Antiviral activity of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil against thymidine kinase negative strains of varicella-zoster virus.
Mechanism of antiviral activity of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) against the YSR strain of varicella-zoster virus (VZV), which is a mutant derived from the wild YS strain and is completely deficient in viral thymidine kinase (TK), was searched in comparison with antiviral activity of other thymidine analogues, guanosine analogue and thymidylate synthase (TS) inhibitor in human embryo lung fibroblast cells. Thymidine analogues, such as BV-araU,5-iododeoxyuridine (IUDR), 1-beta-D-arabinofuranosylthymine (araT), and guanosine analogue, such as 9-(2-hydroxyethoxymethyl)guanine (ACV), showed higher antiviral activity to the YS strain than to the YSR strain. Though, BV-araU also had the antiviral activity of a microgram level against the YSR strain. In contrast to these results, TS inhibitor, 5-fluorodeoxyuridine (FUDR), had higher antiviral activity to the YSR strain than to the YS strain. Highly synergistic antiviral activities of FUDR to the YS strain and the YSR strain were observed in combination with IUDR, araT, or ACV. However, weakly synergistic or additive inhibition to the YSR strain was shown in combination of BV-araU and FUDR, in spite of highly synergistic effect of this combination to the YS strain. The viral and cellular TS activity was partially inhibited by BV-araU monophosphate, but not by BV-araU. These results indicate that BV-araU is converted into BV-araU monophosphate by cellular TK, and the inhibition of TS activity by BV-araU monophosphate in the YSR strain-infected cells results in the suppression of viral replication.
Kawai
H
H
Department of Microbiology, Asahikawa Medical College, Hokkaido, Japan.
Yoshida
I
I
Suzutani
T
T
D000998:Antiviral Agents / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D013937:Thymidine Kinase / Q000032:analysis* / Q000235:genetics; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; C031368:sorivudine; D013940:Thymidylate Synthase; D013937:Thymidine Kinase