Metabolism and mode of inhibition of varicella-zoster virus by L-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-bromovinyl-(2-hydroxymethyl)-1,3-(dioxolanyl)uracil (L-BVOddU) selectively inhibited varicella-zoster virus growth in human embryonic lung (HEL) 299 cell culture with an EC(50) of 0.055 microM, whereas no inhibition of CEM and HEL 299 cell growth or mitochondrial DNA synthesis was observed at concentrations up to 200 microM. L-BVOddU was phosphorylated by viral thymidine kinase but not by human cytosolic thymidine kinase, and the antiviral activity of this compound is dependent on the viral thymidine kinase. Unlike other D-configuration bromovinyl deoxyuridine analogs, such as E-5-(2-bromovinyl)-2'-deoxyuridine and 1-beta-arabinofuranosyl-E-5-(2-bromovinyl)uracil, this compound was metabolized only to its monophosphate metabolite. The di- or triphosphate metabolites were not detected. This suggested that the inhibitory mechanism may be unique and different from other anti-herpesvirus nucleoside analogs.
Li
L
L
Department of Pharmacology, Yale University, New Haven, Connecticut, USA.
Dutschman
G E
GE
Gullen
E A
EA
Tsujii
E
E
Grill
S P
SP
Choi
Y
Y
Chu
C K
CK
Cheng
Y C
YC
D000212:Acyclovir / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D009705:Nucleosides / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D011355:Prodrugs / Q000378:metabolism*; D013937:Thymidine Kinase / Q000378:metabolism*; D014498:Uracil / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
C415375:5-bromovinyl-(2-hydroxymethyl)-(1,3-dioxolanyl)uracil; D000998:Antiviral Agents; D009705:Nucleosides; D011355:Prodrugs; D014498:Uracil; D013937:Thymidine Kinase; D000212:Acyclovir