Anti-herpes simplex virus activity of 5-substituted 2-pyrimidinone nucleosides.
Several 5-substituted 2-pyrimidinone 2'-deoxyribonucleoside (PdR) analogs were examined for their anti-herpes simplex virus (HSV) activity in cell culture. The order of potency of their antiviral activities against HSV type 1 (HSV-1) and HSV-2 was iodo PdR approximately ethynyl PdR approximately propynyl PdR. The antiviral action of iodo PdR is dependent on the ability of HSV to induce virus-specified thymidine kinase in infected cells. Several HSV-1 variants with altered thymidine kinase changed their sensitivity to iodo PdR, whereas HSV-1 variants with altered DNA polymerase were as sensitive as the parental virus to iodo PdR. Continuous presence of iodo PdR for more than one virus replication cycle was required for optimal antiviral activity. Iodo PdR (100 microM) had no activity against Epstein-Barr virus DNA replication in P3HR-1 cells. With an oral, an intraperitoneal, or a subcutaneous route of injection, iodo PdR administered twice a day for 2.5 days could prevent the death of mice infected with HSV-2. This in vivo activity is unlikely to be related to the potential conversion of iodo PdR to iododeoxyuridine, since iodo PdR is not a substrate of xanthine oxidase.
Lewandowski
G A
GA
Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill 26599-7365.
Grill
S P
SP
Fisher
M H
MH
Dutschman
G E
GE
Efange
S M
SM
Bardos
T J
TJ
Cheng
Y C
YC
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis; D002478:Cells, Cultured; D004352:Drug Resistance, Microbial; D005260:Female; D006367:HeLa Cells; D006561:Herpes Simplex / Q000188:drug therapy; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D018139:Simplexvirus / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
D000998:Antiviral Agents; D011744:Pyrimidinones; D006861:Hydrogen Peroxide; D014969:Xanthine Oxidase