Hepatitis C Virus RNA-Dependent RNA Polymerase: Study on the Inhibition Mechanism by Pyrogallol Derivatives

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M. V. Kozlov^*, K. M. Polyakov, A. V. Ivanov, S. E. Filippova, A. O. Kuzyakin, V. L. Tunitskaya, and S. N. Kochetkov

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, ul. Vavilova 32, 119991 Moscow, Russia; fax: (495) 135-1405; E-mail: kozlovmv@hotmail.com

^* To whom correspondence should be addressed.

Received March 22, 2006; Revision received March 29, 2006

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Pyrogallol reversibly and noncompetitively inhibits the activity of the hepatitis C RNA-dependent RNA polymerase. 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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KEY WORDS: hepatitis C virus, RNA-dependent RNA polymerase, pyrogallol derivatives, inhibition mechanism, molecular modeling

DOI: 10.1134/S0006297906090112

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