1887

Abstract

Antiviral activity of the new chemically synthesized compound NIOCH-14 (a derivative of tricyclodicarboxylic acid) in comparison with ST-246 (the condensed derivative of pyrroledione) was observed in experiments and using orthopoxviruses including highly pathogenic ones. After oral administration of NIOCH-14 to outbred ICR mice infected intranasally with 100 % lethal dose of ectromelia virus, it was shown that 50 % effective doses of NIOCH-14 and ST-246 did not significantly differ. The ‘therapeutic window’ varied from 1 day before infection to 6 days post-infection (p.i.) to achieve 100–60 % survival rate. The administration of NIOCH-14 and ST-246 to mice resulted in a significant reduction of ectromelia virus titres in organs examined as compared with the control and also reduced pathological changes in the lungs 6 days p.i. Oral administration of NIOCH-14 and ST-246 to ICR mice and marmots challenged with monkeypox virus as compared with the control resulted in a significant reduction of virus production in the lungs and the proportion of infected mice 7 days p.i. as well as the absence of disease in marmots. Significantly lower proportions of infected mice and virus production levels in the lungs as compared with the control were demonstrated in experiments after oral administration of NIOCH-14 and ST-246 to ICR mice and immunodeficient SCID mice challenged with variola virus 3 and 4 days p.i., respectively. The results obtained suggest good prospects for further study of the chemical compound NIOCH-14 to create a new smallpox drug on its basis.

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2016-05-01
2019-12-06
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References

  1. Anderson P. D., Bokor G.. ( 2012;). Bioterrorism: pathogens as weapons. J Pharm Pract 25: 521–529 [CrossRef] [PubMed].
    [Google Scholar]
  2. Bailey T. R., Rippin S. R., Opsitnick E., Burns C. J., Pevear D. C., Collett M. S., Rhodes G., Tohan S., Huggins J. W., other authors. ( 2007;). N-(3,3a,4,4a,5,5a,6,6a-Octahydro-1,3-dioxo-4,6- ethenocycloprop[f]isoindol-2-(1H)-yl)carboxamides: identification of novel orthopoxvirus egress inhibitors. J Med Chem 50: 1442–1444 [CrossRef] [PubMed].
    [Google Scholar]
  3. Baker R. O., Bray M., Huggins J. W.. ( 2003;). Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections. Antiviral Res 57: 13–23 [CrossRef] [PubMed].
    [Google Scholar]
  4. Baxby D., Bennett M., Getty B.. ( 1994;). Human cowpox 1969-93: a review based on 54 cases. Br J Dermatol 131: 598–607 [CrossRef] [PubMed].
    [Google Scholar]
  5. Biagini P., Thèves C., Balaresque P., Géraut A., Cannet C., Keyser C., Nikolaeva D., Gérard P., Duchesne S., other authors. ( 2012;). Variola virus in a 300-year-old Siberian mummy. N Engl J Med 367: 2057–2059 [CrossRef] [PubMed].
    [Google Scholar]
  6. Damaso C. R., Esposito J. J., Condit R. C., Moussatché N.. ( 2000;). An emergent poxvirus from humans and cattle in Rio de Janeiro State: Cantagalo virus may derive from Brazilian smallpox vaccine. Virology 277: 439–449 [CrossRef] [PubMed].
    [Google Scholar]
  7. Favier A. L., Flusin O., Lepreux S., Fleury H., Labrèze C., Georges A., Crance J. M., Boralevi F.. ( 2011;). Necrotic ulcerated lesion in a young boy caused by cowpox virus infection. Case Rep Dermatol 3: 186–194 [CrossRef] [PubMed].
    [Google Scholar]
  8. Grosenbach D. W., Jordan R., Hruby D. E.. ( 2011;). Development of the small-molecule antiviral ST-246 as a smallpox therapeutic. Future Virol 6: 653–671 [CrossRef] [PubMed].
    [Google Scholar]
  9. Henderson D. A., Inglesby T. V., Bartlett J. G., Ascher M. S., Eitzen E., Jahrling P. B., Hauer J., Layton M., McDade J., other authors. ( 1999;). Smallpox as a biological weapon: medical and public health management. JAMA 281: 2127–2137 [CrossRef] [PubMed].
    [Google Scholar]
  10. Herrlich A.. ( 1960;). Die Pocken Stuttgart: Georg Thieme;.
    [Google Scholar]
  11. Huggins J., Goff A., Hensley L., Mucker E., Shamblin J., Wlazlowski C., Johnson W., Chapman J., Larsen T., other authors. ( 2009;). Nonhuman primates are protected from smallpox virus or monkeypox virus challenges by the antiviral drug ST-246. Antimicrob Agents Chemother 53: 2620–2625 [CrossRef] [PubMed].
    [Google Scholar]
  12. Jahrling P. B., Fritz E. A., Hensley L. E.. ( 2005;). Countermeasures to the bioterrorist threat of smallpox. Curr Mol Med 5: 817–826 [CrossRef] [PubMed].
    [Google Scholar]
  13. Jordan R., Bailey T. R., Rippin S. R.. ( 2006;). Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases. US Patent 2006/0235051 A1. Pub. date: 10.19.06.
  14. Jordan R., Bailey T. R., Rippin S. R.. ( 2008;). Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases. US Patent 2008/0103181 A9. Pub. date: 05.01.08.
  15. Jordan R., Chinsangaram J., Bolken T. C., Tyavanagimatt S. R., Tien D., Jones K. F., Frimm A., Corrado M. L., Pickens M., other authors. ( 2010;). Safety and pharmacokinetics of the antiorthopoxvirus compound ST-246 following repeat oral dosing in healthy adult subjects. Antimicrob Agents Chemother 54: 2560–2566 [CrossRef] [PubMed].
    [Google Scholar]
  16. Jordan R., Bailey T. R., Rippin S. R., Dongcheng D.. ( 2012;). Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases. US Patent 2012/0020922 A1, Pub. date: 01.26.12.
  17. Kabanov A. S., Sergeev Al. A., Bulychev L. E., Bormotov N. I., Shishkina L. N., Sergeev Ar. A., Bodnev S. A., Skarnovich M. O., Shevtsov A. R., other authors. ( 2013;). Studying antiviral activity of chemically synthesized compounds concerning orthopoxviruses in vitro experiments. Problemy osobo opasnykh infektsij 2: 54–59 (in Russian).
    [Google Scholar]
  18. Leparc-Goffart I., Poirier B., Garin D., Tissier M.-H., Fuchs F., Crance J.-M.. ( 2005;). Standardization of a neutralizing anti-vaccinia antibodies titration method: an essential step for titration of vaccinia immunoglobulins and smallpox vaccines evaluation. J Clin Virol 32: 47–52 [CrossRef] [PubMed].
    [Google Scholar]
  19. Magee W. C., Hostetler K. Y., Evans D. H.. ( 2005;). Mechanism of inhibition of vaccinia virus DNA polymerase by cidofovir diphosphate. Antimicrob Agents Chemother 49: 3153–3162 [CrossRef] [PubMed].
    [Google Scholar]
  20. Magee W. C., Aldern K. A., Hostetler K. Y., Evans D. H.. ( 2008;). Cidofovir and (S)-9-[3-hydroxy-(2-phosphonomethoxy)propyl]adenine are highly effective inhibitors of vaccinia virus DNA polymerase when incorporated into the template strand. Antimicrob Agents Chemother 52: 586–597 [CrossRef] [PubMed].
    [Google Scholar]
  21. McCollum A. M., Li Y., Wilkins K., Karem K. L., Davidson W. B., Paddock C. D., Reynolds M. G., Damon I. K.. ( 2014;). Poxvirus viability and signatures in historical relics. Emerg Infect Dis 20: 177–184 [CrossRef] [PubMed].
    [Google Scholar]
  22. McIntosh A. A., Smith G. L.. ( 1996;). Vaccinia virus glycoprotein A34R is required for infectivity of extracellular enveloped virus. J Virol 70: 272–281 [PubMed].
    [Google Scholar]
  23. Nalca A., Hatkin J. M., Garza N. L., Nichols D. K., Norris S. W., Hruby D. E., Jordan R.. ( 2008;). Evaluation of orally delivered ST-246 as postexposure prophylactic and antiviral therapeutic in an aerosolized rabbitpox rabbit model. Antiviral Res 79: 121–127 [CrossRef] [PubMed].
    [Google Scholar]
  24. National Research Council of the National Academies ( 2011;). Guidelines for the Care and Use of Laboratory Animals, 8th edn. Washington, DC: The National Academies Press;.
    [Google Scholar]
  25. Parker S., Chen N. G., Foster S., Hartzler H., Hembrador E., Hruby D., Jordan R., Lanier R., Painter G., other authors. ( 2012;). Evaluation of disease and viral biomarkers as triggers for therapeutic intervention in respiratory mousepox - an animal model of smallpox. Antiviral Res 94: 44–53 [CrossRef] [PubMed].
    [Google Scholar]
  26. Quenelle D. C., Kern E. R.. ( 2010;). Treatment of vaccinia and cowpox virus infections in mice with CMX001 and ST-246. Viruses 2: 2681–2695 [CrossRef] [PubMed].
    [Google Scholar]
  27. Quenelle D. C., Buller R. M., Parker S., Keith K. A., Hruby D. E., Jordan R., Kern E. R.. ( 2007;). Efficacy of delayed treatment with ST-246 given orally against systemic orthopoxvirus infections in mice. Antimicrob Agents Chemother 51: 689–695 [CrossRef] [PubMed].
    [Google Scholar]
  28. Reed K. D., Melski J. W., Graham M. B., Regnery R. L., Sotir M. J., Wegner M. V., Kazmierczak J. J., Stratman E. J., Li Y., other authors. ( 2004;). The detection of monkeypox in humans in the Western Hemisphere. N Engl J Med 350: 342–350 [CrossRef] [PubMed].
    [Google Scholar]
  29. Selivanov B. A., Belanov E. F., Bormotov N. I., Balakhnin S. M., Serova O. A., Svyatchenko V. A., Kiselev N. N., Kazachinskaya E. I., Loktev V. B., Tikhonov A.Ya. ( 2011;). Tricyclo[3.2.2.0(2,4)]non-8-en-6,7-dicarbonic acid derivatives efficiently inhibits the replication of different orthopoxvirus species. Dokl Biol Sci 441: 424–428 [CrossRef] [PubMed].
    [Google Scholar]
  30. Sergeev A. A., Kabanov A. S., Bulychev L. E., Sergeev A. A., Pyankov O. V., Bodnev S. A., Galahova D. O., Zamedyanskaya A. S., Titova K. A., other authors. ( 2015a;) The possibility of using the ICR mouse as an animal model to assess anti-monkeypox drug efficacy. Transbound Emerg Dis [CrossRef] [Epub ahead of print].
    [Google Scholar]
  31. Sergeev A. A., Kabanov A. S., Bulychev L. E., Sergeev A. A., Pyankov O. V., Bodnev S. A., Galahova D. O., Zamedyanskaya A. S., Titova K. A., other authors. ( 2015b;) Using the ground squirrel (Marmota bobak) as an animal model to assess monkeypox drug efficacy. Transbound Emerg Dis [CrossRef] [PubMed] [Epub ahead of print].
    [Google Scholar]
  32. Shishkina L. N., Sergeev A. N., Agafonov A. P., Sergeev A. A., Kabanov A. S., Bulychev L. E., Sergeev A. A., Gorbatovskaya D. O., P'yankov O. V., other authors. ( 2015;). A therapeutic and prophylactic drug against variola virus and methods for its preparation and use. RU Patent no. 2543338, Bulletin no. 6 dated 02.27.15 (in Russian).
  33. Smee D. F., Sidwell R. W., Kefauver D., Bray M., Huggins J. W.. ( 2002;). Characterization of wild-type and cidofovir-resistant strains of camelpox, cowpox, monkeypox, and vaccinia viruses. Antimicrob Agents Chemother 46: 1329–1335 [CrossRef] [PubMed].
    [Google Scholar]
  34. Smee D. F., Wandersee M. K., Bailey K. W., Hostetler K. Y., Holy A., Sidwell R. W.. ( 2005;). Characterization and treatment of cidofovir-resistant vaccinia (WR strain) virus infections in cell culture and in mice. Antivir Chem Chemother 16: 203–211 [CrossRef] [PubMed].
    [Google Scholar]
  35. Smith S. K., Self J., Weiss S., Carroll D., Braden Z., Regnery R. L., Davidson W., Jordan R., Hruby D. E., Damon I. K.. ( 2011;). Effective antiviral treatment of systemic orthopoxvirus disease: ST-246 treatment of prairie dogs infected with monkeypox virus. J Virol 85: 9176–9187 [CrossRef] [PubMed].
    [Google Scholar]
  36. Stabenow J., Buller R. M., Schriewer J., West C., Sagartz J. E., Parker S.. ( 2010;). A mouse model of lethal infection for evaluating prophylactics and therapeutics against Monkeypox virus. J Virol 84: 3909–3920 [CrossRef] [PubMed].
    [Google Scholar]
  37. Stern R. J., Thompson J. P., Moyer R. W.. ( 1997;). Attenuation of B5R mutants of rabbitpox virus in vivo is related to impaired growth and not an enhanced host inflammatory response. Virology 233: 118–129 [CrossRef] [PubMed].
    [Google Scholar]
  38. Titova K. A., Sergeev A. A., Zamedyanskaya A. S., Galahova D. O., Kabanov A. S., Morozova A. A., Bulychev L. E., Sergeev A. A., Glotova T. I., other authors. ( 2015;). Using the ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy. J Gen Virol 96: 2832–2843 [CrossRef] [Epub ahead of print].
    [Google Scholar]
  39. Wienecke R., Wolff H., Schaller M., Meyer H., Plewig G.. ( 2000;). Cowpox virus infection in an 11-year-old girl. J Am Acad Dermatol 42: 892–894 [CrossRef] [PubMed].
    [Google Scholar]
  40. Yang G., Pevear D. C., Davies M. H., Collett M. S., Bailey T., Rippen S., Barone L., Burns C., Rhodes G., other authors. ( 2005;). An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus challenge. J Virol 79: 13139–13149 [CrossRef] [PubMed].
    [Google Scholar]
  41. Zaks L.. ( 1976;). Statistical Estimation Moscow: Statistics;.
    [Google Scholar]
  42. Zhang W. H., Wilcock D., Smith G. L.. ( 2000;). Vaccinia virus F12L protein is required for actin tail formation, normal plaque size, and virulence. J Virol 74: 11654–11662 [CrossRef] [PubMed].
    [Google Scholar]
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