The mode of action of penciclovir

Abstract

This review describes the studies that have been carried out to date to investigate the mode of action of penciclovir. Penciclovir is phosphorylated much more efficiently than acyclovir in herpesvirus-infected cells yet the host cell kinases phosphorylate both compounds to a small but comparable extent. This highly preferential metabolism in herpesvirus-infected cells is a major factor in its selective antiviral activity. (S)-penciclovir-triphosphate is the major enantiomer produced and it has a much longer half-life than acyclovir-triphosphate in HSV-1, HSV-2, and varicella-zoster virus (VZV)-infected cells after drug removal. (S)-penciclovir-triphosphate was formed at sufficiently high concentrations to be an effective inhibitor of viral DNA polymerases. This work suggests that viral DNA polymerase is the key target and that virus replication is prevented by inhibition of viral DNA synthesis, though it does not preclude other modes of action. The long half-life of penciclovir-triphosphate leads to an efficient and prolonged entrapment of the active product in virus-infected cells. This can account for the markedly better antiviral activity of penciclovir than acyclovir when infected cell cultures were treated for a short time followed by further incubation during which time the antiviral effect of acyclovir was reversed quickly. It is proposed that such assays reflect more closely the dynamic changes in plasma concentrations after oral dosing than do standard assays in which the test compounds are kept at a constant concentration. The clinical implications of these findings concerning mode of action are discussed.