Inhibition of varicella-zoster virus-induced DNA polymerase by a new guanosine analog, 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine triphosphate.
The triphosphates of the antiherpesvirus acyclic guanosine analogs 9-[4-hydroxy-2(hydroxymethyl)butyl] guanine (2HM-HBG), 9-(2-hydroxyethoxymethyl)guanine (acyclovir [ACV]), and 9-(3,4-dihydroxybutyl)guanine (buciclovir) were examined for their effects on partially purified varicella-zoster virus (VZV) DNA polymerase as well as cellular DNA polymerase alpha. The triphosphate of 2HM-HBG competitively inhibited the incorporation of dGMP into DNA catalyzed by the VZV DNA polymerase. 2HM-HBG-triphosphate (2HM-HBG-TP) had a higher affinity for the dGTP-binding site on the VZV DNA polymerase than did dGTP; apparent Km and Ki values of dGTP and 2HM-HBG-TP were 0.64 and 0.034 microM, respectively. ACV-triphosphate (ACV-TP) was found to be the most potent inhibitor of VZV DNA polymerase. ACV-TP had a 14 and 464 times better direct inhibitory effect than 2HM-HBG-TP and buciclovir-triphosphate, respectively. The cellular (human embryonic lung fibroblast) DNA polymerase alpha inhibition was related to viral polymerase inhibition as efficacy ratios: 2HM-HBG-TP had a ratio of more than 1,000, which appeared to be similar to that of ACV-TP.
Abele
G
G
Department of Virology, National Bacteriological Laboratory, Stockholm, Sweden.
Eriksson
B
B
Harmenberg
J
J
Wahren
B
B
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002845:Chromatography; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005347:Fibroblasts; D006160:Guanosine Triphosphate / Q000378:metabolism; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D019384:Nucleic Acid Synthesis Inhibitors; D014709:Vero Cells
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; C057611:bucyclovir triphosphate; C057610:9-(4-hydroxy-2-(hydroxymethyl)butyl)-guanine triphosphate; C025114:acyclovir triphosphate; D006160:Guanosine Triphosphate; D004257:DNA Polymerase II; D004259:DNA-Directed DNA Polymerase; D000212:Acyclovir