In vitro and in vivo activities of anti-influenza virus compound T-705.
Journal: 2002/August - Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804
PUBMED: 11897578
Abstract:
T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has been found to have potent and selective inhibitory activity against influenza virus. In an in vitro plaque reduction assay, T-705 showed potent inhibitory activity against influenza A, B, and C viruses, with 50% inhibitory concentrations (IC(50)s) of 0.013 to 0.48 microg/ml, while it showed no cytotoxicity at concentrations up to 1,000 microg/ml in Madin-Darby canine kidney cells. The selectivity index for influenza virus was more than 2,000. It was also active against a neuraminidase inhibitor-resistant virus and some amantadine-resistant viruses. T-705 showed weak activity against non-influenza virus RNA viruses, with the IC(50)s being higher for non-influenza virus RNA viruses than for influenza virus, and it had no activity against DNA viruses. Orally administered T-705 at 100 mg/kg of body weight/day (four times a day) for 5 days significantly reduced the mean pulmonary virus yields and the rate of mortality in mice infected with influenza virus A/PR/8/34 (3 x 10(2) PFU). These results suggest that T-705 may be a compound that is useful and highly selective against influenza virus infections and that has a mode of action different from those of commercially available drugs, such as amantadine, rimantadine, and neuraminidase inhibitors.
Relations:
Content
Citations
(117)
References
(30)
Diseases
(1)
Drugs
(1)
Chemicals
(3)
Organisms
(6)
Anatomy
(2)
Similar articles
Articles by the same authors
Discussion board
Antimicrob Agents Chemother 46(4): 977-981

In Vitro and In Vivo Activities of Anti-Influenza Virus Compound T-705

+3 authors
Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Department of Virology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama, Japan2
Corresponding author. Mailing address: Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama, 930-8508, Japan. Phone: 81-76-431-8257. Fax: 81-76-431-8208. E-mail: pj.oc.lacimehc-amayot@ATURUF_EKUSUOY.
Received 2001 Jun 29; Revised 2001 Sep 10; Accepted 2001 Dec 27.

Abstract

T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has been found to have potent and selective inhibitory activity against influenza virus. In an in vitro plaque reduction assay, T-705 showed potent inhibitory activity against influenza A, B, and C viruses, with 50% inhibitory concentrations (IC50s) of 0.013 to 0.48 μg/ml, while it showed no cytotoxicity at concentrations up to 1,000 μg/ml in Madin-Darby canine kidney cells. The selectivity index for influenza virus was more than 2,000. It was also active against a neuraminidase inhibitor-resistant virus and some amantadine-resistant viruses. T-705 showed weak activity against non-influenza virus RNA viruses, with the IC50s being higher for non-influenza virus RNA viruses than for influenza virus, and it had no activity against DNA viruses. Orally administered T-705 at 100 mg/kg of body weight/day (four times a day) for 5 days significantly reduced the mean pulmonary virus yields and the rate of mortality in mice infected with influenza virus A/PR/8/34 (3 × 10 PFU). These results suggest that T-705 may be a compound that is useful and highly selective against influenza virus infections and that has a mode of action different from those of commercially available drugs, such as amantadine, rimantadine, and neuraminidase inhibitors.

Abstract

Influenza is one of the oldest and most common infections causing significant morbidity and mortality. Compared with infections caused by other respiratory viruses like respiratory syncytial virus, rhinoviruses, and enteroviruses, influenza virus infections can cause more severe complications such as pneumonia and ischemic heart disease and can increase the rates of hospitalization and mortality, particularly in young children and elderly people (6, 20). To date, the M2 ion channel inhibitors, amantadine and rimantadine, have been used for treatment of influenza virus infections worldwide. Amantadine and rimantadine have similar levels of activity, but rimantadine is associated with significantly fewer adverse reactions (2). These drugs are known to reduce the severity and duration of illness when they are taken at the time of onset of symptoms. However, their efficacies against influenza A virus are restricted, and the occurrence of resistant influenza A viruses is inevitable (11, 12). Two new neuraminidase inhibitors, zanamivir and oseltamivir (GS 4104; the prodrug of GS 4071), have recently been used for the treatment of influenza virus infections in the United States and some European countries. Their therapeutic efficacies have been demonstrated in clinical studies (9, 19, 26).

The guanosine analogue ribavirin has been reported to be active against various viruses including influenza A and B viruses by inhibiting RNA synthesis (4, 7, 24). In the United States, aerosolized ribavirin can be used only in the treatment of selected hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus but not against influenza virus infections (3, 27).

We have screened for anti-influenza virus compounds and found an orally active anti-influenza agent, T-705. T-705, a pyrazine derivative, showed strong anti-influenza virus activities in some in vitro and in vivo assays. In this study T-705 has been shown to have a broad spectrum of anti-influenza virus activity with no cytotoxicity and strong therapeutic efficacy in a lethal infection model in mice.

Acknowledgments

We thank Yoshinobu Okuno (Osaka Prefectural Institute of Public Health) and Kiyohito Nakamura (Yamagata University) for providing the influenza viruses. We also thank Masahiko Kurokawa, Seiji Kageyama, and a member of the Department of Virology of Toyama Medical and Pharmaceutical University for discussions and encouragement during the course of this work.

Acknowledgments

REFERENCES

REFERENCES

References

  • 1. Crotty, S., D. Maag, J. J. Arnold, W. Zhong, J. Y. N. Lau, Z. Hong, R. Andino, and C. E. Cameron. 2000. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat. Med.6:1375-1379. [[PubMed]
  • 2. Dolin, R., C. R. Richard, M. H. Paul, M. Raina, N. L. Pamela, and W. J. Joan. 1982. A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N. Engl. J. Med.307:580-584. [[PubMed]
  • 3. Eggleston, M. 1987. Clinical review of ribavirin. Infect. Control8:215-218. [[PubMed]
  • 4. Eriksson, B., E. Helgstrand, N. G. Johansson, A. Larsson, A. Misiorny, J. O. Noren, L. Philipson, K. Stenberg, G. Stening, S. Stridh, and B. Öberg. 1977. Inhibition of influenza virus ribonucleic acid polymerase by ribavirin triphosphate. Antimicrob. Agents Chemother.11:946-951.
  • 5. Fiala, M., and GKenny. 1966. Enhancement of rhinovirus plaque formation in human heteroploid cell cultures by magnesium and calcium. J. Bacteriol.92:1710-1715. [Google Scholar]
  • 6. Glezen, WP. 1982. Serious morbidity and mortality associated with influenza epidemics. Epidemiol. Rev.4:25-44. [[PubMed][Google Scholar]
  • 7. Goswami, B. B., E. Borek, O. K. Sharma, J. Fujitaki, and R. A. Smith. 1979. The broad spectrum antiviral agent ribavirin inhibits capping of mRNA. Biochem. Biophys. Res. Commun.89:830-836. [[PubMed]
  • 8. Graham, B. S., M. D. Perkins, P. F. Wright, and D. T. Karzon. 1988. Primary respiratory syncytial virus infection in mice. J. Med. Virol.26:153-162. [[PubMed]
  • 9. Hayden, F. G., A. D. M. E. Osterhaus, J. J. Treanor, D. M. Fleming, F. Y. Aoki, K. G. Nicholson, A. M. Bohnen, H. M. Hirst, O. Keene, and K. Wightman. 1997. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. N. Engl. J. Med. [[PubMed]
  • 10. Hayden, F. G., K. M. Cote, and R. G. Douglas. 1980. Plaque inhibition assay for drug susceptibility testing of influenza viruses. Antimicrob. Agents Chemother.17:865-870.
  • 11. Hayden, F. G., R. B. Robert, R. D. Clover, A. J. Hay, M. G. Oakes, and W. Soo. 1989. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N. Engl. J. Med.321:1696-1702. [[PubMed]
  • 12. Hayden, F. G., S. J. Sperber, R. B. Belshe, R. D. Clover, A. J. Hay, and S. Pyke. 1991. Recovery of drug-resistant influenza A virus during therapeutic use of rimantadine. Antimicrob. Agents Chemother.35:1741-1747.
  • 13. Hui, M. B. V., E. J. Lien, and M. D. Trousdale. 1994. Inhibition of human adenoviruses by 1-(2′-hydroxy-5′-methoxybenzylidene)amino-3-hydroxyguanidine tosylate. Antivir. Res.24:261-273. [[PubMed]
  • 14. Itzstein, M., W. Y. Wu, G. B. Kok, M. S. Pegg, J. C. Dyason, B. Jin, T. V. Phan, M. L. Smythe, H. F. White, S. W. Oliver, P. M. Colman, J. N. Varghese, D. M. Ryan, J. M. Woods, R. C. Bethell, V. J. Hotham, J. M. Cameron, and C. R. Penn. 1993. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature363:418-423. [[PubMed]
  • 15. Kim, C. U., W. Lew, M. A. Williams, H. Wu, L. Zhang, X. Chen, P. A. Escarpe, D. B. Mendel, W. G. Laver, and R. C. Stevens. 1998. Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors. J. Med. Chem.41:2451-2460. [[PubMed]
  • 16. Kurokawa, M., H. Ochiai, K Nagasaka, M. Neki, H. Xu, S. Kadota, S. Sutardjo, T Matsumoto, T Namba, and K. Shiraki. 1993. Antiviral traditional medicines against herpes simplex virus (HSV-1), poliovirus and measles virus in vitro and their therapeutic efficacies for HSV-1 infection in mice. Antivir. Res.22:175-188. [[PubMed]
  • 17. Markland, W., T. J. Mcquaid, J. Jain, and A. D. Kwong. 2000. Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon. Antimicrob. Agents Chemother.44:859-866.
  • 18. Mendel, D. B., C. Y. Tai, P. A. Escarpe, W. Li, R. W. Sidwell, J. H. Huffman, C. Sweet, K. J. Jakeman, J. Merson, S. A. Lacy, W. Lew, M. A. Williams, L. Zhang, M. S. Chen, N. Bischofberger, and C. U. Kim. 1998. Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets against influenza infection. Antimicrob. Agents Chemother.42:640-646.
  • 19. Nicholson, K. G., F. Y. Aoki, A. D. M. E. Osterhaus, S. Trottier, O. Carewicz, C. H. Mercier, A. Rode, N. Kinnersley, and P. Ward. 2000. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet355:1845-1850. [[PubMed]
  • 20. Perrotta, D. M., M. Decker, and W. P. Glezen. 1985. Acute respiratory disease hospitalizations as a measure of impact of epidemic influenza. Am. J. Epidemiol.122:468-476. [[PubMed]
  • 21. Pionto, L. H., L. J. Holsinger, and R. A. Lamp. 1992. Influenza virus M2 protein has ion channel activity. Cell69:517-528. [[PubMed]
  • 22. Scudiero, D. A., R. H. Shoemaker, K. D. Paull, A. Monks, S. Tierney, T. H. Nofziger, M. J.Currens, D. Seniff, and M. R. Boyd. 1988. Evaluation of a tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res.48:4827-4833. [[PubMed]
  • 23. Sidwell, R. W., J. H. Huffman, G. P. Khare, L. B. Allen, J. T. Witkowski, and R. K. Robins. 1972. Broad-spectrum antiviral activity of virazole: 1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science177:705-706. [[PubMed]
  • 24. Streeter, D. G., J. T. Witkowski, G. P. Khare, R. W. Sidwell, R. J. Bauer, R. K. Robins, and L. N. Simon. 1973. 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. USA70:1174-1178.
  • 25. Tai, C. Y., P. A. Escarpe, R. W. Sidwell, M. A. Williams, W. Lew, H. Wu, C. U. Kim, and D. B. Mendel. 1998. Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071. Antimicrob. Agents Chemother.42:3234-3241.
  • 26. Treanor, J. J., F. G. Hayden, P. S. Vrooman, R. Barbarash, R. Bettis, D. Riff, S. Singh, N. Kinnersley, P. Ward, and R. G. Mills. 2000. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA283:1016-1024. [[PubMed]
  • 27. U.SFood and Drug Administration.1986. Ribavirin aerosol approved for severe cases of RSV in infants and young children. FDA Drug Bull.16:7. [[PubMed][Google Scholar]
  • 28. Wang, C., K. Takeuchi, L. H. Pinto, and R. A. Lamb. 1993. Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block. J. Virol.67:5585-5594.
  • 29. Witkowski, J. T., R. K. Robins, R. W. Sidwell, and L. N. Simon. 1972. Design, synthesis, and broad spectrum antiviral activity of 1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J. Med. Chem.15:1150-1154. [[PubMed]
  • 30. Yukawa, T. A., M. Kurokawa, H. Sato, Y. Yoshida, S. Kageyama, T. Hasegawa, T. Namba, M. Imakita, T. Hozumi, and K. Shiraki. 1996. Prophylactic treatment of cytomegalovirus infection with traditional herbs. Antivir. Res.32:63-70. [[PubMed]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.