Antiviral Activity and Intracellular Metabolism of Bis(tButylSATE) Phosphotriester of β-L-2′,3'Dideoxyadenosine, a Potent Inhibitor of HIV and HBV Replication

• Published in: Antiviral chemistry & chemotherapy Vol. 12; no. 2; pp. 99 - 108
• Main Authors: Placidi, L, Faraj, A, Loi, AG, Pierra, C, Egron, D, Cretton-Scott, E, Gosselin, G, Périgaud, C, Martin, LT, Schinazi, RF, Imbach, JL, el Kouni, MH, Bryant, ML, Sommadossi, JP
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-04-2001; International Medical Press; Sage Publications Ltd
• Subjects: Adenosine; Animals; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral drugs; Antiviral activity; Antiviral agents; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Biological and medical sciences; Chromatography, High Pressure Liquid; Deoxyribonucleic acid; Dideoxyadenosine - analogs & derivatives; Dideoxyadenosine - metabolism; Dideoxyadenosine - pharmacology; Dideoxynucleotides; DNA; DNA-directed DNA polymerase; DNA-Directed DNA Polymerase - metabolism; Half-Life; Hematopoietic Stem Cells - drug effects; Hepatitis; Hepatitis B; Hepatitis B virus - drug effects; Hepatitis B virus - enzymology; Hepatitis B virus - physiology; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; HIV; HIV - drug effects; HIV - enzymology; HIV - physiology; Human immunodeficiency virus; Humans; Inhibitory Concentration 50; Intracellular; Lamivudine - pharmacology; Leukocytes (mononuclear); Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - virology; Marmota - blood; Marmota - virology; Medical sciences; Metabolic activation; Metabolic rate; Metabolism; Metabolites; Nucleic Acid Synthesis Inhibitors; Nucleoside analogs; Peripheral blood mononuclear cells; Pharmacology. Drug treatments; Phosphorylation; Prodrugs; Replication; Reverse Transcriptase Inhibitors - pharmacology; RNA-directed DNA polymerase; RNA-Directed DNA Polymerase - metabolism; Tumor Cells, Cultured; Virus Replication - drug effects; prodrug; HIV; HBV; nucleoside analogue; Phosphorylation; Purine nucleoside; Nucleoside analogue; Metabolite; Toxicity; Orthohepadnavirus; Retroviridae; Metabolism; Lentivirus; In vitro; Biological activity; Virus; Hepadnaviridae; Dideoxynucleoside; Antiviral; Replication; Catabolism; Hepatitis B virus; Human immunodeficiency virus
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632020101200203

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′-monophosphate (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 (tButylSATE) groups, β-L-ddAMP-bis(tButylSATE) was synthesized. β-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 β-L-ddAMP-bis(tButylSATE) 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.