Antiviral activity and intracellular metabolism of bis(tButylSATE) phosphotriester of beta-L-2',3'dideoxyadenosine, a potent inhibitor of HIV and HBV replication.
The beta-L-nucleoside analogue beta-L-2',3'-dideoxy adenosine (beta-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 beta-L-2',3'-dideoxyadenosine-5'-mono phosphate (beta-L-ddAMP) (Placidi et al., 2000). However, the nucleotide beta-L-2',3'-dideoxyadenosine-5'-triphosphate (beta-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 microM without inhibiting human DNA polymerases alpha, beta, or gamma up to a concentration of 100 microM. These results suggested that prodrugs of beta-L-ddAMP may bypass the poor metabolic activation of beta-L-ddA and lead to more potent and selective antiviral activity. Therefore, the mononucleoside phosphotriester derivative of beta-L-ddAMP incorporating the S-pivaloyl-2-thioethyl (tButylSATE) groups, beta-L-ddAMP-bis(tButylSATE) was synthesized. Beta-L-ddAMP-bis(tButylSATE) 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 beta-L-ddAMP-bis(tButylSATE) demonstrated that beta-L-ddATP was the predominant intracellular metabolite in PBMC and liver cells. The intracellular half-life of beta-L-ddATP was 5.4 and 9.2 h in HepG2 and PBMCs, respectively. The intracellular concentrations of beta-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.
Placidi
L
L
Department of Pharmacology, University of Alabama at Birmingham, USA.
Faraj
A
A
Loi
A G
AG
Pierra
C
C
Egron
D
D
Cretton-Scott
E
E
Gosseli
G
G
Périgaud
C
C
Martin
L T
LT
Schinazi
R F
RF
Imbach
J L
JL
el Kouni
M H
MH
Bryant
M L
ML
Sommadossi
J P
JP
D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D054306:Dideoxynucleotides; D006678:HIV / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006207:Half-Life; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D019259:Lamivudine / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008392:Marmota / Q000097:blood / Q000821:virology; D019384:Nucleic Acid Synthesis Inhibitors; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D054306:Dideoxynucleotides; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; C445119:beta-L-2',3'dideoxyadenosine, bis(S-pivaloyl-2-thioethyl) phosphotriester; D019259:Lamivudine; D016048:Dideoxyadenosine; D012194:RNA-Directed DNA Polymerase; D004259:DNA-Directed DNA Polymerase