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J. Biol. Chem., Vol. 282, Issue 34, 25159-25167, August 24, 2007

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Enzymatic Therapeutic Index of Acyclovir

VIRAL VERSUS HUMAN POLYMERASE SPECIFICITY^*

Jeremiah W. Hanes, Yali Zhu¹, Deborah S. Parris, and Kenneth A. Johnson²

From the Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, The University of Texas, Austin, Texas 78712 and the Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, Ohio 43210

We have examined the kinetics of incorporation of acyclovir triphosphate by the herpes simplex virus-1 DNA polymerase holoenzyme (Pol-UL42) and the human mitochondrial DNA polymerase using transient kinetic methods. For each enzyme, we compared the kinetic parameters for acyclovir to those governing incorporation of dGTP. The favorable ground state dissociation constant (6 µM) and rate of polymerization (10 s^-1) afford efficient incorporation of acyclovir triphosphate by the Pol-UL42 enzyme. A discrimination factor of 50 favors dGTP over acyclovir triphosphate, mostly due to a faster maximum rate of dGTP incorporation. Once incorporated, acyclovir is removed with a half-life of 1 h in the presence of a normal concentration of deoxynucleoside triphosphates, leading to a high toxicity index (16,000) toward viral replication. To assess the potential for toxicity toward the host we examined the incorporation and removal of acyclovir triphosphate by the human mitochondrial DNA polymerase. These results suggest moderate inhibition of mitochondrial DNA replication defining a toxicity index of 380. This value is much higher than the value of 1.5 determined for tenofovir, another acyclic nucleoside analog. The enzymatic therapeutic index is only 42 in favoring inhibition of the viral polymerase over polymerase , whereas that for tenofovir is greater than 1,200. Mitochondrial toxicity is relatively low because acyclovir is activated only in infected cells by the promiscuous viral thymidine kinase and otherwise, mitochondrial toxicity would accumulate during long term treatment.

Received for publication, May 14, 2007 , and in revised form, June 14, 2007.

^* This work was supported in part by National Institutes of Health Grants GM044613 (to K. A. J.), GM034930 and GM073832 (to D. S. P.) and Welch Foundation Grant F-1604 (to K. A. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Institutes of Health NCI Training Grant Grant CA 09338.

² To whom correspondence should be addressed. Tel.: 512-471-0434; Fax: 512-471-0435; E-mail: kajohnson{at}mail.utexas.edu.

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