Inhibition of herpes simplex virus DNA polymerase by purine ribonucleoside monophosphates.
Purine ribonucleoside monophosphates were found to inhibit chain elongation catalyzed by herpes simplex virus (HSV) DNA polymerase when DNA template-primer concentrations were rate-limiting. Inhibition was fully competitive with DNA template-primer during chain elongation; however, DNA polymerase-associated exonuclease activity was inhibited noncompetitively with respect to DNA. Combinations of 5'-GMP and phosphonoformate were kinetically mutually exclusive in dual inhibitor studies. Pyrimidine nucleoside monophosphates and deoxynucleoside monophosphates were less inhibitory than purine riboside monophosphates. The monophosphates of 9-beta-D-arabinofuranosyladenine, Virazole (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), 9-(2-hydroxyethoxymethyl)guanine, and 9-(1,3-dihydroxy-2-propoxymethyl)guanine exerted little or no inhibition. In contrast to HSV DNA polymerase, human DNA polymerase alpha was not inhibited by purine ribonucleoside monophosphates. These studies suggest the possibility of a physiological role of purine ribonucleoside monophosphates as regulators of herpesvirus DNA synthesis and a new approach to developing selective anti-herpesvirus compounds.
D000998:Antiviral Agents / Q000494:pharmacology; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000494:pharmacology; D017245:Foscarnet; D006157:Guanosine Monophosphate / Q000494:pharmacology; D007700:Kinetics; D019384:Nucleic Acid Synthesis Inhibitors; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology*; D018139:Simplexvirus / Q000201:enzymology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000998:Antiviral Agents; D003854:Deoxyribonucleotides; D019384:Nucleic Acid Synthesis Inhibitors; D012265:Ribonucleotides; D014764:Viral Proteins; D017245:Foscarnet; D006157:Guanosine Monophosphate; D004259:DNA-Directed DNA Polymerase; D010746:Phosphonoacetic Acid