Metabolism and mode of inhibition of varicella-zoster virus by 1-beta-5-bromovinyl-(2-hydroxymethyl)-(1,3-dioxolanyl)uracil is dependent on viral thymidine kinase

A nonnaturally occurring L-configuration nucleoside analog, L-beta-5-bromov inyl-(2-hydroxymethyl)-1,3-(dioxolanyl)uracil (L-BVOddU) selectively inhibi ted varicella-zoster virus growth in human embryonic lung (HEL) 299 cell cu lture with an EC50 of 0.055 mu M, whereas no inhibition of CEM and HEL 299 cell growth or mitochondrial DNA synthesis was observed at concentrations u p to 200 mu M. L-BVOddU was phosphorylated by viral thymidine kinase but no t by human cytosolic thymidine kinase, and the antiviral activity of this c ompound is dependent on the viral thymidine kinase. Unlike other D-configur ation bromovinyl deoxyuridine analogs, such as E-5-(2-bromovinyl)-2'-deoxyu ridine and 1-beta-arabinofuranosyl-E-5-(2-bromovinyl)uracil, this compound was metabolized only to its monophosphate metabolite. The di- or triphospha te metabolites were not detected. This suggested that the inhibitory mechan ism may be unique and different from other anti-herpesvirus nucleoside anal ogs.