Inhibition of Hepatitis B Virus Replication by Nucleoside Enantiomers of β-2′,3′-Dideoxypurine Analogues

Author:

Alaoui A.M. El1,Faraj A.1,Pierra C.2,Boudou V.2,Johnson R.2,Mathé C.2,Gosselin G.2,Korba B.E.3,Imbach J.-L.2,Schinazi R.F.45,Sommadossi J.-P.1

Affiliation:

1. Department of Pharmacology and Toxicology, The Liver Center, and the Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, AL 35294, USA

2. Laboratoire de Chimie Bioorganique, UMR CNRS 5625, Université de Montpellier II, 34095 Montpellier, France

3. Division of Molecular Virology and Immunology, Georgetown University, Rockville, MD 20852, USA

4. Georgia Research Center for AIDS and HIV Infections, Veterans Affairs Medical Center, Decatur, GA 30033, USA

5. Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, School of Medicine, Atlanta, GA 30322, USA

Abstract

Various purine β-L-2′,3′-dideoxynucleoside analogues with both sugar and base modifications including β-L-ddG, β-L-ddl, β-L-ddA, 2′-azido-β-L-araddA, 2′-amino-β-L-araddA, 2′,5′-anhydro-β-L-araddA, 2′-azido-β-L-ddA, 2′-amino-β-L-ddA, 2′-fluoro-β-L-ddA, 3′-azido-β-L-ddA, 3′-amino-β-L-ddA, 3′-fluoro-β-L-ddA, 2,6-diamino-β-L-2′,3′-dideoxyfuranosylpurine, 6-cyclopropylamino-β-L-ddA, 2′-azido-6-N-triphenylphosphine-β-L-araddA, 2-amino-6-methylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopropylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopentylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2′,3′-didehydro-β-L-ddA and 2′,3′-didehydro-6-N-triphenyl phosphine-β-L-ddA were synthesized and evaluated as potential inhibitors of hepatitis B virus (HBV) replication in HBV DNA-transfected human hepatoblastoma-derived Hep-G2 cells (2.2.15 cells). β-L-ddA, 2′-azido-β-L-ddA, 3′-azido-β-L-ddA, 2″,3′-didehydro-β-L-ddA (β-L-D4A) and a modified base of β-L-D4A, inhibited HBV replication in vitro. β-L-D4A was the more potent and selective antiHBV agent with a 50% effective concentration value of 0.1 μM and a selectivity index of 1800. On the basis of this finding, studies are in progress to synthesize new purine derivatives with the β-L unnatural configuration which hopefully will lead to identifying additional potent and highly selective anti-HBV agents.

Publisher

SAGE Publications

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