Acyclic Guanosine Analogs Inhibit DNA Polymerases α, δ, and ε with Very Different Potencies and Have Unique Mechanisms of Action

Diane D. Ilsley, Suk Hee Lee, Wayne H. Miller, Robert D. Kuchta

Research output: Contribution to journalArticle

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Abstract

Acyclovir triphosphate, ganciclovir triphosphate and penciclovir triphosphate inhibited DNA polymerases α, δ, and ε. Each triphosphate preferentially inhibited pol δ, although ganciclovir triphosphate was the most impressive of the three; the Ki for inhibition of pol δ was 2 µM (competitive with dGTP), while the Kis for inhibition of pol a and e were 80 and 140 µM, respectively. Each of the compounds was polymerized by pol α, δ, and ε. 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 α-catalyzed elongation of primase-synthesized primers. Immediately after DNA primase synthesized a primer, pol α frequently incorporated acyclovir triphosphate with consequent chain termination. If, however, pol α did not immediately polymerize acyclovir triphosphate onto the primase-synthesized primer, further dNTPs were readily added and acyclovir triphosphate was incorporated much less frequently.

Original languageEnglish (US)
Pages (from-to)2504-2510
Number of pages7
JournalBiochemistry
Volume34
Issue number8
DOIs
StatePublished - Feb 1995

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ASJC Scopus subject areas

  • Biochemistry

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