Equine herpes virus 1 and pseudorabies virus resistance to 2'-fluoropyrimidine analogs and to bromovinyldeoxyuridine: implications for dTMP kinase activity.
The 2'-fluoropyrimidine nucleoside analogs 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC). 1(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU), and 1(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) showed higher in vitro activity against herpes simplex virus type 1 (HSV-1), than equine herpesvirus 1 (EHV-1) or pseudorabies virus (PRV). Comparison of the 50% plaque inhibitory doses for HSV-1 and its mutant MMdUr-20 in cell cultures with inhibition constants (Ki's) for the viral deoxythymidine kinases (dTKs) suggests that in the infected cell FMAU is phosphorylated by host enzymes. As compared to HSV-1, EHV-1 and PRV were more resistant to E-5-(2-bromovinyl-2'-deoxyuridine (BVdU) and to the 2'-fluoropyrimidine analogs, as are HSV-2 and the HSV-1 mutants MMdUr-20 and S1. Because the dTKs of the latter lack deoxythymidylate kinase (dTMPK) activity, there appears to be a correlation between resistance to these analogs and BVdU on the one hand, and lack of dTMPK activity on the other. We predict that EHV-1 and PRV dTKs will be shown to lack significant dTMPK activity.
Veerisetty
V
V
Department of Periodontics, University of Mississippi School of Dentistry, Jackson 39216-4505.
Balasubramaniam
N K
NK
Gentry
G A
GA
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D003561:Cytarabine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D006564:Herpesviridae / Q000187:drug effects* / Q000201:enzymology; D011558:Herpesvirus 1, Suid / Q000187:drug effects* / Q000201:enzymology; D006736:Horses; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism*; D011557:Pseudorabies / Q000188:drug therapy; D011741:Pyrimidine Nucleosides / Q000494:pharmacology*; D013379:Substrate Specificity
D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides; D003561:Cytarabine; C020235:brivudine; D001086:Arabinofuranosyluracil; C026023:fiacitabine; C043457:fialuridine; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D001973:Bromodeoxyuridine; C034935:clevudine