Abstract
Evaluation of the elevation of host cell biosynthesis of deoxynucleoside triphosphates (dNTP's) induced by human cytomegalovirus (HCMV) infection as a target for antiviral therapeutics was carried out. The concentrations of all four intracellular dNTP's rose rapidly following HCMV infection, and were markedly above baseline by 8 h post infection (p.i.). All tour deoxynucleoside triphosphates remained elevated above baseline for at least 72 h p.i. The effects of inhibitors of the de-novo pathway of pyrimidine biosynthesis on HCMV viral replication were quantified by DNA dot blot. All pyrimidine biosynthesis inhibitors examined inhibited the HCMV DNA replication at concentrations that were non-toxic to the cell. These drugs were also more effective against HCMV, which is highly dependent on host de-novo synthesis, than against HSV-1 which encodes enzymes capable of increasing the supply of dNTP's. The antiviral effect of brequinar, an inhibitor of one of the enzymes of the de-novo pathway (dihydro-orotate dehydrogenase), was examined to determine if it coincided with a decrease in dNTP's. HCMV-infected fibroblasts and uninfected control cells were treated with a concentration of brequinar able to inhibit HCMV DNA levels 90%. It was found that brequinar markedly lowered the levels of dTTP found in treated cells compared to untreated cells in both HCMV-infected and uninfected cells.
Original language | English (US) |
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Pages (from-to) | 7-13 |
Number of pages | 7 |
Journal | Antiviral Chemistry and Chemotherapy |
Volume | 7 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1996 |
Externally published | Yes |
Keywords
- Acivicin
- Antiviral
- Azaserine
- Brequinar
- Cytomegalovirus
- Deoxynucleotide metabolism
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Virology