Demonstration of viral thymidine kinase inhibitor and its effect on deoxynucleotide metabolism in cells infected with herpes simplex virus.
The thymidine analog 5'-ethynylthymidine was a potent inhibitor of herpes simplex virus type 1 (strain KOS)-induced thymidine kinase with a Ki value of 0.09 microM. 5'-Ethynylthymidine was less inhibitory against herpes simplex virus type 2 (strain 333)-induced thymidine kinase with a Ki of 0.38 microM and showed no inhibition against human cytosolic thymidine kinase under the conditions tested. The compound was effective against the altered thymidine kinase induced by acyclovir- and bromovinyldeoxyuridine-resistant virus variants. At 100 microM 5'-ethynylthymidine, the cellular pool size of dTTP in herpes simplex virus type 1-infected cells was 5% that of infected cells receiving no drug treatment, while there was no significant effect on the pool sizes of dATP, dGTP, and dCTP. There was a positive correlation between dTTP pools and the intracellular thymidine kinase activity of herpes simplex virus type 1-infected cells. When tested alone, 5'-ethynylthymidine exhibited no antiviral activity, but it antagonized the antiviral efficacy of five compounds which require viral thymidine kinase for their action.
D000998:Antiviral Agents / Q000494:pharmacology; D003854:Deoxyribonucleotides / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology; D013936:Thymidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; D003854:Deoxyribonucleotides; C052263:5'-ethynylthymidine; D013937:Thymidine Kinase; D013936:Thymidine