Disease relevance of PMEA-DP

• The effects of the presumed active forms of these inhibitors, ddATP and PMEA-diphosphate (PMEApp), upon the FIV reverse transcriptase (RT) were examined with two different template-primer systems [1].
• PMEApp does not inhibit the enzyme isolated from the mutant HSV-1 KOS strain PMEAr which is resistant to PMEA at a concentration of 100 micrograms/ml [2].
• In support of this idea, the inhibitory effect of PMEApp on HIV reverse transcriptase has been demonstrated with both RNA and DNA template-primer systems [3].
• PMEA diphosphate (PMEApp), the active antiviral metabolite of PMEA, is a potent inhibitor of human cytomegalovirus (HCMV) DNA polymerase [4].

High impact information on PMEA-DP

• A crystal structure of EF-CaM-PMEApp reveals that the catalytic site of EF forms better van der Waals contacts and more hydrogen bonds with PMEApp than with its endogenous substrate, ATP, providing an explanation for the approximately 10,000-fold higher affinity EF-CaM has for PMEApp versus ATP [5].
• 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) [6].
• Thus, the inhibition of HSV DNA polymerase by PMEApp appears to involve chain termination after its incorporation into DNA [7].
• Studies with a defined primed DNA template showed that PMEGpp was a potent inhibitor of both human polymerases alpha and delta, two key enzymes involved in cellular DNA replication, whereas PMEApp inhibited these enzymes relatively poorly [8].
• The inhibitory effects of other PME, PMP and HPMP diphosphates on telomerase reverse transcriptase decreased in the order: (R)-PMPGpp>(R)-HPMPGpp>PMEDAPpp>(S)-PMPGpp>(S)-HPMPApp>PMEO-DAPypp>(R)-6-cyprPMPDAPpp>(R)-PMPApp>(R)-PMPDAPpp> or =PMEApp> or =PMECpp>PMETpp>(S)-PMPApp approximately 6-Me2PMEDAPpp [9].

Chemical compound and disease context of PMEA-DP

• (2) Diphosphates of both series inhibit HSV-1 ribonucleotide reductase; the greatest inhibition of CDP reduction to dCDP is exhibited by HPMPApp and PMEApp [10].

Biological context of PMEA-DP

• Similar Km values for PMEApp and dATP in pol epsilon and pol epsilon* catalyzed reactions revealed that proteolysis of the enzyme probably does not affect the dNTP binding site [11].
• Of the compounds studied, the most efficient inhibitors of CDP reduction (at 5.1 mumols.l-1) by the HSV-1-encoded enzyme are HPMPApp (IC50 = 0.9 mumols.l-1) and PMEApp (IC50 = 8 mumol.l-1) [2].

Anatomical context of PMEA-DP

• PMEA is efficiently taken up and phosphorylated to PMEApp in numerous human cell lines [4].

References