Mechanism of selective inhibition of human cytomegalovirus replication by 1-beta-D-arabinofuranosyl-5-fluorouracil.
Four kinds of 1-beta-D-arabinofuranosyl-5-halogenouracil were examined for inhibition of human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) replication. 1-beta-D-Arabinofuranosyl-5-fluorouracil (ara-FU) was the most effective against HCMV, whereas 1-beta-D-arabinofuranosyl-5-bromouracil was the most effective against HSV-1 and HSV-2. The mechanism of action of ara-FU on HCMV replication was also studied. The dTTP pool size in human embryonic fibroblasts was increased 33-fold by HCMV infection. However, treatment with ara-FU decreased the size of the dTTP pool by approximately 50%. On the other hand, 1-beta-D-arabinofuranosyl-5-fluorouracil-5'-triphosphate inhibited HCMV DNA polymerase activity competitively with dTTP. These results suggest that ara-FU acts as a bifunctional inhibitor of HCMV replication. Ara-FU is phosphorylated by cellular thymidine kinase to 1-beta-D-arabinofuranosyl-5-fluorouracil-5'-monophosphate, which inhibits cellular thymidylate synthetase, which in turn decreases the dTTP pool size in infected cells. As the dTTP pool size is reduced, inhibition of viral DNA polymerase by 1-beta-D-arabinofuranosyl-5-fluorouracil-5'-triphosphate becomes more efficient.
D000998:Antiviral Agents; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D001087:Arabinonucleosides / Q000494:pharmacology*; D001088:Arabinonucleotides / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D007700:Kinetics; D019384:Nucleic Acid Synthesis Inhibitors; D013329:Structure-Activity Relationship; D013942:Thymine Nucleotides / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D001087:Arabinonucleosides; D001088:Arabinonucleotides; D019384:Nucleic Acid Synthesis Inhibitors; D013942:Thymine Nucleotides; C048712:1-arabinofuranosyl-5-fluorouracil; D001086:Arabinofuranosyluracil; D004259:DNA-Directed DNA Polymerase; D005472:Fluorouracil; D014529:Uridine