Acyclovir (Zovirax) is a guanine nucleoside analogue most effective against HSV-1 and HSV-2, but it has some activity against VCV, CMV, and EBV. Valacyclovir (Valtrex) is the l-valine ester prodrug of acyclovir. Acyclovir is converted to its active metabolite via three phosphorylation steps. First, viral thymidine kinase converts acyclovir to acyclovir monophosphate. Next, host cell enzymes convert the monophosphate to the diphos-phate and then to the active compound, acyclovir triphosphate. Because viral thymidine kinase has a much greater affinity for acyclovir triphosphate than does mammalian thymidine kinase, acyclovir triphosphate accumulates only in virus-infected cells.
The active metabolite of acyclovir inhibits her-pesvirus DNA replication in two ways. Acyclovir triphos-phate acts as a competitive inhibitor for the incorporation of deoxyguanosine triphosphate (dGTP) into the viral DNA. In addition, acyclovir that is incorporated into viral DNA acts as a chain terminator because it lacks the 3'-hydroxy group necessary for further chain elongation. Viral DNA polymerase becomes irreversibly bound to an acyclovir-terminated DNA chain and is unavailable for further replicative activity. The effect of acyclovir on host cell DNA synthesis is much smaller than its effect on the viral enzyme. Concentrations of acyclovir significantly beyond the therapeutic range are required to inhibit host cell growth.
In HSV and VZV, the most common mechanism of resistance to acyclovir involves mutations that result in decreased thymidine kinase activity. Therefore, these viral mutants exhibit cross-resistance to other antiviral agents that require thymidine kinase activation, such as famciclovir, ganciclovir, and valacyclovir. Less commonly, thymidine kinase mutations result in altered substrate specificity. A rare mechanism of acyclovir resistance involves decreased affinity of viral DNA poly-merase for the drug.
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