An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus

A Corrigendum to this article was published on 20 November 2003

Abstract

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality1,2,3. Current interferon-based therapies4 are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics5,6. The HCV-encoded NS3 protease is essential for viral replication7,8 and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Chemical structure of BILN 2061.
Figure 2: BILN 2061 inhibition of HCV polyprotein processing.
Figure 3: BILN 2061 concentration in human plasma after single-dose oral administration.
Figure 4: Antiviral efficacy of BILN 2061 in HCV-infected patients.

References

  1. 1

    Choo, Q. L. et al. Isolation of a cDNA clone derived from a blood-borne non-A non-B viral hepatitis genome. Science 244, 359–362 (1989)

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2

    Kuo, G. et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244, 362–364 (1989)

    ADS  CAS  PubMed  Article  Google Scholar 

  3. 3

    Di Bisceglie, A. M. Hepatitis C. Lancet 351, 351–355 (1998)

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Chander, G. et al. Treatment of chronic hepatitis C: a systematic review. Hepatology 36, S135 (2002)

    ADS  PubMed  Google Scholar 

  5. 5

    Tan, S.-L., Pause, A., Shi, Y. & Sonenberg, N. Hepatitis C therapeutics: current status and emerging strategies. Nature Rev. Drug Discov. 1, 867–881 (2002)

    CAS  Article  Google Scholar 

  6. 6

    Di Bisceglie, A. M., McHutchison, J. & Rice, C. M. New therapeutic strategies for hepatitis C. Hepatology 35, 224–231 (2002)

    PubMed  Article  Google Scholar 

  7. 7

    Reed, K. E. & Rice, C. M. Overview of hepatitis C virus genome structure, polyprotein processing, and protein properties. Curr. Top. Microbiol. Immunol. 242, 55–84 (2000)

    CAS  PubMed  Google Scholar 

  8. 8

    Kolykhalov, A. A., Mihalik, K., Feinstone, S. M. & Rice, C. M. Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo. J. Virol. 74, 2046–2051 (2000)

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9

    Lohmann, V. et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285, 103–107 (1999)

    Article  Google Scholar 

  10. 10

    Mercer, D. F. et al. Hepatitis C virus replication in mice with chimeric human livers. Nature Med. 7, 927–933 (2001)

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Schechter, I. & Berger, A. Protease subsite nomenclature. Biochem. Biophys. Res. Commun. 27, 157–162 (1967)

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Llinàs-Brunet, M. et al. Peptide-based inhibitors of the hepatitis C virus serine protease. Bioorg. Med. Chem. Lett. 8, 1713–1718 (1998)

    PubMed  Article  Google Scholar 

  13. 13

    Steinkühler, C. et al. Product inhibition of the hepatitis C virus NS3 protease. Biochemistry 37, 8899–8905 (1998)

    PubMed  Article  Google Scholar 

  14. 14

    Llinàs-Brunet, M. et al. Studies on the C-terminal of hexapeptide inhibitors of the hepatitis C virus serine protease. Bioorg. Med. Chem. Lett. 8, 2719–2724 (1998)

    PubMed  Article  Google Scholar 

  15. 15

    Llinàs-Brunet, M. et al. Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease: towards smaller inhibitors. Bioorg. Med. Chem. Lett. 10, 2267–2270 (2000)

    PubMed  Article  Google Scholar 

  16. 16

    Poupart, M.-A. et al. Solid-phase synthesis of peptidomimetic inhibitors for the hepatitis C virus NS3 protease. J. Org. Chem. 66, 4743–4751 (2001)

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Goudreau, N. et al. NMR structural characterization of peptide inhibitors bound to the HCV NS3 protease: design of a new P2 substituent. J. Med. Chem. (submitted)

  18. 18

    Pause, A. et al. An NS3 serine protease inhibitor abrogates replication of subgenomic hepatitis C virus RNA. J. Biol. Chem. 278, 20374–20380 (2003)

    CAS  PubMed  Article  Google Scholar 

  19. 19

    LaPlante, S. R. et al. Solution structure of substrate-based ligands when bound to hepatitis C virus NS3 protease domain. J. Biol. Chem. 274, 18618–18624 (1999)

    CAS  PubMed  Article  Google Scholar 

  20. 20

    LaPlante, S. R. et al. NMR line-broadening and transferred NOESY as a medicinal chemistry tool for studying inhibitors of the hepatitis C virus NS3 protease domain. Bioorg. Med. Chem. Lett. 10, 2271–2274 (2000)

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor tripeptides. US patent 6,323,180 B1 (2001).

  22. 22

    Tsantrizos, Y. et al. Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection. Angew. Chem. Int. Edn Engl. 42, 1356–1360 (2003)

    CAS  Article  Google Scholar 

  23. 23

    Narjes, H., Yong, C. L., Stahle, H. & Steinmann, G. Tolerability and pharmacokinetics of BILN 2061: a novel serine protease HCV inhibitor after oral single doses of 5 mg to 2,400 mg in healthy male subjects. Hepatology 36(4), Abst. 800 (2002)

    Google Scholar 

  24. 24

    Hinrichsen, H. et al. First report on the antiviral efficacy of BILN 2061, a novel oral serine protease inhibitor, in patients with chronic hepatitis C genotype 1. Hepatology 36, 297A, Abst. 866 (2002)

    Google Scholar 

  25. 25

    Benhamou, Y. et al. Safety, tolerability and antiviral effect of BILN 2061, a novel HCV serine protease inhibitor, after oral treatment over 2 days in patients with chronic hepatitis C, genotype 1, with advanced liver fibrosis. Hepatology 36, 304A, Abst. 563 (2002)

    Google Scholar 

  26. 26

    Neumann, A. U. et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282, 103–107 (1998)

    ADS  CAS  PubMed  Article  Google Scholar 

  27. 27

    Neumann, A. U. et al. Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus. J. Infect. Dis. 182, 28–35 (2000)

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Zeuzem, S. et al. Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha 2a. Gastroenterology 120, 1438–1447 (2001)

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Foy, E. et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300, 1145–1148 (2003)

    ADS  CAS  PubMed  Article  Google Scholar 

  30. 30

    Boehringer Ingelheim (Canada) Ltd. Macrocyclic peptides active against the Hepatitis C virus. US patent 6,608,027 B1 (2003).

Download references

Acknowledgements

We wish to thank F. Dô, J. Duan, M. Garneau, N. Lapeyre-Paquette, S. Lefebvre, F. Liard, M. Marquis, R. Maurice, G. McKercher, A. Pause, C. Pellerin, L. Pilote, C. Plouffe and M. Rhéaume from the Biological Sciences Department, and N. Aubry, J. Bordeleau, C. Boucher, Y. Bousquet, C. Brochu, C. Chabot, R. Déziel, J.-S. Duceppe, G. Fazal, J.-M. Ferland, E. Ghiro, J. Gillard, V. Gorys, S. Goulet, C. Grand-Maître, B. Haché, T. Halmos, P. Lavallée, M. Little, E. Malenfant, R. Plante, M. Poirier, S. Valois and D. Wernic from the Chemistry Department. We also thank B. Willems and the Centre de Recherche Clinique André Viallet, Hôpital St-Luc, CHUM. We acknowledge the BILN 2061 development team and members of the departments of Drug Metabolism and Pharmacokinetics, Pharmacology, Pharmaceutics, Analytical Sciences, Process Chemistry, Toxicology, Drug Regulatory Affairs and Medical at Boehringer Ingelheim Pharmaceuticals, Inc., Connecticut, USA; J. Croenlein, G. Nehmiz and the clinical research teams at Boehringer Ingelheim Pharma KG, Biberach, Germany; and Academisch Medisch Centrum, The Netherlands. We thank the volunteers and patients who participated in the clinical trials of BILN 2061. R.E.S. was clinical investigator and received honorarium from Boehringer Ingelheim. All other authors are or were employees of Boehringer Ingelheim.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Daniel Lamarre.

Ethics declarations

Competing interests

The authors have amended their Competing interests statement: it previously read 'The authors declare that they have no competing financial interests.' it should read ‘The authors declare competing financial interests: R.E.S. was the clinical investigator and received an honorarium from Boehringer Ingelheim. All the other authors are or were employees of Boehringer Ingelheim.’ A Corrigendum will soon be published.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lamarre, D., Anderson, P., Bailey, M. et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426, 186–189 (2003). https://doi.org/10.1038/nature02099

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing