Inhibition of Hepatitis C Virus replication by GS-6620, a potent C-nucleoside monophosphate prodrug

Antimicrobial Agents and Chemotherapy

Volumn 58, Issue 4, 2014, Pages 1930-1942

  Feng, Joy Y ^a   Cheng, Guofeng ^a   Perry, Jason ^a   Barauskas, Ona ^a   Xu, Yili ^a   Fenaux, Martijn ^a,b   Eng, Stacey ^a   Tirunagari, Neeraj ^a   Peng, Betty ^a   Yu, Mei ^a   Tian, Yang ^a   Lee, Yu Jen ^a   Stepan, George ^a   Lagpacan, Leanna L ^a   Jin, Debi ^a   Hung, Magdeleine ^a   Ku, Karin S ^a   Han, Bin ^a   Kitrinos, Kathryn ^a   Perron, Michel ^a   Birkus, Gabriel ^a   Wong, Kelly A ^a,b   Zhong, Weidong ^a,b   Kim, Choung U ^a,c   Carey, Anne ^a   Cho, Aesop ^a   Ray, Adrian S ^a   more..

^a GILEAD SCIENCES   (United States)

^b NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^c Asan Institute for Life Sciences   (South Korea)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE DERIVATIVE; ANTIVIRUS AGENT; C NUCLEOSIDE; DRUG METABOLITE; GS 441285; GS 441326; GS 6620; UNCLASSIFIED DRUG; VIRUS RNA; [(SP) ISOPROPYL 2 ((3 ISOBUTYROXY 5 (4 AMINOPYRROLO[1,2 F][1,2,4]TRIAZIN 7 YL) 5 CYANO 4 HYDROXY 4 METHYLTETRAHYDROFURAN 2 YL)METHOXY)(PHENOXY)PHOSPHORYLAMINO)PROPANOATE];

ANTIVIRAL ACTIVITY; ANTIVIRAL RESISTANCE; ARTICLE; COMPETITIVE INHIBITION; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG CYTOTOXICITY; DRUG POTENCY; HEPATITIS C VIRUS; HEPATITIS C VIRUS SUBTYPE 2A; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; MITOCHONDRIAL TOXICITY; PRIORITY JOURNAL; RNA SYNTHESIS; VIRUS INHIBITION; VIRUS MUTATION; VIRUS REPLICATION;

ANTIVIRAL AGENTS; CELL LINE, TUMOR; CELL SURVIVAL; HEP G2 CELLS; HEPACIVIRUS; HUMANS; NUCLEOSIDES; PRODRUGS; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

EID: 84896905217     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.02351-13     Document Type: Article

References (40)

1. Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver Diseases. 2009. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49:1335-1374. http://dx.doi.org/10.1002/hep.22759.
2. Murray CL, Rice CM. 2011. Turning hepatitis C into a real virus. Annu. Rev. Microbiol. 65:307-327. http://dx.doi.org/10.1146/annurev-micro-090110- 102954.
3. Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. 2012. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann. Intern. Med. 156:271-278. http://dx.doi.org/10.7326/0003- 4819-156-4-201202210-00004.
4. Nelson DR. 2011. The role of triple therapy with protease inhibitors in hepatitis C virus genotype 1 naïve patients. Liver Int. 31(Suppl 1):53-57. http://dx.doi.org/10.1111/j.1478-3231.2010.02391.x.
5. Brown NA. 2009. Progress towards improving antiviral therapy for hepatitis C with hepatitis C virus polymerase inhibitors. Part I: nucleoside analogues. Expert Opin. Investig. Drugs 18:709-725. http://dx.doi.org/10.1517/ 13543780902854194.
6. Sofia MJ. 2011. Nucleotide prodrugs for HCV therapy. Antivir. Chem. Chemother. 22:23-49. http://dx.doi.org/10.3851/IMP1797.
7. Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, Shiffman ML, Lawitz E, Everson G, Bennett M, Schiff E, Al-Assi MT, Subramanian GM, An D, Lin M, McNally J, Brainard D, Symonds WT, McHutchison JG, Patel K, Feld J, Pianko S, Nelson DR. 2013. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N. Engl. J. Med. 368:1867-1877. http://dx.doi.org/10.1056/NEJMoa1214854.
8. Watkins WJ, Ray AS, Chong LS. 2010. HCV NS5B polymerase inhibitors. Curr. Opin. Drug Discov. Devel. 13:441-465.
9. Cho A, Zhang L, Xu J, Lee R, Butler T, Metobo S, Aktoudianakis V, Lew W, Ye H, Clarke M, Doerffler E, Byun D, Wang T, Babusis D, Carey AC, German P, Sauer D, Zhong W, Rossi S, Fenaux M, McHutchison JG, Perry J, Feng J, Ray AS, Kim CU. 2 April 2013. Discovery of the first C-nucleoside HCV polymerase inhibitor (GS-6620) with demonstrated antiviral response in HCV infected patients. J. Med. Chem. http://dx.doi.org/10.1021/jm400201a.
10. Arnold JJ, Sharma SD, Feng JY, Ray AS, Smidansky ED, Kireeva ML, Cho A, Perry J, Vela JE, Park Y, Xu Y, Tian Y, Babusis D, Barauskus O, Peterson BR, Gnatt A, Kashlev M, Zhong W, Cameron CE. 2012. Sensitivity of mitochondrial transcription and resistance of RNA polymerase II dependent nuclear transcription to antiviral ribonucleosides. PLoS Pathog. 8: e1003030. http://dx.doi.org/10.1371/journal.ppat.1003030.
11. Hung M, Gibbs CS, Tsiang M. 2002. Biochemical characterization of rhinovirus RNA-dependent RNA polymerase. Antiviral Res. 56:99-114. http://dx.doi.org/10.1016/S0166-3542(02)00101-8. (Pubitemid 35279660)
12. Hung M, Wang R, Liu X. 2011. Preparation of HCV NS3 and NS5B proteins to support small-molecule drug discovery. Curr. Protoc. Pharmacol. Chapter 13:Unit13B.16. http://dx.doi.org/10.1002/0471141755.ph13b06s54.
13. Johnson AA, Tsai Y, Graves SW, Johnson KA. 2000. Human mitochondrial DNA polymerase holoenzyme: reconstitution and characterization. Biochemistry 39:1702-1708. http://dx.doi.org/10.1021/bi992104w. (Pubitemid 30108960)
14. Graves SW, Johnson AA, Johnson KA. 1998. Expression, purification, and initial kinetic characterization of the large subunit of the human mitochondrial DNA polymerase. Biochemistry 37:6050-6058. http://dx.doi.org/10.1021/bi972685u. (Pubitemid 28196761)
15. Robinson M, Yang H, Sun SC, Peng B, Tian Y, Pagratis N, Greenstein AE, Delaney WE, IV. 2010. Novel hepatitis C virus reporter replicon cell lines enable efficient antiviral screening against genotype 1a. Antimicrob. Agents Chemother. 54:3099 -3106. http://dx.doi.org/10.1128/AAC.00289-10.
16. Lohmann V, Körner F, Koch J, Herian U, Theilmann L, Bartenschlager R. 1999. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110-113. http://dx.doi.org/10.1126/science.285.5424.110. (Pubitemid 29307577)
17. Cheng G, Chan K, Yang H, Corsa A, Pokrovskii M, Paulson M, Bahador G, Zhong W, Delaney W, IV. 2011. Selection of clinically relevant protease inhibitor-resistant viruses using the genotype 2a hepatitis C virus infection system. Antimicrob. Agents Chemother. 55:2197-2205. http://dx.doi.org/10.1128/ AAC.01382-10.
18. Yu M, Corsa AC, Xu S, Peng B, Gong R, Lee YJ, Chan K, Mo H, Delaney W, IV, Cheng G. 2013. In vitro efficacy of approved and experimental antivirals against novel genotype 3 hepatitis C virus subgenomic replicons. Antiviral Res. 100:439-445. http://dx.doi.org/10.1016/j.antiviral.2013.08.018.
19. Peng B, Yu M, Xu S, Lee YJ, Tian Y, Yang H, Chan K, Mo H, McHutchison J, Delaney W, IV, Cheng G. 2013. Development of robust hepatitis C virus genotype 4 subgenomic replicons. Gastroenterology 144:59-61. http://dx.doi.org/10.1053/j. gastro.2012.09.033.
20. Herlihy KJ, Graham JP, Kumpf R, Patick AK, Duggal R, Shi ST. 2008. Development of intergenotypic chimeric replicons to determine the broad-spectrum antiviral activities of hepatitis C virus polymerase inhibitors. Antimicrob. Agents Chemother. 52:3523-3531. http://dx.doi.org/10.1128/AAC.00533-08.
21. Wong KA, Xu S, Martin R, Miller MD, Mo H. 2012. Tegobuvir (GS-9190) potency against HCV chimeric replicons derived from consensus NS5B sequences from genotypes 2b, 3a, 4a, 5a, and 6a. Virology 429:57-62. http://dx.doi.org/10. 1016/j.virol.2012.03.025.
22. Pokrovskii MV, Bush CO, Beran RK, Robinson MF, Cheng G, Tirunagari N, Fenaux M, Greenstein AE, Zhong W, Delaney WE, IV, Paulson MS. 2011. Novel mutations in a tissue culture-adapted hepatitis C virus strain improve infectious-virus stability and markedly enhance infection kinetics. J. Virol. 85:3978-3985. http://dx.doi.org/10.1128/JVI.01760-10.
23. Fenaux M, Eng S, Leavitt SA, Lee YJ, Mabery EM, Tian Y, Byun D, Canales E, Clarke MO, Doerffler E, Lazerwith SE, Lew W, Liu Q, Mertzman M, Morganelli P, Xu L, Ye H, Zhang J, Matles M, Murray BP, Mwangi J, Zhang J, Hashash A, Krawczyk SH, Bidgood AM, Appleby TC, Watkins WJ. 2013. Preclinical characterization of GS-9669, a thumb site II inhibitor of the hepatitis C virus NS5B polymerase. Antimicrob. Agents Chemother. 57:804-810. http://dx.doi.org/10. 1128/AAC.02052-12.
24. Zhu Y, Curtis M, Borroto-Esoda K. 2011. HBV DNA replication mediated by cloned patient HBV reverse transcriptase genes from HBV genotypes A-H and its use in antiviral phenotyping assays. J. Virol. Methods 173:340-346. http://dx.doi.org/10.1016/j.jviromet.2011.03.006.
25. Birkus G, Hitchcock MJM, Cihlar T. 2002. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 46:716-723. http://dx.doi.org/10.1128/AAC.46.3.716-723.2002. (Pubitemid 34157656)
26. Copeland RA. 2000. Chapter 8: reversible inhibitors, p 266-304. In Enzymes: a practical introduction to structure, mechanism, and data analysis, 2nd ed. Wiley-VCH, Inc., New York, NY.
27. Lodeiro MF, Uchida AU, Arnold JJ, Reynolds SL, Moustafa IM, Cameron CE. 2010. Identification of multiple rate-limiting steps during the human mitochondrial transcription cycle in vitro. J. Biol. Chem. 285:16387-16402. http://dx.doi.org/10.1074/jbc.M109.092676.
28. Mosley RT, Edwards TE, Murakami E, Lam AM, Grice RL, Du J, Sofia MJ, Furman PA, Otto MJ. 2012. Structure of hepatitis C virus polymerase in complex with primer-template RNA. J. Virol. 86:6503-6511. http://dx.doi.org/10.1128/JVI. 00386-12.
29. Gong P, Peersen OB. 2010. Structural basis for active site closure by the poliovirus RNA-dependent RNA polymerase. Proc. Natl. Acad. Sci. U. S. A. 107:22505-22510. http://dx.doi.org/10.1073/pnas.1007626107.
30. Zamyatkin DF, Parra F, Alonso JM, Harki DA, Peterson BR, Grochulski P, Ng KK. 2008. Structural insights into mechanisms of catalysis and inhibition in Norwalk virus polymerase. J. Biol. Chem. 283:7705-7712. http://dx.doi.org/10. 1074/jbc.M709563200.
31. Smith DB, Bukh J, Kuiken C, Muerhoff AS, Rice CM, Stapleton JT, Simmonds P. 2013. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and assignment web resource. Hepatology 59:318-327. http://dx.doi.org/10.1002/hep.26744.
32. Murakami E, Wang T, Babusis D, Lepist EI, Sauer D, Park Y, Vela JE, Shih R, Birkus G, Stefanidis D, Kim CU, Cho A, Ray AS. 2014. Metabolism and pharmacokinetics of the anti-hepatitis C virus nucleotide prodrug GS-6620. Antimicrob. Agents Chemother. 58:1943-1951. http://dx.doi.org/10.1128/AAC.02350- 13.
33. Combet C, Garnier N, Charavay C, Grando D, Crisan D, Lopez J, Dehne-Garcia A, Geourjon C, Bettler E, Hulo C, Le Mercier P, Bartenschlager R, Diepolder H, Moradpour D, Pawlotsky JM, Rice CM, Trépo C, Penin F, Deléage G. 2007. euHCVdb: the European hepatitis C virus database. Nucleic Acids Res. 35:D363-D366. http://dx.doi.org/10.1093/nar/gkl970. (Pubitemid 46056232)
34. Carroll SS, Tomassini JE, Bosserman M, Getty K, Stahlhut MW, Eldrup AB, Bhat B, Hall D, Simcoe AL, LaFemina R, Rutkowski CA, Wolanski B, Yang Z, Migliaccio G, De Francesco R, Kuo LC, MacCoss M, Olsen DB. 2003. Inhibition of hepatitis C virus RNA replication by 2′-modified nucleoside analogs. J. Biol. Chem. 278:11979-11984. http://dx.doi.org/10.1074/jbc.M210914200. (Pubitemid 36800172)
35. Olsen DB, Eldrup AB, Bartholomew L, Bhat B, Bosserman MR, Ceccacci A, Colwell LF, Fay JF, Flores OA, Getty KL, Grobler JA, LaFemina RL, Markel EJ, Migliaccio G, Prhavc M, Stahlhut MW, Tomassini JE, MacCoss M, Hazuda DJ, Carroll SS. 2004. A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Antimicrob. Agents Chemother. 48:3944-3953. http://dx.doi.org/10.1128/AAC.48.10. 3944-3953.2004. (Pubitemid 39304626)
36. Carroll SS, Ludmerer S, Handt L, Koeplinger K, Zhang NR, Graham D, Davies ME, MacCoss M, Hazuda D, Olsen DB. 2009. Robust antiviral efficacy upon administration of a nucleoside analog to hepatitis C virus-infected chimpanzees. Antimicrob. Agents Chemother. 53:926-934. http://dx.doi.org/10.1128/AAC.01032- 08.
37. Lawitz E, Hill J, Marbury T, Hazan L, Gruener D, Webster L, Majauskas R, Morrison R, DeMicco M, German P, Stefanidis D, Svaroskaia E, Arterburn S, Ray A, Rossi S, McHutchison J, Rodriguez-Torres M. 2012. GS-6620, a liver-targeted nucleotide prodrug, exhibits antiviral activity and favorable safety profile over 5 days in treatment naïve chronic HCV genotype 1 subjects, abstr 1188. Abstr. 47th Annual Meeting of the European Association for the Study of the Liver (EASL), Barcelona, Spain, 18 to 22 April 2012.
38. Johnson AA, Ray AS, Hanes J, Suo Z, Colacino JM, Anderson KS, Johnson KA. 2001. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J. Biol. Chem. 276:40847-40857. http://dx.doi.org/10.1074/jbc. M106743200. (Pubitemid 37373231)
39. White AJ. 2001. Mitochondrial toxicity and HIV therapy. Sex. Transm. Infect. 77:158-173. http://dx.doi.org/10.1136/sti.77.3.158. (Pubitemid 32595736)
40. Kang I, Lin J, Wang JH. 1994. Affinity labeling and measurement of DNA-induced conformation change in RNA polymerase II. Biochemistry 33:2696-2702. http://dx.doi.org/10.1021/bi00175a044. (Pubitemid 24099681)