ПОДАВЛЕНИЕ РЕПЛИКАЦИИ СУБГЕНОМНОГО РНК РЕПЛИКОНА ВИРУСА ГЕПАТИТА С ИНГИБИТОРОМ NS3 ПРОТЕАЗЫ SCH 503034 В Huh-7 КЛЕТКАХ: СТОХАСТИЧЕСКАЯ МОДЕЛЬ

Вирус гепатита С (ВГС) вызывает опасное заболевание печени, часто сопровождающееся циррозом и гепатоклеточной карциномой. Против ВГС до сих пор нет эффективной терапии. Для предсказания эффективности действия новых потенциальных лекарств, направленных против ВГС, актуально применение математического моделирования. Впервые предложена стохастическая модель репликации субгеномного РНК репликона ВГС в Huh-7 клетках в присутствии ингибитора NS3 протеазы ВГС SCH 503034. Модель описывает экспериментально полученные кинетики подавления вирусной РНК в присутствии разных концентраций SCH 503034 и может применяться для разработки оптимальных стратегий подавления РНК ВГС в Huh-7 клетках.

1. Castro C., Arnold J.J., Cameron C.E. Incorporation fidelity of the viral RNA-dependent RNA polymerase: a kinetic, thermodynamic and structural perspective // Virus. Res. 2005. V. 107. P. 141–149.

2. Dahari H., Ribeiro R.M., Rice C.M., Perelson A.S. Mathematical modeling of subgenomic hepatitis C viral replication in Huh-7 cells // J. Virol. 2007. V. 81. P. 750–760.

3. Egger D., Wölk B., Gosert R. et al. Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex // J. Virol. 2002. V. 76. P. 5974–5984.

4. Gillespie D.T. General method for numerically simulating stochastic time evolution of coupled chemical reactions // J. Comput. Phys. 1976. V. 22. P. 403–434.

5. Kieffer T.L., Sarrazin C., Miller J.S. et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients // Hepatology. 2007. V. 46. P. 631–639.

6. Lin C., Pragai B.M., Grakoui A. et al. Hepatitis C virus NS3 serine proteinase: trans-cleavage requirements and processing kinetics // J. Virol. 1994. V. 68. P. 8147–8157.

7. Lohmann V., Korner F., Koch J. et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line // Science. 1999. V. 285. P. 110–113.

8. Malcolm B.A., Liu R., Lahser F. et al. SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells // Antimicrob. Agents. Chemother. 2006. V. 50. P. 1013–1020.

9. Miller S., Krijnse-Locker J. Modification of intracellular membrane structures for virus replication // Nat. Rev. Microbiol. 2008. V. 6. P. 363–374.

10. Mishchenko E.L., Bezmaternykykh K.D., Likhoshvai V.A. et al. Mathematical model for suppression of subgenomic hepatitis C virus RNA replication in cell culture // J. Bioinform. Comput. Biol. 2007. V. 5. P. 593–609.

11. Moradpdpour D., Gosert R., Egger D. et al. Membrane association of hepatitis C virus nonstructural proteins and identification of the membrane alteration that harbors the viral replication complex // Antiviral. Res. 2003. V. 60. P. 103–109.

12. Moriishi K., Matsuura Y. Host factors involved in the replication of hepatitis C virus // Rev. Med. Virol. 2007. V. 17. P. 343–354.

13. Nakabayashi J. A compartmentalization model of hepatitis C virus replication: An appropriate distribution of HCV RNA for the effective replication // J. Theor. Biol. 2012. V. 300. P. 110–117.

14. Pietschmann T., Lohmann V., Rutter G. et al. Characterization of cell lines carrying self-replicating hepatitis C virus RNAs // J. Virol. 2001. V. 75. P. 1252–1264.

15. Quinkert D., Bartenschlager R., Lohmann V. Quantitative analysis of the hepatitis C virus replication complex // J. Virol. 2005. V. 79. P. 13594–13605.

16. Reiss S., Rebhan I., Backes P. et alal. Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment // Cell Host Microbe. 2011. V. 9. P. 32–45.

17. Robinson M., Tian Y., Delaney W.E. 4th, Greenstein A.E. Preexisting drug-resistance mutations reveal unique barriers to resistance for distinct antivirals // Proc. Natl Acad. Sci. USA. 2011. V. 108. P. 10290–10295.

18. Srivastava R., Peterson M.S., Bentley W.E. Stochastic kinetic analysis of the Escherichia coli stress circuit using σ32-targeted antisense // Biotechnol. Bioengineer. 2001, V. 75. P. 120–129.

19. Stone M., Jia S., Heo W.D. et al. Participation of rab5, an early endosome protein, in hepatitis C virus RNA replication machinery // J. Virol. 2007. V. 81. P. 4551–4563.

20. Tang H., Grisé H. Cellular and molecular biology of HCV infection and hepatitis // Clin. Sci. (Lond.) 2009. V. 117. P. 49–65.

21. Targett-Adams P., Boulant S., McLauchlan J. Visualization of double-stranded RNA in cells supppporting hepatitis C virus RNA replication // J. Virol. 2008. V. 82. P. 2182–2195.

22. Zoulim F., Chevallier M., Maynard M., Trepo C. Clinical consequences of hepatitis C virus infection // Rev. Med. Virol. 2003. V. 13. P. 57–68.