Ribonucleotide Reductase: An Important Enzyme in the Replication of Herpes Simplex Virus Type 1 and a Target for Antiviral Chemotherapy

Herpes simplex virus encodes a ribonucleotide reductase that catalyzes the formation of deoxyribonucleotides from ribonucleotides. The enzyme is not essential for either viral DNA synthesis or replication, yet inhibitors of this enzyme suppress viral replication. To clarify the role of the ribonucleotide reductase in virus infection and to evaluate it as an antiviral target, the metabolism of deoxyribonucleotides in infected cells was examined. Our results show that the cellular ribonucleotide reductase is incapable of generating adequate deoxyribonucleoside triphosphate pools to support efficient virus replication. Additionally, we have shown that the virus is unable to efficiently utilize salvaged deoxyribonucleosides from degraded cellular DNA. A selective inhibitor of the viral ribonucleotide reductase, 2-acetylpyridine thiosemicarbazone, decreased deoxyribonucleotide pools in infected cells, thus inhibiting viral DNA synthesis. This compound also inhibited the cellular ribonucleotide reductase to some extent, thereby enhancing its antiviral activity. The antiviral effects of acyclovir were potentiated by 2-acetylpyridine thiosemicarbazone in the wild-type virus but not in the ribonucleotide reductase mutant, ICP6 delta. Collectively, these data strongly suggest that the viral ribonucleotide reductase is an important enzyme in viral replication and a valid target for antiviral chemotherapy.