Abstract
Pyrogallol reversibly and noncompetitively inhibits the activity of the hepatitis C RNA-dependent RNA polyme rase. Based on molecular modeling of the inhibitor binding in the active site of the enzyme, the inhibition was suggested to be realized via chelation of two magnesium cations involved in the catalysis at the stage of the phosphoryl residue transfer. The proposed model allowed us to purposefully synthesize new derivatives with higher inhibitory capacity.
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Abbreviations
- DKA:
-
2,4-dioxo-4-phenylbutanoic acid
- CN-DKA:
-
4-[2-(3-cyanopropoxy)phenyl]-2,4-dioxobutanoic acid
- Pyr:
-
pyrogallol
- CN-Pyr:
-
cyanoacetylhydrazone 5-formylpyrogallol
- DMSO:
-
dimethylsulfoxide
- HCV:
-
hepatitis C virus
- NTP:
-
nucleoside triphosphate
- RdRp:
-
RNA-dependent RNA polymerase
References
Rosen, H. R., and Gretch, D. R. (1999) Mol. Med. Today, 5, 393–399.
Report of a WHO Consultation Organized in Collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium (1999) J. Viral. Hepat., 6, 35–47.
Seeff, L. B., and Hoofnagle, J. H. (2003) Clin. Liver Dis., 7, 261–287.
Davis, G. L., Esteban-Mur, R., Rustgi, V., Hoefs, J., Gordon, S. C., Trepo, C., Shiffman, M. L., Zeuzem, S., Craxi, A., Ling, M. H., and Albrecht, J. (1998) N. Engl. J. Med., 339, 1493–1499.
Bressanelli, S., Tomei, L., Rey, F. A., and de Francesco, R. (2002) J. Virol., 76, 3482–3492.
De Francesco, R., Tomei, L., Altamura, S., Summa, V., and Migliaccio, G. (2003) Antiviral Res., 58, 1–16.
Gordon, C. P., and Keller, P. A. (2005) J. Med. Chem., 48, 1–20.
Summa, V., Petrocchi, A., Pace, P., Matassa, V. G., de Francesco, R., Altamura, S., Tomei, L., Koch, U., and Neuner, P. (2004) J. Med. Chem., 47, 14–17.
Summa, V., Petrocchi, A., Matassa, V. G., Taliani, M., Laufer, R., de Francesco, R., Altamura, S., and Pace, P. (2004) J. Med. Chem., 47, 5336–5339.
Grobler, J. A., Stillmock, K., Hu, B., Witmer, M., Felock, P., Espeseth, A. S., Wolfe, A., Egberston, M., Bourgeois, M., Melamed, J., Wai, J. S., Young, S., Vacca, J., and Hazuda, D. J. (2004) Proc. Natl. Acad. Sci. USA, 99, 6661–6666.
Maurin, C., Bailly, F., Buisine, E., Vezin, H., Mbemba, G., Mouscadet, J. F., and Cotelle, P. (2004) J. Med. Chem., 47, 5583–5586.
Ivanov, A. V., Kozlov, M. V., Kuzyakin, A. O., Kostyuk, D. A., Tunitskaya, V. L., and Kochetkov, S. N. (2004) Biochemistry (Moscow), 69, 782–788.
Roussel, A., and Cambillau, C. (1991) Silicon Graphics Geometry Partners Directory, Mountain View, CA, USA, Silicon Graphics, p. 81.
Kraulis, P. J. (1991) J. Appl. Crystallogr., 24, 946–950.
Temyakov, D., Patlan, V., Anikin, M., McAllister, W. T., Yokoyama, S., and Vassylyev, D. G. (2004) Cell, 116, 381–391.
Arnold, J. J., and Cameron, C. E. (2004) Biochemistry, 43, 5126–5137.
Castro, C., Arnold, J. J., and Cameron, C. E. (2005) Virus Res., 107, 141–149.
O’Farell, D., Trowbridge, R., Rowlands, D., and Jager, J. (2003) J. Mol. Biol., 326, 1025–1035.
Butcher, S. J., Grimes, J. M., Makeyev, E. V., Bamford, D. H., and Stuart, D. I. (2001) Nature, 410, 235–240.
Palla, G., Predieri, G., Domiano, P., Vignali, C., and Turner, W. (1986) Tetrahedron, 42, 3649–3654.
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Original Russian Text © M. V. Kozlov, K. M. Polyakov, A. V. Ivanov, S. E. Filippova, A. O. Kuzyakin, V. L. Tunitskaya, S. N. Kochetkov, 2006, published in Biokhimiya, 2006, Vol. 71, No. 9, pp. 1253–1259.
Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM06-072, June 11, 2006.
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Kozlov, M.V., Polyakov, K.M., Ivanov, A.V. et al. Hepatitis C virus RNA-dependent RNA polymerase: Study on the inhibition mechanism by pyrogallol derivatives. Biochemistry (Moscow) 71, 1021–1026 (2006). https://doi.org/10.1134/S0006297906090112
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DOI: https://doi.org/10.1134/S0006297906090112