Acyclovir inhibits viral DNA synthesis by selective interaction with two distinct viral proteins. Cellular uptake and initial phosphorylation are facilitated by thymidine kinase. Cellular enzymes convert the monophosphate to acyclovir triphosphate and compete for endogeneous deoxyguanosine triphos-phate (dGTP). Acyclovir triphosphate competively inhibits viral DNA polymerases and, to a much smaller extent, cellular DNA polymerases. Acyclovir triphosphate is also incorporated into viral DNA, where it acts as a chain terminator because of the lack of 3’-hydroxyl group. By a mechanism termed suicide inactivation, the terminated DNA template containing acyclovir binds the enzym and leads to irreversible inactivation of the DNA polymerase.
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