title: Intracellular metabolism and mechanism of anti-retrovirus action of 9-(2-phosphonylmethoxyethyl)adenine, a potent anti-human immunodeficiency virus compound.
abstract: 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.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: Z
authors.initials: Z
authors.lastname: Hao
authors.forename: P
authors.initials: P
authors.lastname: Herdewijn
authors.forename: D G
authors.initials: DG
authors.lastname: Johns
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D001711:Biotransformation; D002417:Cattle; D002460:Cell Line; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors*; D006678:HIV / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D063065:Organophosphonates; D010766:Phosphorylation; D018894:Reverse Transcriptase Inhibitors; D012268:Ribose-Phosphate Pyrophosphokinase / Q000378:metabolism; D013950:Thymus Gland / Q000201:enzymology; D014316:Tritium
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D014316:Tritium; C053001:adefovir; D012268:Ribose-Phosphate Pyrophosphokinase; D004257:DNA Polymerase II; D000225:Adenine