Antiviral activity and intracellular metabolism of bis(tButyISATE) phosphotriester of β-L-2′,3′dideoxyadenosine, a potent inhibitor of HIV and HBV replication

Academic Article


  • The β-L-nucleoside analogue β-L-2′,3′-dideoxy adenosine (β-L-ddA) has been shown to exhibit limited antiviral activities. This was attributed to its rapid catabolism through cleavage of the glycosidic bond and poor phosphorylation to the nucleotide β-L-2′,3′-dideoxyadenosine-5′-mono phosphate (β-L-ddAMP) (Placidi et al., 2000). However, the nucleotide β-L-2′,3′-dideoxyadenosine-5′-triphosphate (β-L-ddATP) inhibited the activity of both HIV-1 reverse transcriptase (RT) and viral DNA polymerase isolated from woodchuck hepatitis virus-infected serum (a model of hepatitis B) with an inhibitory concentration (IC50) of 2.0 μM without inhibiting human DNA polymerases α, β, or γ up to a concentration of 100 μM. These results suggested that prodrugs of β-L-ddAMP may bypass the poor metabolic activation of β-L-ddA and lead to more potent and selective antiviral activity. Therefore, the mononucleoside phosphotriester derivative of β-L-ddAMP incorporating the S-pivaloyl-2-thioethyl (tButyISATE) groups, β-L-ddAMP-bis(tButyISATE) was synthesized. β-L-ddAMP-bis(tButyISATE) inhibited HIV replication in human peripheral blood mononuclear cells (PBMCs) and HBV replication in 2.2.15 cells with effective concentrations (EC50s) of 2 and 80 nM, respectively. Intracellular metabolism of β-L-ddAMP-bis(tButyISATE) demonstrated that β-L-ddATP was the predominant intracellular metabolite in PBMC and liver cells. The intracellular half-life of β-L-ddATP was 5.4 and 9.2 h in HepG2 and PBMCs, respectively. The intracellular concentrations of β-L-ddATP were maintained above the EC50 for the inhibition of HIV RT and hepatitis B virus (HBV) for as long as 24 h after removal of the drug.
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    Author List

  • Placidi L; Faraj A; Loi AG; Pierra C; Egron D; Cretton-Scott E; Gosselin G; Périgaud C; Martin LT; Schinazi RF
  • Start Page

  • 99
  • End Page

  • 108
  • Volume

  • 12
  • Issue

  • 2