Skip to main content
SpringerLink
Log in

Testing Antivirals Against Hepatitis Delta Virus

Farnesyl Transferase Inhibitors

  • Protocol
Hepatitis B and D Protocols

Part of the book series: Methods in Molecular Medicine™ ((MIMM,volume 96))

  • 549 Accesses

Abstract

Since the discovery of hepatitis delta virus (HDV) about 25 yr ago (1–3), no medical therapy has yet been developed to eradicate effectively this cause of acute and chronic liver disease. This small RNA virus is composed of three main elements: a 1.7-kb circular single-stranded RNA genome, two isoforms of an antigenome-encoded protein—the delta antigens—and a lipid envelope embedded with hepatitis B virus (HBV) surface antigens (HBsAgs) (Fig. 1 [4,5]). These latter proteins are necessary for the production of infectious HDV particles, which explains why clinical infections with HDV occur only in the presence of an HBV infection. The presence of HDV can dramatically increase the severity of the underlying HBV infection (6–8). Clearance of delta infections is refractory to interferon (9), and recent improved therapies that clear HBV viremia but still fail to abolish HBsAg levels have no impact on HDV (10). Thus other anti-HDV strategies need to be considered.

Schematic overview showing the principal structural elements of a HDV particle: genomic circular RNA, complexed with delta antigen (large and small), is surrounded by a lipid envelope embedded with HBV surface antigen proteins. (The precise stoichiometry is not known and simplified here for illustrative purposes.)

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Rizzetto, M., Canese, M.G., Aricò, S., et al. (1977) Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut 18, 997–1003.

    Article  PubMed  CAS  Google Scholar 

  2. Rizzetto, M., Canese, M.G., Gerin, J. L., London, W.T., Sly, D. L., and Purcell, R. H. (1980) Transmission of the hepatitis B virus-associated delta antigen to chimpanzees. J. Infect. Dis. 141, 590–602.

    PubMed  CAS  Google Scholar 

  3. Rizzetto, M., Hoyer, B., Canese, M. G., Shih, J. W.K., Purcell, R.H., and Gerin, J.L. (1980) Delta agent: association of delta antigen with hepatitis B surface antigen and RNA in serum of delta-infected chimpanzees. Proc. Natl. Acad. Sci. USA 77, 6124–6128.

    Article  PubMed  CAS  Google Scholar 

  4. Rizzetto, M. (1983) The delta agent. Hepatology 3, 729–737.

    Article  PubMed  CAS  Google Scholar 

  5. Casey, J. L. (1998) Hepatitis delta virus: molecular biology, pathogenesis and immunology. Antiviral Ther. 3, 37–42.

    CAS  Google Scholar 

  6. Buti, M., Estebán, R., Jardi, R., et al., (1987) Clinical and serological outcome of acute delta infection. J. Hepatol. 5, 59–64.

    Article  PubMed  CAS  Google Scholar 

  7. Casey, J. L. (1996) Hepatitis delta virus. Genetics and pathogenesis. Clin. Lab. Med. 16, 451–464.

    PubMed  CAS  Google Scholar 

  8. de Man, R.A., Sprey, R. P., Niesters, H. G., et al. (1995) Survival and complications in a cohort of patients with anti-delta positive liver disease presenting in a tertiary referral clinic. J. Hepatol. 23, 662–667.

    Article  PubMed  Google Scholar 

  9. Farci, P., Mandas, A., Coiana, A., et al. (1994) Treatment of chronic hepatitis D with interferon alfa-2a. N. Engl. J. Med. 330, 88–94.

    Article  PubMed  CAS  Google Scholar 

  10. Lau, D., Doo, E., Park, Y., et al. (1999) Lamivudine for chronic delta hepatitis. Hepatology 30, 546–549.

    Article  PubMed  CAS  Google Scholar 

  11. Modahl, L.E., Macnaughton, T.B., Zhu, N., Johnson, D.L., and Lai, M.M. (2000) RNA-dependent replication and transcription of hepatitis delta virus RNA involve distinct cellular RNA polymerases. Mol. Cell. Biol. 20, 6030–6039.

    Article  PubMed  CAS  Google Scholar 

  12. Yamaguchi, Y., Filipovska, J., Yano, K., et al. (2001) Stimulation of RNA polymerase II elongation by hepatitis delta antigen. Science 293, 124–127.

    Article  PubMed  CAS  Google Scholar 

  13. Moraleda, G. and Taylor, J. (2001) Host RNA polymerase requirements for transcription of the human hepatitis delta virus genome. J. Virol. 75, 10161–10169.

    Article  PubMed  CAS  Google Scholar 

  14. Luo, G., Chao, M., Hsieh, S.-Y., Sureau, C., Nishikura, K., and Taylor, J. (1990) A specific base transition occurs on replicating hepatitis delta virus RNA. J. Virol. 64, 1021–1027.

    PubMed  CAS  Google Scholar 

  15. Casey, J. L. and Gerin, J. L. (1995) Hepatitis delta virus: RNA editing and genotype variations, in The Unique Hepatitis Delta Virus (Dinter-Gottlieb, G., ed.), R.C. Landes Austin, pp. 111–124.

    Google Scholar 

  16. Polson, A. G., Bass, B.L., and Casey, J. L. (1996) RNA editing of hepatitis delta virus antigenome by dsRNA-adenosine deaminase. Nature 380, 454–456.

    Article  PubMed  CAS  Google Scholar 

  17. Chao, M., Hsieh, S.-Y., and Taylor, J. (1990) Role of two forms of hepatitis delta virus antigen: evidence for a mechanism of self-limiting genome replication. J. Virol. 64, 5066–5069.

    PubMed  CAS  Google Scholar 

  18. Glenn, J. S. and White, J. M. (1991) Trans-dominant inhibition of human hepatitis delta virus genome replication. J. Virol. 65, 2357–2361.

    PubMed  CAS  Google Scholar 

  19. Chang, F.-L., Chen, P.-J., Tu, S.-J., Wang, C.-J., and Chen, D.-S. (1991) The large form of hepatitis δ antigen is crucial for assembly of hepatitis δ virus. Proc. Natl. Acad. Sci. USA 88, 8490–8494.

    Article  PubMed  CAS  Google Scholar 

  20. Lee, C.-Z., Chen, P.-J., and Chen, D.-S. (1995) Large hepatitis delta antigen in packaging and replication inhibition: role of the carboxyl-terminal 19 amino acids and amino-terminal sequences. J. Virol. 69, 5332–5336.

    PubMed  CAS  Google Scholar 

  21. Maltese, W. A. (1990) Posttranslational modification of proteins by isoprenoids in mammalian cells. FASEB J. 4, 3319–3328.

    PubMed  CAS  Google Scholar 

  22. Schafer, W. R. and Rine, J. (1992) Protein prenylation: genes, enzymes, targets, and functions. Annu. Rev. Genet. 30, 209–237.

    Article  Google Scholar 

  23. Zhang, F.L. and Casey, P.J. (1996) Protein prenylation: molecular mechanisms and functional consequences. Annu. Rev. Biochem. 65, 241–269.

    Article  PubMed  CAS  Google Scholar 

  24. Glenn, J. S., Watson, J. A., Havel, C. M., and White, J. M. (1992) Identification of a prenylation site in delta virus large antigen. Science 256, 1331–1333.

    Article  PubMed  CAS  Google Scholar 

  25. Hwang, S. B. and Lai, M. M. C. (1993) Isoprenylation mediates direct protein-protein interactions between hepatitis large delta antigen and hepatitis B virus surface antigen. J. Virol. 67, 7659–7662.

    PubMed  CAS  Google Scholar 

  26. Park, H.W. and Beese, L. S. (1997) Protein farnesyltransferase. Curr. Opin. Struct. Biol. 7, 873–880.

    Article  PubMed  CAS  Google Scholar 

  27. Casey, P. J. and Seabra, M. C. (1996) Protein prenyltransferases. J. Biol. Chem. 271, 5289–5292.

    Article  PubMed  CAS  Google Scholar 

  28. Seabra, M.C., Goldstein, J.L., Südhof, T.C., and Brown, M.S. (1992) Rab geranylgeranyl transferase. A multisubunit enzyme that prenylates GTP-binding proteins terminating in Cys-X-Cys or Cys-Cys. J. Biol. Chem. 267, 14497–14503.

    PubMed  CAS  Google Scholar 

  29. Farnsworth, C. C., Wolda, S. L., Gelb, M. H., and Glomset, J. A. (1989) Human lamin B contains a farnesylated cysteine residue. J. Biol. Chem. 264, 20422–20429.

    PubMed  CAS  Google Scholar 

  30. James, G. L., Goldstein, J. L., Pathak, R. K., Anderson, R. G., and Brown, M. S. (1994) PxF, a prenylated protein of peroxisomes. J. Biol. Chem. 269, 14182–14190.

    PubMed  CAS  Google Scholar 

  31. Hancock, J.F., Magee, A. I., Childs, J.E., and Marshall, C.J. (1989) All ras proteins are poly-isoprenylated but only some are palmitoylated. Cell 57, 1167–1177.

    Article  PubMed  CAS  Google Scholar 

  32. Casey, P. J., Solski, P.A., Der, C. J., and Buss, J.E. (1989) p21ras is modified by a farnesyl isoprenoid. Proc. Natl. Acad. Sci. USA. 86, 8323–8327.

    Article  PubMed  CAS  Google Scholar 

  33. Rowinsky, E. K., Windle, J. J., and Von Hoff, D. D. (1999) Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J. Clin. Oncol. 17, 3631–3652.

    PubMed  CAS  Google Scholar 

  34. Sebti, S. M. and Hamilton, A. D. (2000) Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies. Oncogene 19, 6584–6593.

    Article  PubMed  CAS  Google Scholar 

  35. Brown, M. S., Goldstein, J.L., Paris, K. J., Burnier, J.P., and Jarsters, J.C, Jr. (1992) Tetrapeptide inhibitors of protein farnesyltransferase: amino-terminal substitution in phenylalanine-containing tetrapeptides restores farnesylation. Proc. Natl. Acad. Sci USA 89, 8313–8316.

    Article  PubMed  CAS  Google Scholar 

  36. Kohl, N.E., Mosser, S.D., deSolms, S. J., et al. (1993) Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 260, 1934–1937.

    Article  PubMed  CAS  Google Scholar 

  37. Patel, D.V., Schmidt, R.J., Biller, S.A., Gordon, E.M., Robinson, S.S., and Manne, V. (1995) Farnesyl diphosphate-based inhibitors of Ras farnesyl protein transferase. Med. Chem. 21, 2906–2921.

    Article  Google Scholar 

  38. Manne, V., Yan, N., Carboni, J. M., et al. (1995) Bisubstrate inhibitors of farnesyltransferase: a novel class of specific inhibitors of ras transformed cells. Oncogene 10, 1763–1779.

    PubMed  CAS  Google Scholar 

  39. Bishop, W. R., Bond, R., Petrin, J., et al. (1995) Novel tricyclic inhibitors of farnesyl protein transferase. J. Biol. Chem. 270, 30611–30618.

    Article  PubMed  CAS  Google Scholar 

  40. Pompliano, D. L., Rands, E., Schaber, M. D., Mosser, S.D., Anthony, N.J., and Gibbs, J. B. (1992) Steady-state kinetic mechanism of Ras farnesyl:protein transferase. Biochemistry 31, 3800–3807.

    Article  PubMed  CAS  Google Scholar 

  41. Bordier, B. B., Marion, P.L., Ohashi, K., et al. (2002) A prenylation inhibitor prevents production of HDV particles. J. Virol. 76, 10465–10472.

    Article  PubMed  CAS  Google Scholar 

  42. Kuo, M.Y., Chao, M., and Taylor, J. (1989) Initiation of replication of the human hepatitis delta virus genome from cloned DNA: role of delta antigen. J. Virol. 63, 1945–1950.

    PubMed  CAS  Google Scholar 

  43. Ohashi, K., Marion, P. L., Nakai, H., et al. (2000) Sustained survival of human hepatocytes in mice: a model for in vivo infection with human hepatitis B and hepatitis delta viruses. Nat. Med. 6, 327–331.

    Article  PubMed  CAS  Google Scholar 

  44. Glenn, J.S., Marsters, J. C., Jr., and Greenberg, H. B. (1998) Use of a prenylation inhibitor as a novel antiviral agent. J. Virol. 72, 9303–9306.

    PubMed  CAS  Google Scholar 

  45. Tamanoi, F. (1993) Inhibitors of Ras farnesyltransferases. Trends Biochem. Sci. 18, 349–353.

    Article  PubMed  CAS  Google Scholar 

  46. Marsters, Jr., J.C., McDowell, R. S., Reynolds, M. E., et al. (1994) Benzodiazepine peptidomimetic inhibitors of farnesyltransferase. Bioorg. Med. Chem. 2, 949–957.

    Article  PubMed  CAS  Google Scholar 

  47. Lerner, E.C., Qian, Y., Blaskovich, M.A., et al. (1995) Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J. Biol. Chem. 270, 26802–26806.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Stanford University School of Medicine and Veterans Administration Medical Center, Palo Alto, CA

    Bruno B. Bordier & Jeffrey S. Glenn

Authors
  1. Bruno B. Bordier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey S. Glenn
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Ribapharm Inc., Costa Mesa, CA

    Robert K. Hamatake PhD  & Johnson Y. N. Lau MD  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Humana Press Inc.

About this protocol

Cite this protocol

Bordier, B.B., Glenn, J.S. (2004). Testing Antivirals Against Hepatitis Delta Virus. In: Hamatake, R.K., Lau, J.Y.N. (eds) Hepatitis B and D Protocols. Methods in Molecular Medicine™, vol 96. Humana Press. https://doi.org/10.1385/1-59259-670-3:539

Download citation

  • DOI: https://doi.org/10.1385/1-59259-670-3:539

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-108-0

  • Online ISBN: 978-1-59259-670-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation