Using cells expressing herpes simplex virus (HSV)
thymidine kinase, we investigated the metabolism of the acyclic antiherpes
guanosine analog
buciclovir, in relation to the effects of the
drug on
viral DNA and
protein synthesis. In these cells the predominant metabolite of
buciclovir was its
triphosphate, as in the HSV-1 infected Vero cells investigated in parallel. Further metabolism of
buciclovir led to incorporation into
RNA and
DNA.
Buciclovir inhibited
DNA synthesis, not
RNA synthesis, and prevented an increase in the size of newly synthesized
DNA. To study the relative effects of BCV on cellular and
viral DNA synthesis, human TK-cells transformed to a TK+ phenotype with HSV-2
DNA, were infected with HSV-1. In these HSV-1 infected cells
buciclovir-triphosphate caused a preferential inhibition of
viral DNA synthesis. Despite incorporation of
buciclovir into
RNA, and the presence of
buciclovir-triphosphate from the time of
infection onwards, no effect was observed on the synthesis of the beta
proteins ICP-6 and ICP-8. Presumably as a consequence of inhibition of
viral DNA synthesis, the synthesis of a beta gamma
protein (gD) and a gamma
protein (gC) were inhibited, and synthesis of the beta
proteins (ICP-6 and ICP-8) was not shut-off. Glycosylation of gC that was still synthesized, was not inhibited. Thus, the
biological effects of
buciclovir can be explained by its inhibition of
DNA synthesis.