Antiviral activity of inhibitors of pyrimidine de-novo biosynthesis

M. Wachsman, F. M. Hamzeh, N. B. Assadi, P. S. Lietman

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)7-13
Number of pages7
JournalAntiviral Chemistry and Chemotherapy
Volume7
Issue number1
DOIs
StatePublished - Jan 1996

Keywords

  • Acivicin
  • Antiviral
  • Azaserine
  • Brequinar
  • Cytomegalovirus
  • Deoxynucleotide metabolism

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Virology

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