Prospects for hepatitis C virus therapeutics: Levovirin and viramidine as improved derivatives of ribavirin

Current Opinion in Investigational Drugs

Volumn 3, Issue 5, 2002, Pages 680-683

  Watson, Julia ^a  

^a GILEAD SCIENCES   (United States)

Author keywords

Hepatitis C virus; Levovirin; Ribavirin; Viramidine

Indexed keywords

ALANINE AMINOTRANSFERASE; ALPHA INTERFERON; LEVOVIRIN; MYCOPHENOLIC ACID; PEGINTERFERON ALPHA2A; PLACEBO; PRODRUG; RIBAMIDINE; RIBAVIRIN; RIBAVIRIN DERIVATIVE; UNCLASSIFIED DRUG; VIRUS RNA;

ANEMIA; ANTIVIRAL ACTIVITY; BLOOD TOXICITY; CELL TYPE; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; DOSE RESPONSE; DRUG ACCUMULATION; DRUG BIOAVAILABILITY; DRUG EFFECT; DRUG EFFICACY; DRUG ERYTHROCYTE LEVEL; DRUG MECHANISM; DRUG METABOLISM; DRUG POTENTIATION; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; DRUG TOXICITY; ENANTIOMER; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; IMMUNE RESPONSE; IMMUNOMODULATION; MONOTHERAPY; NONHUMAN; REVIEW; VIRUS INHIBITION; VIRUS REPLICATION;

ANTIVIRAL AGENTS; HEPATITIS C; HUMANS; RIBAVIRIN; STEREOISOMERISM;

EID: 0036591188     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (50)

1. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK: Interferon α-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med (1998) 339(21):1485-1492.
2. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet (2001) 358(9286):958-965.
3. Dusheiko G, Main J, Thomas H, Reichard O, Lee C, Dhillon A, Rassam S, Fryden A, Reesink H, Bassendine M, Norkrans G, Cuypers T, Lelie N, Telfer P, Watson J, Weegink C, Sillikens P, Weiland O: Ribavirin treatment for patients with chronic hepatitis C: Results of a placebo-controlled study. J Hepatol (1996) 25(5):591-598.
4. Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, Shiffman ML, Zeuzem S, Craxi A, Ling MH, Albrecht J: Interferon α-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med (1998) 339(21):1493-1499.
5. Hosoya M, Shigeta S, Ishii T, Suzuki H, De Clercq E: Comparative inhibitory effects of various nucleoside and nonnucleoside analogues on replication of influenza virus types A and B in vitro and in vivo. J Infect Dis (1993) 168(3):641-646.
6. Huffman JH, Sidwell RW, Khare GO, Witkowski JT, Allen LB, Robins RK: In vitro effect of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole, ICN 1229) on deoxyribonucleic acid and ribonucleic acid viruses. Antimicrob Agents Chemother (1973) 3(2):235-241.
7. Sidwell RW, Huffman JH, Khare GP, Allen LB, Witkowski JT, Robins RK: Broad-spectrum antiviral activity of Virazole: 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science (1972) 177(50):705-706.
8. Streeter DG, Witkowski JT, Khare GP, Sidwell RW, Bauer RJ, Robins RK, Simon LN: Mechanism of action of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent. Proc Natl Acad Sci USA (1973) 70(4):1174-1178.
9. Sintchak MD, Nimmesgern E: The structure of inosine 5′-monophosphate dehydrogenase and the design of novel inhibitors. Immunopharmacology (2000) 47(2-3):163-184.
10. Fairbanks LD, Bofill M, Ruckemann K, Simmonds HA: Importance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans. Disproportionate expression of pyrmidine pools and contrasting effects of de novo synthesis inhibitors. J Biol Chem (1995) 270(50):29682-29689.
11. Najera I, Laxton C, Hobbs E, Wilkinson T, Bartenschlager R, Graves M, Devos R: Characterisation of interferon α-2a and pegylated interferon α-2a in combination with ribavirin, mycophenolic acid or VX-497 as inhibitors of HCV replicon replication. Antiviral Res (2001) 50(1):A89.
12. Pravdina NF, Kraevskii AA, Skaptsova NV, Florent'ev VL, Galegov GA: Inhibition of influenza virus A RNA-polymerase activity by various 3′-amino-3′-deoxy- and 3prime;-azido-3′-deoxyribonucleoside-5′-triphosphates. Mol Gen Mikrobiol Virusol (1987) (2):39-42.
13. Fernandez-Larsson R, O'Connell K, Koumans E, Patterson JL: Molecular analysis of the inhibitory effect of phosphorylated ribavirin on the vesicular stomatitis virus in vitro polymerase reaction. Antimicrob Agents Chemother (1989) 33(10):1668-1673.
14. Hong Z, Ferrari E, Wright-Minogue J, Skelton A, Glue P, Zhong W, Lau J: Direct antiviral activity of ribavirin: Hepatitis C virus NS5B polymerase incorporates ribavirin triphosphate into nascent RNA product. Hepatology (1999) 30(4 Pt 2):P773A.
15. Maag D, Castro C, Hong Z, Cameron CE: Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. J Biol Chem (2001) 276(49):46094-46098.
16. Crotty S, Maag D, Arnold JJ, Zhong W, Lau JY, Hong Z, Andino R, Cameron CE: The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med (2000) 6(12):1375-1379.
17. Lanford RE, Chavez D, Guerra B, Lau JY, Hong Z, Brasky KM, Beames B: Ribavirin induces error-prone replication of GB virus B in primary tamarin hepatocytes. J Virol (2001) 75(17):8074-8081.
18. Souvignet C, Zarski JP: Combination treatment for chronic hepatitis C: What is the role of ribavirin? Fundam Clin Pharmacol (2000) 14(4):321-325. A concise review of the various effects of ribavirin and their relevance in HCV infection.
19. Parkin J, Cohen B: An overview of the immune system. Lancet (2001) 357(9270):1777-1789. A detailed review of immune cells and cytokines.
20. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV: Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med (2001) 194(10):1395-1406.
21. Tam RC, Lim C, Bard J, Pai B: Contact hypersensitivity responses following ribavirin treatment in vivo are influenced by type 1 cytokine polarization, regulation of IL-10 expression, and costimulatory signaling. J Immunol (1999) 163(7):3709-3717.
22. Hultgren C, Milich DR, Weiland O, Sallberg M: The antiviral compound ribavirin modulates the T helper (Th) 1/Th2 subset balance in hepatitis B and C virus-specific immune responses. J Gen Virol (1998) 79(Pt 10):2381-2391.
23. Fang SH, Hwang LH, Chen DS, Chiang BL: Ribavirin enhancement of hepatitis C virus core antigen-specific type 1 T helper cell response correlates with the increased IL-12 level. J Hepatol (2000) 33(5):791-798.
24. Fang SH, Lai MY, Hwang LH, Yang PM, Chen PJ, Chiang BL, Chen DS: Ribavirin enhances interferon-γ levels in patients with chronic hepatitis C treated with interferon-α. J Biomed Sci (2001) 8(6):484-491.
25. Ning Q, Brown D, Parodo J, Cattral M, Gorczynski R, Cole E, Fung L, Ding JW, Liu MF, Rotstein O, Phillips MJ, Levy G: Ribavirin inhibits viral-induced macrophage production of TNF, IL-1, the procoagulant fgl12 prothrombinase and preserves Th1 cytokine production but inhibits Th2 cytokine response. J Immunol (1998) 160(7):3487-3493.
26. Tam RC, Ramasamy K, Bard J, Pai B, Lim C, Averett DR: The ribavirin analog ICN 17261 demonstrates reduced toxicity and antiviral effects with retention of both immunomodulatory activity and reduction of hepatitis-induced serum alanine aminotransferase levels. Antimicrob Agents Chemother (2000) 44(5):1276-1283. This paper details Levovirin's biological effects on cytokine production in comparison to ribavirin.
27. Ramasamy KS, Tam RC, Bard J, Averett DR: Monocyclic L-nucleosides with type 1 cytokine-inducing activity. J Med Chem (2000) 43(5):1019-1028.
28. Sarih M, Bouchrit N, Benslimane A: Different cytokine profiles of peripheral blood mononuclear cells from patients with persistent and self-limited hepatitis C virus infection. Immunol Lett (2000) 74(2):117-120.
29. Cramp ME, Rossol S, Chokshi S, Carucci P, Williams R, Naoumov NV: Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C. Gastroenterology (2000) 118(2):346-355.
30. Yee LJ, Tang J, Gibson AW, Kimberly R, Van Leeuwen DJ, Kaslow RA: Interleukin 10 polymorphisms as predictors of sustained response in antiviral therapy for chronic hepatitis C infection. Hepatology (2001) 33(3):708-712.
31. Page T, Connor JD: The metabolism of ribavirin in erythrocytes and nucleated cells. Int J Biochem (1990) 22(4):379-383.
32. Jarvis SM, Thorn JA, Glue P: Ribavirin uptake by human erythrocytes and the involvement of nitrobenzylthioinosine-sensitive (es)-nucleoside transporters. Br J Pharmacol (1998) 123(8):1587-1592.
33. ICN Pharmaceuticals Inc: ICN exploring licensing Levovirin. Press Release (2001) May 04
34. ICN Pharmaceuticals Inc: Roche licenses potential second-generation drug from ICN to set new standards in hepatitis C treatment. Press Release (2001) July 01.
35. Lin C-C, Tam R, Orr R, Hong Z, Lau JY: Development of Levovirin as a second generation ribavirin for the treatment of chronic hepatitis C. Gastroenterology (2001) 120(5 Suppl 1):Abs 2890.
36. Rossi S, Wright T, Lin CC, Lau JY, Edalatpour N, Fang JW: Phase I clinical studies of Levovirin - A second generation ribavirin candidate. Hepatology (2001) 34(4 Pt 2):327A.
37. Fang JW, Luu K, Huang JF, Lau JY, Lin CC: Pharmacokinetic characterization of Levovirin, a second generation ribavirin candidate - Adsorption, distribution, metabolism and excretion (ADME) studies. Hepatology (2001) 34(4 Pt 2):429A.
38. Lin CC, Lau JY: A novel in vitro partition approach to evaluate RBC accumulation/toxicity of ribavirin and its analogues. Hepatology (2001) 34(4 Pt 2):218A.
39. Corritori S, Lau JY, Lin CC: Safety studies of Levovirin, a second generation ribavirin candidate, showed excellent safety profile. Hepatology (2001) 34(4 Pt 2):219A.
40. Hong Z, Zhong W, Hamatake R, Tam R, Lai VC, Ramasamy K, Cheney W, Zhang Z, Raney A, Horscroft N, Huggins J, Lau JY: Antiviral activities of new generation of ribavirin analogues: Levovirin and viramidine. Hepatology (2001) 34(4 Pt 2):415A.
41. Tam R, Lin CC, Lau JY: Characterization of Levovirin, a nucleoside analogue with similar immunomodulatory activities but without the antiviral activity/toxicity of ribavirin. Hepatology (2000) 32(4 Pt 2):372A.
42. He Q, Flaherty J, Cheney CP, Tam RC, Koziel MJ: Enhancement of hepatitis C virus-specific type 1 cytokine and T cell proliferative responses by ribavirin and Levovirin (ICN 17261) in vitro. Hepatology (2000) 32(4 Pt 2):394A.
43. Griffith DA, Jarvis SM: Nucleoside and nucleobase transport systems of mammalian cells. Biochim Biophys Acta (1996) 1286(3):153-181.
44. Lin CC, Luu K, Lourenco D, Corritori S, Hong Z, Lau JY: Viramidine, a prodrug of ribavirin, demonstrated superior liver-targeting properties and a much improved toxicity profile in cynomolgus monkey studies. Hepatology (2001) 34(4 Pt 2):453A.
45. Lin CC, Luu K, Lourenco D, Huang J, Fang JW, Lau JY: Comparative absorption, metabolism and excretion studies of ribavirin versus viramidine, a liver-targeted ribavirin prodrug. Hepatology (2001) 34(4 Pt 2):219A.
46. Tam RC, Lim C, Bard J, Bagha P, Lau JY, Hong Z: Immunomodulatory activities of viramidine, a liver-targeting ribavirin prodrug, in vitro and in vivo. Hepatology (2001) 34(4 Pt 2):351A.
47. Jaeckel E, Comberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M, Pastore G, Dietrich M, Trautwein C, Manns MP: Treatment of acute hepatitis C with interferon α-2b. N Engl J Med (2001) 345(20):1452-1457.
48. Wilkinson T: Hepatitis C virus: Prospects for future therapies. Curr Opin Investig Drugs (2001) 2(11):1516-1522. This review describes progress in discovery of small molecule inhibitors of HCV non-structural proteins.
49. ICN Pharmaceuticals Inc (Tam, RC): Specific modulation of Th1/Th2 cytokine expression by ribavirin in activated T-lymphocytes. US-05767097 (1998). This patent includes a description of ribavirin's immunomodulatory effects.
50. ICN Pharmaceuticals Inc (Lau J, Hong Z): Methods of drug delivery to hepatocytes and treatment of Flavivirdae infections. WO-00215904 (2001). This patent describes viramidine, the carboxamidine derivative of ribavirin, and discloses data concerning drug uptake into hepatocyte cell lines.