Identification of PTC725, an orally bioavailable small molecule that selectively targets the hepatitis C virus NS4B protein

Antimicrobial Agents and Chemotherapy

Volumn 57, Issue 7, 2013, Pages 3250-3261

  Gu, Zhengxian ^a   Graci, Jason D ^a   Lahser, Frederick C ^b   Breslin, Jamie J ^a   Jung, Stephen P ^a   Crona, James H ^a   McMonagle, Patricia ^b   Xia, Ellen ^b   Liu, Shaotang ^b   Karp, Gary ^a   Zhu, Jin ^a   Huang, Song ^a   Nomeir, Amin ^b   Weetall, Marla ^a   Almstead, Neil G ^a   Peltz, Stuart W ^a   Tong, Xiao ^b,c   Ralston, Robert ^b,d   Colacino, Joseph M ^a  

^a PTC THERAPEUTICS   (United States)

^b MERCK RESEARCH LABORATORIES   (United States)

^c HOFFMANN LA ROCHE INC   (United States)

^d UNIVERSITY OF KANSAS SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 [3 CYANO 6 ETHYL 5 FLUORO 1 (PYRIMIDIN 2 YL) 1H INDOL 2 YL]N(1,1,1 TRIFLUOROPROPAN 2 YL)PYRIDINE 3 SULFONAMIDE; ALPHA INTERFERON; ANTIVIRUS AGENT; BOCEPREVIR; LOMIBUVIR; NONSTRUCTURAL PROTEIN 4B; NS3 POLYMERASE; NS5B POLYMERASE; PTC 725; UNCLASSIFIED DRUG; VIRUS ENZYME;

AMINO ACID SUBSTITUTION; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIVIRAL ACTIVITY; ARTICLE; CONCENTRATION RESPONSE; CONTROLLED STUDY; CYTOTOXICITY TEST; DRUG POTENTIATION; DRUG SELECTIVITY; DRUG STRUCTURE; ENZYME LOCALIZATION; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HUMAN CELL; IMMUNOFLUORESCENCE MICROSCOPY; MALE; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN TARGETING; RAT; REPLICON; VIRUS MUTANT;

AMINO ACID SUBSTITUTION; ANIMALS; ANTIVIRAL AGENTS; CELL LINE, TUMOR; DRUG RESISTANCE, VIRAL; DRUG SYNERGISM; HEPACIVIRUS; HEPATITIS C; HUMANS; INDOLES; INTERFERON-ALPHA; MALE; MICE; MICROBIAL SENSITIVITY TESTS; RATS; RATS, SPRAGUE-DAWLEY; SULFONAMIDES; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

EID: 84879015904     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.00527-13     Document Type: Article

References (56)

1. Alter MJ. 2007. Epidemiology of hepatitis C virus infection. World J. Gastroenterol. 13:2436-2441. (Pubitemid 46929498)
2. Ghobrial RM, Steadman R, Gornbein J, Lassman C, Holt CD, Chen P, Farmer DG, Danino N, Collisson E, Baquarizo A, Han SS, Saab S, Donovan JA, Esrason K, Busuttil RW. 2001. A 10-year experience of liver transplantation for hepatitis C: analysis of factors determining outcome in over 500 patients. Ann. Surg. 234:384-393.
3. Manns MP, Cornberg M, Wedemeyer H. 2001. Current and future treatment of hepatitis C. Indian J. Gastroenterol. 20(Suppl. 1):C47-C51. (Pubitemid 32246282)
4. Nainan OV, Alter MJ, Kruszon-Moran D, Gao FX, Xia G, McQuillan G, Margolis HS. 2006. Hepatitis C virus genotypes and viral concentrations in participants of a general population survey in the United States. Gastroenterology 131:478-484. (Pubitemid 44142463)
5. Asselah T, Marcellin P. 2011. New direct-acting antivirals' combination for the treatment of chronic hepatitis C. Liver Int. 31:68-77.
6. Melnikova I. 2011. Hepatitis C-pipeline update. Nat. Rev. Drug Discov. 10:93-94.
7. Halfon P, Locarnini S. 2011. Hepatitis C virus resistance to protease inhibitors. J. Hepatol. 55:192-206.
8. Legrand-Abravanel F, Nicot F, Izopet J. 2010. New NS5B polymerase inhibitors for hepatitis C. Expert. Opin. Investig. Drugs 19:963-975.
9. Sarrazin C, Zeuzem S. 2010. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 138:447-462.
10. Dvory-Sobol H, Pang PS, Glenn JS. 2010. The future of HCV therapy: NS4B as an antiviral target. Viruses 2:2481-2492.
11. Gouttenoire J, Penin F, Moradpour D. 2010. Hepatitis C virus nonstructural protein 4B: a journey into unexplored territory. Rev. Med. Virol. 20:117-129.
12. De Vos R, Verslype C, Depla E, Fevery J, Van DB, Desmet V, Roskams T. 2002. Ultrastructural visualization of hepatitis C virus components in human and primate liver biopsies. J. Hepatol. 37:370-379. (Pubitemid 34975685)
13. Egger D, Wolk B, Gosert R, Bianchi L, Blum HE, Moradpour D, Bienz K. 2002. Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex. J. Virol. 76:5974-5984. (Pubitemid 34556292)
14. El-Hage N, Luo G. 2003. Replication of hepatitis C virus RNA occurs in a membrane-bound replication complex containing nonstructural viral proteins and RNA. J. Gen. Virol. 84:2761-2769. (Pubitemid 37220255)
15. Elazar M, Liu P, Rice CM, Glenn JS. 2004. An N-terminal amphipathic helix in hepatitis C virus (HCV) NS4B mediates membrane association, correct localization of replication complex proteins, and HCV RNA replication. J. Virol. 78:11393-11400. (Pubitemid 39299681)
16. Gosert R, Egger D, Lohmann V, Bartenschlager R, Blum HE, Bienz K, Moradpour D. 2003. Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons. J. Virol. 77:5487-5492. (Pubitemid 36460961)
17. Gretton SN, Taylor AI, McLauchlan J. 2005. Mobility of the hepatitis C virus NS4B protein on the endoplasmic reticulum membrane and membrane-associated foci. J. Gen. Virol. 86:1415-1421. (Pubitemid 40613259)
18. Konan KV, Giddings TH, Jr, Ikeda M, Li K, Lemon SM, Kirkegaard K. 2003. Nonstructural protein precursor NS4A/B from hepatitis C virus alters function and ultrastructure of host secretory apparatus. J. Virol. 77:7843-7855. (Pubitemid 36792781)
19. Lundin M, Monne M, Widell A, Von HG, Persson MA. 2003. Topology of the membrane-associated hepatitis C virus protein NS4B. J. Virol. 77: 5428-5438. (Pubitemid 36460956)
20. Lundin M, Lindstrom H, Gronwall C, Persson MA. 2006. Dual topology of the processed hepatitis C virus protein NS4B is influenced by the NS5A protein. J. Gen. Virol. 87:3263-3272. (Pubitemid 44608361)
21. Moradpour D, Gosert R, Egger D, Penin F, Blum HE, Bienz K. 2003. Membrane association of hepatitis C virus nonstructural proteins and identification of the membrane alteration that harbors the viral replication complex. Antiviral Res. 60:103-109. (Pubitemid 37452453)
22. Pfeifer U, Thomssen R, Legler K, Böttcher U, Gerlich W, Weinmann E, Klinge O. 1980. Experimental non-A, non-B hepatitis: four types of cytoplasmic alteration in hepatocytes of infected chimpanzees. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 33:233-243. (Pubitemid 10086023)
23. Targett-Adams P, Boulant S, McLauchlan J. 2008. Visualization of double-stranded RNA in cells supporting hepatitis C virus RNA replication. J. Virol. 82:2182-2195. (Pubitemid 351293519)
24. Einav S, Elazar M, Danieli T, Glenn JS. 2004. A nucleotide binding motif in hepatitis C virus (HCV) NS4B mediates HCV RNA replication. J. Virol. 78:11288-11295. (Pubitemid 39299668)
25. Thompson AA, Zou A, Yan J, Duggal R, Hao W, Molina D, Cronin CN, Wells PA. 2009. Biochemical characterization of recombinant hepatitis C virus nonstructural protein 4B: evidence for ATP/GTP hydrolysis and adenylate kinase activity. Biochemistry 48:906-916.
26. Einav S, Gerber D, Bryson PD, Sklan EH, Elazar M, Maerkl SJ, Glenn JS, Quake SR. 2008. Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat. Biotechnol. 26: 1019-1027.
27. Jones DM, Patel AH, Targett-Adams P, McLauchlan J. 2009. The hepatitis C virus NS4B protein can trans-complement viral RNA replication and modulates production of infectious virus. J. Virol. 83:2163-2177.
28. Welker MW, Welsch C, Meyer A, Antes I, Albrecht M, Forestier N, Kronenberger B, Lengauer T, Piiper A, Zeuzem S, Sarrazin C. 2010. Dimerization of the hepatitis C virus nonstructural protein 4B depends on the integrity of an aminoterminal basic leucine zipper. Protein Sci. 19: 1327-1336.
29. Welsch C, Albrecht M, Maydt J, Herrmann E, Welker MW, Sarrazin C, Scheidig A, Lengauer T, Zeuzem S. 2007. Structural and functional comparison of the non-structural protein 4B in flaviviridae. J. Mol. Graph. Model. 26:546-557. (Pubitemid 47334962)
30. Benureau Y, Warter L, Malcolm BA, Martin A. 2010. A comparative analysis of the substrate permissiveness of HCV and GBV-B NS3/4A proteases reveals genetic evidence for an interaction with NS4B protein during genome replication. Virology 406:228-240.
31. Dimitrova M, Imbert I, Kieny MP, Schuster C. 2003. Protein-protein interactions between hepatitis C virus nonstructural proteins. J. Virol. 77:5401-5414. (Pubitemid 36460954)
32. Koch JO, Bartenschlager R. 1999. Modulation of hepatitis C virus NS5A hyperphosphorylation by nonstructural proteins NS3, NS4A, and NS4B. J. Virol. 73:7138-7146. (Pubitemid 29383194)
33. Neddermann P, Clementi A, De FR. 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. 73:9984-9991.
34. Paredes AM, Blight KJ. 2008. A genetic interaction between hepatitis C virus NS4B and NS3 is important for RNA replication. J. Virol. 82:10671-10683. (Pubitemid 352691196)
35. Piccininni S, Varaklioti A, Nardelli M, Dave B, Raney KD, McCarthy JE. 2002. Modulation of the hepatitis C virus RNA-dependent RNA polymerase activity by the non-structural (NS) 3 helicase and the NS4B membrane protein. J. Biol. Chem. 277:45670-45679. (Pubitemid 36159179)
36. Tripathi LP, Kataoka C, Taguwa S, Moriishi K, Mori Y, Matsuura Y, Mizuguchi K. 2010. Network based analysis of hepatitis C virus core and NS4B protein interactions. Mol. Biosyst. 6:2539-2553.
37. Manna D, Aligo J, Xu C, Park WS, Koc H, Heo WD, Konan KV. 2010. Endocytic Rab proteins are required for hepatitis C virus replication complex formation. Virology 398:21-37.
38. Tong WY, Nagano-Fujii M, Hidajat R, Deng L, Takigawa Y, Hotta H. 2002. Physical interaction between hepatitis C virus NS4B protein and CREB-RP/ATF6beta. Biochem. Biophys. Res. Commun. 299:366-372. (Pubitemid 35365636)
39. Florese RH, Nagano-Fujii M, Iwanaga Y, Hidajat R, Hotta H. 2002. Inhibition of protein synthesis by the nonstructural proteins NS4A and NS4B of hepatitis C virus. Virus Res. 90:119-131. (Pubitemid 35375829)
40. He Y, Yan W, Coito C, Li Y, Gale M, Jr, Katze MG. 2003. The regulation of hepatitis C virus (HCV) internal ribosome-entry site-mediated translation by HCV replicons and nonstructural proteins. J. Gen. Virol. 84: 535-543. (Pubitemid 36267125)
41. Kato J, Kato N, Yoshida H, Ono-Nita SK, Shiratori Y, Omata M. 2002. Hepatitis C virus NS4A and NS4B proteins suppress translation in vivo. J. Med. Virol. 66:187-199. (Pubitemid 34020068)
42. Cho NJ, Dvory-Sobol H, Lee C, Cho SJ, Bryson P, Masek M, Elazar M, Frank CW, Glenn JS. 2010. Identification of a class of HCV inhibitors directed against the nonstructural protein NS4B. Sci. Transl. Med. 2:15ra6. doi:10.1126/ scitranslmed.3000331.
43. Rai R, Deval J. 2011. New Opportunities in anti-hepatitis C virus drug discovery: targeting NS4B. Antiviral Res. 90:93-101.
44. PTC Therapeutics Inc. 2010. Indole derivatives and methods for antiviral treatment. WO 2012/117932 A1.
45. Lohmann V, Körner F, Koch J, Theilmann L, Bartenschlager R. 1999. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110-113. (Pubitemid 29307577)
46. Yi M, Villanueva RA, Thomas DL, Wakita T, Lemon SM. 2006. Production of infectious genotype 1a hepatitis C virus (Hutchinson strain) in cultured human hepatoma cells. Proc. Natl. Acad. Sci. U. S. A. 103:2310-2315. (Pubitemid 43271666)
47. Chou TC, Talalay P. 1984. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22:27-55.
48. Blight KJ, Kolykhalov AA, Rice CM. 2000. Efficient initiation of HCV RNA replication in cell culture. Science 290:1972-1974.
49. Graham EJ, Hunt R, Shaw SM, Pickford C, Hammond J, Westby M, Targett-Adams P. 2011. Colony-forming assays reveal enhanced suppression of hepatitis C virus replication using combinations of direct-acting antivirals. J. Virol. Methods 174:153-157.
50. Tong X, Chase R, Skelton A, Chen T, Wright-Minogue J, Malcolm BA. 2006. Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Antiviral Res. 70:28-38.
51. Bhattacharyya A, Trotta CR, Peltz SW. 2007. Mining the GEMS-a novel platform technology targeting post-transcriptional control mechanisms. Drug Discov. Today 12:553-560. (Pubitemid 47031659)
52. Bryson PD, Cho NJ, Einav S, Lee C, Tai V, Bechtel J, Sivaraja M, Roberts C, Schmitz U, Glenn JS. 2010. A small molecule inhibits HCV replication and alters NS4B's subcellular distribution. Antiviral Res. 87: 1-8.
53. Shotwell JB, Baskaran S, Chong P, Creech KL, Crosby RM, Dickson H, Fang J, Garrido D, Mathis A, Maung J, Parks DJ, Pouliot JJ, Price DJ, Rai R, Seal JW, Schmitz U, Tai VWF, Thomson M, Xie M, Xiong ZZ, Peat AJ. 2012. Imidazo[1,2-a]pyridines that directly interact with hepatitis C NS4B: initial preclinical characterization. ACS Med. Chem. Lett. 3:565-569.
54. Hosea NA, Collard WT, Cole S, Maurer TS, Fang RX, Jones H, Kakar SM, Nakai Y, Smith BJ, Webster R, Beaumont K. 2009. Prediction of human pharmacokinetics from preclinical information: comparative accuracy of quantitative prediction approaches. J. Clin. Pharmacol. 49:513-533.
55. Kuiken C, Yusim K, Boykin L, Richardson R. 2005. The Los Alamos hepatitis C sequence database. Bioinformatics 21:379-384. (Pubitemid 40246609)
56. Boleti H, Smirlis D, Dalagiorgou G, Meurs EF, Christoforidis S, Mavromara P. 2010. ER targeting and retention of the HCV NS4B protein relies on the concerted action of multiple structural features including its transmembrane domains. Mol. Membr. Biol. 27:50-74.