholar
  5. 5.
    Lim PJ, Chatterji U, Cordek D et al (2012) Correlation between NS5A dimerization and hepatitis C virus replication. J Biol Chem 287:30861–30873PubMedPubMedCentralGoogle Scholar
  6. 6.
    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
  7. 7.
    Tellinghuisen TL, Marcotrigiano J, Gorbalenya AE, Rice CM (2004) The NS5A protein of hepatitis C virus is a zinc metalloprotein. J Biol Chem 279:48576–48587PubMedPubMedCentralGoogle Scholar
  8. 8.
    Tellinghuisen TL, Marcotriqiano 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
  9. 9.
    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
  10. 10.
    Lambert SM, Langley DR, Garnett JA, Angell R, 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
  11. 11.
    Blight KJ, Kolykhalov AA, Rice CM (2000) Efficient initiation of HCV RNA replication in cell culture. Science 290:1972–1974PubMedPubMedCentralGoogle Scholar
  12. 12.
    Lohmann V, Korner F, Dobierzewska A, Bartenschlager R (2001) Mutations in hepatitis C virus RNAs conferring cell culture adaptation. J Virol 75:1437–1449PubMedPubMedCentralGoogle Scholar
  13. 13.
    Tellinghuisen TL, Foss KL, Treadaway JC, Rice CM (2008) Identification of residues required for RNA replication in domains II and III of the hepatitis C virus NS5A protein. J Virol 82:1073–1083PubMedPubMedCentralGoogle Scholar
  14. 14.
    Liang Y, Ye H, Kang CB, Yoon HS (2007) Domain 2 of nonstructural protein 5A (NS5A) of hepatitis C virus is natively unfolded. Biochemistry 46:11550–11558PubMedGoogle Scholar
  15. 15.
    Hanoulle X, Verdeqem D, Badillo A, Wieruszeski JM, Penin F, Lippens G (2009) Domain 3 of non-structural protein 5A from hepatitis C virus is natively unfolded. Biochem Biophys Res Commun 381:634–638PubMedGoogle Scholar
  16. 16.
    Foster TL, Gallay P, Stonehouse NJ, Harris M (2011) Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner. J Virol 85:7460–7464PubMedPubMedCentralGoogle Scholar
  17. 17.
    Fischer G, Gallay P, Hopkins S (2010) Cyclophilin inhibitors for the treatment of HCV infection. Curr Opin Investig Drugs 11:911–918PubMedGoogle Scholar
  18. 18.
    Tellinghuisen TL, Foss KL, Treadaway JC (2008) Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLoS Pathog 4:e1000032PubMedPubMedCentralGoogle Scholar
  19. 19.
    Appel N, Zayas M, Miller S, Krijnse-Locker J, Schaller T, Friebe P, Kallis S, Engel U, Bartenschlager R (2008) Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly. PLoS Pathog 4:e1000035PubMedPubMedCentralGoogle Scholar
  20. 20.
    Fridell RA, Valera L, Qiu D, Kirk MJ, Wang C, Gao M (2013) Intragenic complementation of hepatitis C virus NS5A replication-defective alleles. J Virol 87:2320–2329PubMedPubMedCentralGoogle Scholar
  21. 21.
    Evans MJ, Rice CM, Goff SP (2004) Phosphorylation of hepatitis C virus nonstructural protein 5A modulates its protein interactions and viral RNA replication. Proc Natl Acad Sci U S A 101:13038–13043 PubMedPubMedCentralGoogle Scholar
  22. 22.
    Neddermann P, Quintavalle M, Di Pietro C, Clementi A, Cerretani M, Altamura S et al (2004) Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culture. J Virol 78:13306–13314PubMedPubMedCentralGoogle Scholar
  23. 23.
    Ross-Thriepland D, Harris M (2015) Hepatitis C virus NS5A: enigmatic but still promiscuous 10 years on. J Gen Virol 96:727–738PubMedGoogle Scholar
  24. 24.
    Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Kräusslich HG, Mizokami M, Bartenschlager R, Liang TJ (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11:791–796PubMedPubMedCentralGoogle Scholar
  25. 25.
    Saeed M, Andreo U, Chung HY, Espiritu C, Branch AD, Silva JM, Rice CM (2015) SEC14L2 enables pan-genotype HCV replication in cell culture. Nature 524:471–475PubMedPubMedCentralGoogle Scholar
  26. 26.
    Kaneko T, Tanji Y, Satoh S, Hijikata M, Asabe S, Kumura K, Shimotohno K (1994) Production of two phosphoproteins from the NS5A region of the hepatitis C viral genome. Biochem Biophys Res Commun 205:320–326PubMedGoogle Scholar
  27. 27.
    Appel N, Pietschmann T, Bartenschlager R (2005) Mutational analysis of hepatitis C virus nonstructural protein 5A: potential role of differential phosphorylation in RNA replication and identification of a genetically flexible domain. J Virol 79:3187–3194PubMedPubMedCentralGoogle Scholar
  28. 28.
    Asabe SI, Tanji Y, Satoh S, Kaneko T, Kimura K, Shimotohno K (1997) The N-terminal region of hepatitis C virus-encoded NS5A is important for NS4A-dependent phosphorylation. J Virol 71:790–796PubMedPubMedCentralGoogle Scholar
  29. 29.
    Liu QY, Bhat RA, Prince AM, Zhang P (1999) The hepatitis C virus NS2 protein generated by NS2-3 autocleavage is required for NS5A phosphorylation. Biochem Biophys Res Commun 254:572–577PubMedGoogle Scholar
  30. 30.
    Neddermann P, Clementi A, De Francesco R (1999) Hyperphosphorylation of the hepatitis C virus NS5A protein requires an active NS3 protease, NS4A, NS4B, and NS5A encoded on the same polyprotein. J Virol 73:9984–9991PubMedPubMedCentralGoogle Scholar
  31. 31.
    Koch JO, Bartenschlager R (1999) Modulation of hepatitis C virus NS5A hyperphosphorylation by nonstructural proteins NS3, NS4A, and NS4B. J Virol 73:7138–7146PubMedGoogle Scholar
  32. 32.
    Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110–113PubMedPubMedCentralGoogle Scholar
  33. 33.
    O’Boyle 2nd DR, Nower PT, Lemm JA, Valera L, Sun JH, 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
  34. 34.
    Lemm JA, O’Boyle II DR, Liu M, Nower PT, Colonno R, Deshpande MS, Snyder LB, Martin SW, St Laurent DR, Serrano-Wu MH et al (2010) Identification of hepatitis C virus NS5A inhibitors. J Virol 84:482–491PubMedPubMedCentralGoogle Scholar
  35. 35.
    Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O’Boyle II DR et al (2010) Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 465:96–100Google Scholar
  36. 36.
    Quintavalle M, Sambucini S, Di Pietro C, De Francesco R, Neddermann P (2006) The alpha isoform of protein kinase CKI is responsible for hepatitis C virus NS5A hyperphosphorylation. J Virol 80:11305–11312PubMedPubMedCentralGoogle Scholar
  37. 37.
    Fridell RA, Qiu D, Valera L, Wang C, Rose RE, Gao M (2011) Distinct functions of NS5A in hepatitis C virus RNA replication uncovered by studies with the NS5A inhibitor BMS-790052. J Virol 85:7312–7320PubMedPubMedCentralGoogle Scholar
  38. 38.
    Gao M, Fridell R, O’Boyle II D, Qiu D, Sun JH, Lemm J, Nower P, Valera L, Voss S, Liu M, Belema M, Nguyen V, Romine J, Martin S, Serrano-Wu M, St. Laurent D, Snyder L, Colonno R, Hamann L, Meanwell N (2008) HCV NS5A inhibitors: from screen lead to clinic. In: 15th international symposium on HCV and related virus, San AntonioGoogle Scholar
  39. 39.
    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 HCV-induced membranous replication factories, independent of RNA replication. Gastroenterology 147:1094–1105PubMedGoogle Scholar
  40. 40.
    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. Sci Rep 4:4765PubMedPubMedCentralGoogle Scholar
  41. 41.
    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 10:e0122844.  https://doi.org/10.1371/journal.pone.0122844 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Zein NN (2000) Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev 13:223–235PubMedPubMedCentralGoogle Scholar
  43. 43.
    Conte I, Giuliano C, Ercolani C, Narjes F, Koch U, Rowley M, Altamura S, De Francesco R, Neddermann P, Migliaccio G, Stansfield I (2009) Synthesis and SAR of piperazinyl-N-phenylbenzamides as inhibitors of hepatitis C virus RNA replication in cell culture. Bioorg Med Chem Lett 19:1779–1783Google Scholar
  44. 44.
    Lemm JA, Leet JE, O’Boyle II D, Romine L, JL X, Huang SX, Alberts J, Sun JH, Nower PT, Martin SW, Serrano-Wu MH, Meanwell NA, Snyder LB, Gao M (2011) Discovery of potent NS5A inhibitors with dimeric structures. Antimicrob Agents Chemother 55:3795–3802PubMedPubMedCentralGoogle Scholar
  45. 45.
    Nettles RE, Min Gao M, Bifano M, Chung E, Persson A, Marbury TC, Goldwater R, DeMicco MP, Rodriguez-Torres M, Vutikullird A et al (2011) Multiple ascending dose study to evaluate BMS-790052, a novel NS5A inhibitor, in patients infected with hepatitis C virus genotype 1. Hepatology 54:1956–1966PubMedGoogle Scholar
  46. 46.
    Fridell RA, Wang C, Sun JH, O’Boyle II DR, Nower P, Valera L, Qiu D, Roberts S, Huang X, Kienzle B et al (2011) Genotypic and phenotypic analysis of variants resistant to HCV NS5A replication complex inhibitor BMS-790052: in vitro and in vivo correlations. Hepatology 54:1924–1935PubMedGoogle Scholar
  47. 47.
    Wang KA, Worth A, Martin R, Svarovskaia E, Brainard DM, Lawitz E, Miller MD, Mo H (2013) Characterization of hepatitis C virus resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885. Antimicrob Agents Chemother 57:6333–6340Google Scholar
  48. 48.
    Cheng G, Tian Y, Doehle B, Peng B, Corsa A, Lee Y-J, Gong R, Yu M, Han B, Xu S et al (2016) In vitro antiviral activity and resistance profile characterization of the HCV NS5A inhibitor ledipasvir. Antimicrob Agents Chemother 60:1847–1853PubMedPubMedCentralGoogle Scholar
  49. 49.
    Lawitz EJ, Dvory-Sobol H, Doehle B, Worth AS, McNally J, Brainard DM, Link JO, Miller M, Mo H (2016) Clinical resistance to velpatasvir (GS-5816), a novel pan-genotypic inhibitor of the hepatitis C virus NS5A protein. Antimicrob Agents Chemother 60:5368–5378PubMedPubMedCentralGoogle Scholar
  50. 50.
    Chen G, Yu M, Peng B, Lee YJ, Trejo-Martin A, Gong R, Bush C, Worth A, Nash M, Chan K, Yang H, Beran R, Tian Y, Perry J, Taylor J, Yang C, Paulson M, Delaney W, Link LO (2013) GS-5816, a second generation HCV NS5A inhibitor with potent antiviral activity, broad genotypic coverage and a high resistance barrier. J Hepatol 58:S484Google Scholar
  51. 51.
    Coburn CR, Meinke PT, Chang W, Fandozzi CM, Graham DJ, Hu B, Huang Q, Kargman S, Kozlowski J, Liu R, McCauley JA, Nomeir AA, Soll RM, Vacca JP, Wang D, Wu H, Zhong B, Olsen DB, Ludmerer SW (2013) Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem 8:1930–1940PubMedGoogle Scholar
  52. 52.
    Liu R, Curry S, McMonagle P, Yeh WW, Ludmerer SW, Jumes PA, Marshall WL, Kong S, Ingravallo P, Black S et al (2015) Susceptibilities of GT 1a, 1b, and 3 HCV variants to the NS5A inhibitor Elbasvir. Antimicrob Agents Chemother 59:6922–6929PubMedPubMedCentralGoogle Scholar
  53. 53.
    Ng TI, Krishnan P, Pilot-Matias T, Kati W, Schnell G, Beyer J, Reisch T, Lu L, Dekhtyar T, Irvin M, Tripathi R, Maring C, Randolph JT, Wagner R, Collins C (2017) In vitro antiviral activity and resistance profile of the next-generation hepatitis C virus NS5A inhibitor Pibrentavir. Antimicrob Agents Chemother 61(5):e02558–e02516PubMedPubMedCentralGoogle Scholar
  54. 54.
    Krishnan P, Beyer J, Mistry N, Koev G, Reisch T, DeGoey D, Kati W, Campbell A, Williams L, Xie W, Setze C, Molla A, Collins C, Pilot-Matias T (2015) In vitro and in vivo antiviral activity and resistance profile of ombitasvir, an inhibitor of hepatitis C virus NS5A. Antimicrob Agents Chemother 59:979–987PubMedPubMedCentralGoogle Scholar
  55. 55.
    Pol S (2013) Daclatasvir, an effective inhibitor of the hepatitis C virus replication complex protein NS5A: review of virologic data, treatment rationale and clinic trials. Clin Invest 3:191–207Google Scholar
  56. 56.
    Pawlotsky JM (2013) NS5A inhibitors in the treatment of hepatitis C. J Hepatol 59:375–382PubMedGoogle Scholar
  57. 57.
    Zhou N, Han Z, Hartman-Neumann S, DeGray B, Ueland J, Vellucci V, Hernandez D, McPhee F (2016) Characterization of NS5A polymorphisms and their impact on response rates in patients with HCV genotype 2 treated with daclatasvir-based regimens. J Antimicrob Chemother 71:3495–3505PubMedGoogle Scholar
  58. 58.
    Benzine T, Brandt R, Lovell WC, Yamane D, Neddermann P, De Francesco R, Lemon SM, Perelson AS, Ke R, McGivern DR (2017) NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains. PLoS Pathog 13:e1006343.  https://doi.org/10.1371/journal.ppat.1006343 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Fridell RA, Qiu D, Wang C, Valera L, Gao M (2010) Resistance analysis of the HCV NS5A inhibitor, BMS-790052, in the in vitro replicon system. Antimicrob Agents Chemother 54:3641–3650PubMedPubMedCentralGoogle Scholar
  60. 60.
    Lawitz EJ, Gruener D, Hill JM, Marbury T, Moorehead L, Mathias A, Cheng G, Link JO, Wong KA, Mo H, McHutchison JG, Brainard DM (2012) A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C. J Hepatol 57:24–31Google Scholar
  61. 61.
    Lawitz E, Freilich B, Link J, German P, Mo H, Han L, Brainard DM, McNally J, Marbury T, Rodriguez-Torres M (2015) A phase 1, randomized, dose-ranging study of GS-5816, a once-daily NS5A inhibitor, in patients with genotype 1-4 hepatitis C virus. J Viral Hepat 22:1011–1019PubMedPubMedCentralGoogle Scholar
  62. 62.
    Yeh WW, Lipardi C, Jumes P, De Lepeleire I, Caro L, Huang X, Mangin E, Nachbar RB, Gane E, Popa S, Ghicavii N, Wagner F, Butterton JR (2013) MK-8742, an HCV NS5A inhibitor with a broad Spectrum of HCV genotypic activity, demonstrates potent antiviral activity in Genotype-1 and -3 HCV-infected patients. In: 64th AASLD, WashingtonGoogle Scholar
  63. 63.
    Lawitz EJ, O’Riordan WD, Asatryan A, Freilich BL, Box TD, Overcash JS, Lovell S, Ng TI, Liu W et al (2015) Potent antiviral activity of ABT-493 and ABT-530 with 3-day monotherapy in patients with and without compensated cirrhosis with HCV GT1a infection. Antimicrobial.  https://doi.org/10.1128/AAC.02524-15.AAC
  64. 64.
    Lawitz E, Marbury T, Campbell A, Dumas E, Kapoor M, Pilot-Matias T, Krishnan P, Setze C, Xie W, Podsadecki T et al (2012) Safety and antiviral activity of ABT-267, a novel NS5A inhibitor, during 3-day monotherapy: first study in HCV genotype-1 (GT1)-infected treatment-naïve patients. J Hepatol 56:S469–S470Google Scholar
  65. 65.
    FDA News Release: FDA approves Gilead’s Harvoni® (Ledipasvir/Sofosbuvir) for the treatment of genotype 1 chronic hepatitis C (released by gild), 10 Oct 2014Google Scholar
  66. 66.
    FDA News Release: FDA approves two hepatitis C drugs for pediatric patients, 7 Apr 2017Google Scholar
  67. 67.
    FDA News Release: FDA approves Epclusa for treatment of chronic hepatitis C virus infection, 28 June 2016Google Scholar
  68. 68.
    FDA News Release: FDA approves Vosevi for hepatitis C, 18 July 2017Google Scholar
  69. 69.
    FDA News Release: FDA approves Zepatier for the treatment of chronic hepatitis C virus (HCV) genotypes 1 and 4 infections, 28 Jan 2016Google Scholar
  70. 70.
    FDA News Release: FDA approves Mavyret for hepatitis C, 3 Aug 2017Google Scholar
  71. 71.
    Feld JJ, Jacobson IM, Hézode C, ASTRAL-1 Investigators et al (2015) Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 373:2599–2607PubMedPubMedCentralGoogle Scholar
  72. 72.
    Zeuzem S, Ghalib R, Reddy KR et al (2015) Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med 163:1–13PubMedPubMedCentralGoogle Scholar
  73. 73.
    McPhee F, Hernandez D, Zhou N (2016) Effect of minor populations of NS5A and NS5B resistance-associated variants on HCV genotype-3 response to daclatasvir plus sofosbuvir, with or without ribavirin. Antivir Ther 22:237–246PubMedGoogle Scholar
  74. 74.
    Zhou N, Hernandez D, Ueland J, Yang X, Yu F, Sims K, Yin PD, McPhee F (2016) NS5A sequence heterogeneity and mechanisms of Daclatasvir resistance in hepatitis C virus genotype 4 infection. J Infect Dis 213:206–215PubMedGoogle Scholar
  75. 75.
    Camus G, Han B,| Asselah T,| Hsieh D, Dvory-Sobol H, Lu J, Svarovskaia E, Martin R, Parhy B, Miller MD, Brainard DM, Kersey K, Abergel A Mo H. Resistance characterization of ledipasvir and velpatasvir in hepatitis C virus genotype 4. J Viral Hepat 2018;25:134-143PubMedGoogle Scholar
  76. 76.
    Wang C, Jia L, O’Boyle II DR, Sun JH, 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 58:5155PubMedPubMedCentralGoogle Scholar
  77. 77.
    Sun JH, O’Boyle II DR, Zhang DR, Wang Y, Nower C, Valera P, Roberts L, Nettles S, Fridell RA, Gao M (2012) Impact of a baseline polymorphism on the emergence of resistance to the hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052. Hepatology 55:1692–1699PubMedGoogle Scholar
  78. 78.
    Pelosi LA, Voss S, Liu M, Gao M, Lemm JA (2012) Effect on hepatitis C virus replication of combinations of direct-acting antivirals, including NS5A inhibitor Daclatasvir. Antimicrob Agents Chemother 56:5230 PubMedPubMedCentralGoogle Scholar
  79. 79.
    Guedj J, Dahari H, Uprichard SL, Perelson AS (2013) The rapid viral decline with the HCV NS5A inhibitor daclatasvir reveals a dual mode of action and leads to a new HCV half-life estimate. Exp Rev Gastroenterol Heoatol 7:397–399Google Scholar
  80. 80.
    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
  81. 81.
    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
  82. 82.
    Quinkert D, Bartenschlager R, Lohmann V (2005) Quantitative analysis of the hepatitis C virus replication complex. J Virol 79:13594–13605PubMedPubMedCentralGoogle Scholar
  83. 83.
    Pietschmann T, Lohmann V, Rutter G, Kurpanek K, Bartenschlager R (2001) Characterization of cell lines carrying self-replicating hepatitis C virus RNAs. J Virol 75:1252–1264PubMedPubMedCentralGoogle Scholar
  84. 84.
    Sun JH, O’Boyle II DR, Fridell RA, Langley DR, Wang C, Roberts SB, Nower P, Johnson BM, Moulin F, Nophsker MJ, Wang YK, 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-resistant hepatitis C variants by allosteric modulation of NS5A. Nature 527(7577):245–248PubMedGoogle Scholar
  85. 85.
    Beldar S, Manimekalai MSS, Cho N-J, Baek K, Grüber G, Yoon HS (2018) Self-association and conformational variation of NS5A domain 1 of hepatitis C virus. J Gen Virol 99:194.  https://doi.org/10.1099/jgv.0.001000 CrossRefPubMedGoogle Scholar
  86. 86.
    O’Boyle II DR, Sun JH, Nower PT, Lemm JA, Fridell RA, Wang C, Romine JL, Belema M, Nguyen V, St. Laurent DR, Serrano-Wu M, Snyder LB, Meanwell NA, Langley DR, Gao M (2013) Characterizations of HCV NS5A replication complex inhibitors. Virology 444:343–354PubMedGoogle Scholar
  87. 87.
    O’Boyle 2nd DR, Nower PT, Gao M, Fridell R, Wang C, Hewawasam P, Lopez O, Tu Y, Meanwell NA, Belema M, Roberts SB, Cockett M, Sun JH (2015) Synergistic activity of combined NS5A inhibitors. Antimicrob Agents Chemother 60(3):1573–1583PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Bristol-Myers Squibb CompanyPenningtonUSA
  2. 2.Arbutus BioPharmaWarminsterUSA

Personalised recommendations