Effects of various nucleosides on antiviral activity and metabolism of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil against herpes simplex virus types 1 and 2.
Uptake of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) into herpes simplex virus type 1 (HSV-1)- and 2 (HSV-2)-infected cells was elevated about 190 to 40 times, compared with that into mock-infected human embryo lung fibroblast cells. Uptake was not enhanced by infection with thymidine kinase-negative HSV-1 and HSV-2 mutants, however. In HSV-1-infected cells, 9.7% of BV-araU was phosphorylated to BV-araU triphosphate, but only 1.1% was phosphorylated in HSV-2-infected cells. The antiviral effect, uptake, and turnover of BV-araU were inhibited significantly by thymidine (dThd), moderately by deoxyuridine, and not at all by deoxycytidine. On the other hand, the antiviral activity of acyclovir (ACV) was inhibited only by dThd. The effect of BV-araU was influenced by dThd and dThd phosphates (mono-, di-, and triphosphates), and the effect of ACV was influenced only by dThd, which competitively inhibited the phosphorylation of ACV to ACV monophosphate. The combination of 5-fluorodeoxyuridine (FUdR)-BV-araU or FUdR-ACV had a synergistic effect on HSV-1 and HSV-2 replication. The effect of FUdR on the turnover of BV-araU in HSV-1- and HSV-2-infected cells was analyzed by high-performance liquid chromatography. In HSV-1-infected cells, 86% of the BV-araU was phosphorylated to BV-araU triphosphate, but no effect was observed in HSV-2-infected cells, in which 98% of the BV-araU remained as BV-araU monophosphate.
Suzutani
T
T
Department of Microbiology, Asahikawa Medical College, Japan.
Machida
H
H
Sakuma
T
T
Azuma
M
M
D000998:Antiviral Agents / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D009705:Nucleosides / Q000494:pharmacology*; D010766:Phosphorylation; D018139:Simplexvirus / Q000187:drug effects* / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives*
D000998:Antiviral Agents; D009705:Nucleosides; D001086:Arabinofuranosyluracil; C031368:sorivudine; D014529:Uridine