Acyclic guanosine analogs inhibit DNA polymerases alpha, delta, and epsilon with very different potencies and have unique mechanisms of action.
Acyclovir triphosphate, ganciclovir triphosphate and penciclovir triphosphate inhibited DNA polymerases alpha, delta, and epsilon. Each triphosphate preferentially inhibited pol delta, although ganciclovir triphosphate was the most impressive of the three; the Ki for inhibition of pol delta was 2 microM (competitive with dGTP), while the Kis for inhibition of pol alpha and epsilon were 80 and 140 microM, respectively. Each of the compounds was polymerized by pol alpha, delta, and epsilon. Incorporation of acyclovir triphosphate resulted in immediate chain termination, whereas incorporation of ganciclovir triphosphate often allowed polymerization of additional dNTPs. Interestingly, chain termination most often occurred after polymerization of just one additional dNTP onto the ganciclovir monophosphate. All three compounds were very weak inhibitors of DNA primase. Acyclovir triphosphate, however, was a unique inhibitor of the pol alpha-catalyzed elongation of primase-synthesized primers. Immediately after DNA primase synthesized a primer, pol alpha frequently incorporated acyclovir triphosphate with consequent chain termination. If, however, pol alpha did not immediately polymerize acyclovir triphosphate onto the primase-synthesized primer, further dNTPs were readily added and acyclovir triphosphate was incorporated much less frequently.
Ilsley
D D
DD
Department of Chemistry and Biochemistry, University of Colorado, Boulder 80309.
Lee
S H
SH
Miller
W H
WH
Kuchta
R D
RD
D000212:Acyclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D004247:DNA / Q000235:genetics; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D004258:DNA Polymerase III; D019915:DNA Primase; D015774:Ganciclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008969:Molecular Sequence Data; D019384:Nucleic Acid Synthesis Inhibitors; D009838:Oligodeoxyribonucleotides / Q000235:genetics; D012316:RNA Nucleotidyltransferases / Q000037:antagonists & inhibitors; D013379:Substrate Specificity
D019384:Nucleic Acid Synthesis Inhibitors; D009838:Oligodeoxyribonucleotides; C092309:ganciclovir triphosphate; C092310:penciclovir triphosphate; D006151:Guanosine; C025114:acyclovir triphosphate; D004247:DNA; D019915:DNA Primase; D012316:RNA Nucleotidyltransferases; D004257:DNA Polymerase II; D004258:DNA Polymerase III; D015774:Ganciclovir; D000212:Acyclovir