Intracellular metabolism and mechanism of anti-retrovirus action of 9-(2-phosphonylmethoxyethyl)adenine, a potent anti-human immunodeficiency virus compound

Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1499-503. doi: 10.1073/pnas.88.4.1499.


9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of retrovirus (i.e., human immunodeficiency virus) replication in vitro and in vivo. Uptake of PMEA by human MT-4 cells and subsequent conversion to the mono- and diphosphorylated metabolites (PMEAp and PMEApp) are dose-dependent and occur proportionally with the initial extracellular PMEA concentrations. Adenylate kinase is unable to phosphorylate PMEA. However, 5-phosphoribosyl-1-pyrophosphate synthetase directly converts PMEA to PMEApp with a Km of 1.47 mM and a Vmax that is 150-fold lower than the Vmax for AMP. ATPase, 5'-phosphodiesterase, and nucleoside diphosphate kinase are able to dephosphorylate PMEApp to PMEAp, albeit to a much lower extent than the dephosphorylation of ATP. PMEApp has a relatively long intracellular half-life (16-18 hr) and has a much higher affinity for the human immunodeficiency virus-specified reverse transcriptase than for the cellular DNA polymerase alpha (Ki/Km: 0.01 and 0.60, respectively). PMEApp is at least as potent an inhibitor of human immunodeficiency virus reverse transcriptase as 2',3'-dideoxyadenosine 5'-triphosphate. Being an alternative substrate to dATP, PMEApp acts as a potent DNA chain terminator, and this may explain its anti-retrovirus activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / metabolism
  • Adenine / pharmacology
  • Animals
  • Antiviral Agents / metabolism*
  • Biotransformation
  • Cattle
  • Cell Line
  • DNA Polymerase II / antagonists & inhibitors*
  • HIV / drug effects*
  • HIV / enzymology
  • Humans
  • Kinetics
  • Organophosphonates*
  • Phosphorylation
  • Reverse Transcriptase Inhibitors*
  • Ribose-Phosphate Pyrophosphokinase / metabolism
  • Thymus Gland / enzymology
  • Tritium


  • Antiviral Agents
  • Organophosphonates
  • Reverse Transcriptase Inhibitors
  • Tritium
  • adefovir
  • Ribose-Phosphate Pyrophosphokinase
  • DNA Polymerase II
  • Adenine