Novel protease and polymerase inhibitors for the treatment of hepatitis C virus infection

Expert Opinion on Investigational Drugs

Volumn 16, Issue 8, 2007, Pages 1171-1181

  Sheldon, Julie ^a   Barreiro, Pablo ^a   Soriano, Vincent ^a  

^a HOSPITAL UNIVERSITARIO LA PAZ   (Spain)

Author keywords

Antiviral treatment; Hepatitis C; Polymerase inhibitors; Protease inhibitors

Indexed keywords

7 DEAZA 2' C METHYLADENOSINE; A 837093; ACH 806; AG 021541; ANTIVIRUS AGENT; BOCEPRAVIR; CILUPREVIR; GS 9132; GS 9190; HCV 796; ITMN 191; NUCLEOSIDE DERIVATIVE; PEGINTERFERON; PLACEBO; PSI 6130; PYRIMIDINE NUCLEOSIDE DERIVATIVE; R 1479; R 1626; R 7128; RECOMBINANT ALPHA INTERFERON; RIBAMIDINE; RIBAVIRIN; RNA DIRECTED DNA POLYMERASE INHIBITOR; SCH 503034; SERINE PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; VALOPICITABINE; VX 950; XTL 2125;

ANEMIA; ANTIVIRAL ACTIVITY; CHRONIC HEPATITIS; CLINICAL TRIAL; DRUG DOSE ESCALATION; DRUG POTENCY; DRUG POTENTIATION; DRUG SAFETY; DRUG TOLERABILITY; HEPATITIS C; HUMAN; MULTIPLE CYCLE TREATMENT; NONHUMAN; REVIEW; SINGLE DRUG DOSE; UNSPECIFIED SIDE EFFECT; VIRUS REPLICATION; VIRUS RESISTANCE;

ANIMALS; ENZYME INHIBITORS; HEPACIVIRUS; HEPATITIS C; HUMANS; PROTEASE INHIBITORS; RNA REPLICASE;

EID: 34548271074     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543784.16.8.1171     Document Type: Review

References (61)

1. SHARMA P, LOK A: Viral hepatitis and liver transplantation. Semin. Liver Dis. (2006) 26(3):285-297.
2. FRIED MW, HADZIYANNIS SJ: Treatment of chronic hepatitis C infection with peginterferons plus ribavirin. Semin. Liver Dis. (2004) 24(Suppl. 2):47-54.
3. LOHMANN V, KORNER F, KOCH J et al.: Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science (1999) 285:110-113.
4. WAKITA T. PIETSCHMANN T, KATO T et al.: Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat. Med. (2005) 11(7):791-796.
5. HORSCROFT N, LAI VC, CHENEY W et al.: Replicon cell culture system as a valuable tool in antiviral drug discovery against hepatitis C virus. Antivir. Chem. Chemother. (2005) 16(1):1-12.
6. DI BISCEGLIE AM, MCHUTCHISON J, RICE CM: New therapeutic strategies for hepatitis C. Hepatology (2002) 35(1):224-231.
7. MORADPOUR D, BRASS V, GOSERT R, WOLK B, BLUM HE: Hepatitis C: molecular virology and antiviral targets. Trends Mol. Med. (2002) 8(10):476-482.
8. PAWLOTSKY JM, CHEVALIEZ S, MCHUTCHISON JG: The hepatitis C virus life cycle as a target for new antiviral therapies. Gastroentrology (2007) 132(5):1979-1998.
9. WARDELL AD, ERRINGTON W, CIARAMELLA G, MERSON J, MCGARVEY MJ: Characterization and mutational analysis of the helicase and NTPase activities of hepatitis C virus full-length NS3 protein. J. Gene Virol. (1999) 80(Part 3):701-709.
10. BOROWSKI R SCHALINSKI S, SCHMITZ H: Nucleotide triphosphatase/helicase of hepatitis C virus as a target for antiviral therapy. Antiviral Res. (2002) 55(3):397-412.
11. KOLYKHALOV AA, MIHALIK K, FEINSTONE SM, RICE CM: Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo. J. Virol. (2000) 74(4):2046-2051.
12. LIN C, KWONG AD, PERNI RB: Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of hepatitis C virus NS3.4A serine protease. Infect. Disord. Drug Targets (2006) 6(1)3-16.
13. PERNI RB, ALMQUIST SJ, BYRN RA et al.: Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob. Agents Chemother. (2006) 50(3):899-909.
14. LIN K, PERNI RB, KWONG AD, LIN C: VX-950, a novel hepatitis C virus (HCV) NS3-4A protease inhibitor, exhibits potent antiviral activities in HCV replicon cells. Antimicrob. Agents Chemother. (2006) 50(5):1813-1822.
15. MCHUTCHISON JG, EVERSON G, GORDON SC et al.: Results of an interim analysis of a Phase 2 study of telaprevir (VX-950) with peginterferon α-2a and ribavirin in previously untreated subjects ith hepatitis C. Hepatology (2007) 46(Sl):S296.
16. LAWITZ EJ, RODRIGUEZ-TORRES M, MUIR A et al.: 28 Days of the hepatitis c protease inhibitor VX-950, in combination with peg-interferon-(X-2α and ribavirin, is well-tolerated and demonstrates robust antiviral effects. Gastroenterology(2006) 130(4):(Suppl. 2).
17. MALCOLM BA, LIU R, LAHSER F et al.: SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of α interferon in replicon cells. Antimicrob. Agents Chemother. (2006) 50(3):1013-1020.
18. ZEUZEM S, SARRAZIN C, WAGNER F et al.: 78 The HCV NS3 protease inhibitor SCH 503034 in combination with PEG-IFNa-2b in the treatment of HCV-1 PEG-IFNa-2b non-responders: antiviral activity and HCV variant analysis. J. Hepatol. (2006) 42(Suppl. 2):S35.
19. SEIWERT S, ANDREWS S, YANG H et al.: Preclinical characteristics of ITMN 191, an orally active inhibitor of the HCV NS3/4a protease nominated for preclinical development. Digestive Disease Week. Los Angeles, California, USA (20 - 25 May 2006).
20. INTERMUNE: InterMune Submits Clinical Trial Authorization Application for ITMN- 191 for Hepatitis C Infections (2006) (Press Release).
21. TAN H, SEIWERT S, BLATT L: In vitro synergistic antiviral activity of ITMN - 191, an orally active inhibitor of the hepatitis C virus ( HCV) NS3/4A protease, in combination with PEG-interferon α-2a. Hepatology (2006) 44(S1):A534.
22. SEIWERT S, TAN H, BLATT L: Additive to synergistic antiviral effects of an NS3/4a protease inhibitor (ITMN-191) and an NS5b RNA-dependent RNA dependent polymerase inhibitor (R1479) in an HCV replicon system. Hepatology (2007) 46(S1):S167.
23. HINRICHSEN H, BENHAMOU Y, WEDEMEYER H et al.: Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients. Gastroenterology (2004) 127(5):1347-1355.
24. LAMARRE D, ANDERSON PC, BAILEY M et al.: An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature (2003) 426(6963):186-189.
25. REISER M, HINRICHSEN H, BENHAMOU Y et al.: Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C. Hepatology (2005) 41(4):832-835.
26. LESBURG CA, CABLE MB, FERRARI E et al..: Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat. Struct. Biol. (1999) 6(10):937-943.
27. BRESSANELLI S, TOMEI L, REY FA, DE FRANCESCO R: Structural analysis of the hepatitis C virus RNA polymerase in complex with ribonucleotides. J. Virol. (2002) 76(7):3482-3492.
28. LEE JH, NAM IY, MYUNG H: Nonstructural protein 5B of hepatitis C virus. Mol. Cells (2006) 21(3):330-336.
29. PIERRA C, AMADOR A, BENZARIA S et al.: Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2′-C-methylcytidine. J. Med. Chem. (2006) 49(22):6614-6620.
30. LAWITZ EJ, NGUYEN T, YOUNES Z et al.: Clearance of HCV RNA with valopitabine (NM283) plus peg-interferon in treatment-naive patients with HCV-1 infection: results at 24 and 48 weeks. Hepatology (2007) 46(S1):S9.
31. TONIUTTO P, FABRIS C, BITETTO D et al.: Valopicitabine dihydrochloride:a specific polymerase inhibitor of hepatitis C virus. Curr. Opin. Investig. Drugs (2007) 8(2):150-158.
32. RODRIGUEZ-TORRES M, LAWITZ E, GODOFSKY E: Valopicitabine (nm283) alone and in combination with peg-interferon in patients with genotype 1 chronic hepatitis C: preliminary results from an ongoing Phase II, multicenter study. Gastroenterology (2005) 128(4 Suppl. 2):A695-A696.
33. AFDAL N, O'BRIEN C, GODOFSKY E et al.: Valopicitabine (NM283), alone or with peg-interferon, compared to peg-interferon/ribervirin (PEGIFN/RBV) retreatment in patients with HCV-1 infection and prior non-response to PEGIFN/RBV: one year results. Hepatology (2007) 46(S1):S5.
34. COELMONT L, PAESHUYSE J, WINDISCH MP et al.: Ribavirin antagonizes the in vitro anti-hepatitis C virus activity of 2′-C-methylcytidine, the active component of valopicitabine. Antimicrob. Agents Chemother. (2006) 50(10):3444-3446.
35. STUYVER L, MCBRAYER T, THARNISH P et al.: β-d-2′-deoxy-2′-fluoro-2′-c-methylcytidine is a potent and specific inhibitor of hepatitis C virus in Huh-7 cells. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, USA (16 - 19 December 2005), (Abstract F-481).
36. MURAKAMI E, RAMESH M, MCBRAYER T et al.: Mechanism of activation of β-D-2′-deoxy-2′-fluoro-2′-C-methylcyridine and inhibition of hepatitis C virus NS5B RNA polymerase. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, USA (16 - 19 December 2005), (Abstract 476).
37. XTL, BIOPHARMACUETICALS, INC.: XTL Biopharmaceuticals Ltd initiates patient dosing in Phase I clinical trial of XTL-2125, an oral non-nucleoside polymerase inhibitor for the treatment of hepatitis C. 4 May 2006, New York, USA (Press Release).
38. VILLANO S, CHANDRA P, RAIBLE D et al.: Antiviral activity of the non-nucleoside polymerase inhibitor, HCV-796, in patients with chronic hepatitis C virus: preliminary results from a randomized, double-blind, placebo-controlled, ascending multiple dose study. Digestive Disease Week; Los Angeles, California, USA (20 - 25 May 2006), (Abstract 1).
39. VILLANO S, RAIBLE D, HARPER D et al.: Antiviral activity of the non-nucleoside polymerase inhibitor, HCV-796, in combination with pegylated interferon α-2b in treatment-naive patients with chronic HCV. Hepatology (2007) 46(S1):S24.
40. KLUMPP K, LEVEQUE V, LE POGAM S et al.: The novel nucleoside analog R1479 (4′-azidocytidine) is a potent inhibitor of NS5B-dependent RNA synthesis and hepatitis C virus replication in cell culture. J. Biol. Chem. (2006) 281(7):3793-3799.
41. ROBERTS S, COOKSLEY G, DORE G et al.: Results of a Phase 1B, multiple dose study of R1626, a novel nucleoside analog targeting HCV polymerase in chronic HCV genotype 1 patients. Hepatology (2006) 44(S1):A692.
42. JIANG W, CHIU S, ALI S et al.: In vitro antiviral interactions of a novel HCV inhibitor R1479 with interferon α - 2α, ribavirin and other HCV inhibitors. Hepatology (2006) 44(S1)A533.
43. WAGNER R, LARSON D, BOSSE T et al.: Discovery, characterization and anti-HCV activity of a novel NS5B inhibitor. Hepatology (2006) 44(S1):A236-A237.
44. KOEV G, DEKHTYAR T, HAN L et al.: In vitro antiviral effects of combinations of Abbott HCV polymerase inhibitors with IFN or NS314A protease inhibitors. Hepatology (2006) 44(S1):A352.
45. CARROLL S, DAVIES M, HANDT L et al.: Robust suppression of viral replication by a nucleoside polymerase inhibitor in chimpanzees infected with hepatitis C virus. Hepatology (2006) 44(S1):A535.
46. LU L, PILOT-MATIAS TJ, STEWART KD et al..: Mutations conferring resistance to a potent hepatitis C virus serine protease inhibitor in vitro. Antimicrob. Agents Chemother. (2004) 48(6):2260-2266.
47. LIN C, LIN K, LUONG YP et al.: In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J. Biol Chem. (2004) 279(17):17508-17514.
48. TONG X, CHASE R, SKELTON A et al.: Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Antiviral Res. (2006) 70(2):28-38.
49. SARRAZIN C, KIEFFER TL, BARTELS D et al.: Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology (2007) 132(5):1767-1777.
50. SEIWERT S, ANDREWS S, TAN H et al.: Generation and characterisation of HCV replicons with reduced sensitivity to ITMN 191, a macrocyclic inhibitor of NS3/4a. Digestive Disease Week. Los Angeles, California, USA (2006), (Abstract 195).
51. YANG W, ZHAO Y, FABRYCKI J et al.: Induction of resistance by a novel class of compounds active against hepatitis C virus with no cross-resistance to NS3 protease and NS513 polymeme inhibitors. Hepatology (2006) 44(S1):A535.
52. OLSEN D, CARROLL SS, HANDT L et al.: HCV antiviral activity and resistance analysis in chronically infected chimpanzees treated with Ns3/ 4a protease and NS5b polymerase inhibitors. Hepatology (2007) 46(Suppl. 1):S298.
53. MIGLIACCIO G, TOMASSINI JE, CARROLL SS et al..: Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J. Biol. Chem. (2003) 278(49):49164-49170.
54. CARROLL SS, TOMASSINI JE, BOSSERMAN M et al.: Inhibition of hepatitis C virus RNA replication by 2′-modified nucleoside analogs. J. Biol. Chem. (2003) 278(14):11979-11984.
55. LUDMERER SW, GRAHAM DJ, BOOTS E et al.: Replication fitness and NS5B drug sensitivity of diverse hepatitis C virus isolates characterized by using a transient replication assay. Antimicrob. Agents Chemother. (2005) 49(5):2059-2069.
56. LE POGAM S, JIANG WR, LEVEQUE V et al.: In vitro selected Con1 subgenomic replicons resistant to 2′-C-methyl-cytidine or to R1479 show lack of cross resistance. Virology (2006) 351(2):349-359.
57. LU L, KRISHNAN P, PITHAWALLA R et al.: Selection and characterization of hepatitis C virus replicons resistant to a potent polymerase inhibitor A-837093. Hepatology (2006) 44(S2):A351.
58. VILLANO S, HOWE A, RAIBLE D et al.: Analysis of HCV NS5B genetic variants following monotherapy with HCV-796, a non-nucleoside polymerase inhibitor, in treatment-naive HCV-infected patients. Hepatology (2006) 44(S1):A607-A608.
59. SHI S, HERLIHY K, GONZALEZ J, PATICK A, DUGGAL R: In vitro resistance studies of AG-02154 1, a novel nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Hepatology (2006) 44(S1):A534.
60. SORIANO V, PUOTI M, SULKOWSKI M et al.: Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS (2007) 21(9):1073-1089.
61. AMPARO E, SAHA A, YOUNG C et al.: HCV-796: a potent and selective non-nucleoside inhibitor of HCV NS5b. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, USA (2006), (Abstract FI-1378).