Inhibition of herpes simplex virus DNA polymerase by diphosphates of acyclic phosphonylmethoxyalkyl nucleotide analogues

Antiviral Res. 1990 May;13(5):209-18. doi: 10.1016/0166-3542(90)90066-g.


The inhibition of HSV-1 DNA polymerase and HeLa DNA polymerases alpha and beta by diphosphoryl derivatives of acyclic phosphonylmethoxyalkyl nucleotide analogues was studied and compared with the inhibition by ACV-TP, araCTP, ddTTP and AZT-TP. In the series of phosphonylmethoxyethyl (PME-) derivatives of heterocyclic bases, the inhibitory effect of their diphosphates on HSV-1 DNA polymerase decreased in the order 2-amino-PMEApp (Ki = 0.03 microM) much greater than PMEGpp greater than PMEApp greater than PMETpp much greater than PMECpp much greater than n8z7PMEApp greater than PMEUpp. The diphosphate derivative of the antiherpes agent (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl) adenine (HPMPA) proved to be a relatively weak inhibitor of HSV-1 DNA polymerase (Ki = 1.4 microM). The inhibitors could be divided into three groups: (a) the diphosphoryl derivatives of acyclic nucleotide analogues (PME-type and HPMPA) and ACV-TP specifically inhibit HSV-1 DNA polymerase and DNA polymerase alpha and do not significantly inhibit DNA polymerase beta; (b) AZT-TP and ddTTP are effective only against DNA polymerase beta, and (c) araCTP inhibits all three enzymes. When dATP was omitted from the reaction mixture, the addition of HPMPApp stimulated DNA synthesis by HSV-1 DNA polymerase indicating that HPMPApp is an alternative substrate for in vitro DNA synthesis catalyzed by this enzyme.

Publication types

  • Comparative Study

MeSH terms

  • Acyclovir / analogs & derivatives
  • Acyclovir / chemical synthesis
  • Acyclovir / pharmacology
  • Adenine / analogs & derivatives
  • Adenine / chemical synthesis
  • Adenine / pharmacology
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology*
  • Arabinofuranosylcytosine Triphosphate / pharmacology
  • DNA Polymerase I / antagonists & inhibitors
  • DNA Polymerase II / antagonists & inhibitors
  • DNA Replication / drug effects
  • Dideoxynucleotides
  • HeLa Cells
  • Humans
  • Kinetics
  • Nucleic Acid Synthesis Inhibitors*
  • Organophosphonates*
  • Organophosphorus Compounds / chemical synthesis
  • Organophosphorus Compounds / pharmacology
  • Simplexvirus / drug effects
  • Simplexvirus / enzymology*
  • Thymine Nucleotides / pharmacology
  • Zidovudine / analogs & derivatives
  • Zidovudine / pharmacology


  • Antiviral Agents
  • Dideoxynucleotides
  • Nucleic Acid Synthesis Inhibitors
  • Organophosphonates
  • Organophosphorus Compounds
  • Thymine Nucleotides
  • Arabinofuranosylcytosine Triphosphate
  • Zidovudine
  • acyclovir triphosphate
  • adefovir
  • zidovudine triphosphate
  • 9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine
  • DNA Polymerase I
  • DNA Polymerase II
  • 2',3'-dideoxythymidine triphosphate
  • Adenine
  • Acyclovir