Antiviral, metabolic, and pharmacokinetic properties of the isomeric dideoxynucleoside 4(S)-(6-amino-9H-purin-9-yl)tetrahydro-2(S)-furanmethanol.
4(S)-(6-Amino-9H-purin-9-yl)tetrahydro-2(S)-furanmethanol (IsoddA) is the most antivirally active member of a novel class of optically active isomeric dideoxynucleosides in which the base has been transposed from the natural 1' position to the 2' position and the absolute configuration is (S,S). IsoddA was active against human immunodeficiency virus type 1 (HIV-1) (strain IIIB), HIV-2 (strain ZY), and HIV-1 clinical isolates. Combinations of the compound with zidovudine (3'-azido-3'-deoxythymidine), 2',3'-dideoxyinosine, or 5-fluoro-2'-deoxy-3'-thiacytidine showed synergistic inhibition of HIV. A moderate reduction of activity was observed with clinical isolates resistant to zidovudine. An IsoddA-resistant virus (eightfold-increased 50% inhibitory concentration) was selected in vitro by repeated passage of HIV-1 (HXB2) in the presence of increasing concentrations of IsoddA. The reverse transcriptase-coding region of the mutant virus contained a single base change resulting in a change at codon 184 from Met to Val. IsoddA was also active against hepatitis B virus (HBV) in vitro; however, it lacked substantial selective activity in an in vivo HBV model. IsoddA was inefficiently phosphorylated in CEM cells; however, the half-life of the triphosphate was 9.4 h, and IsoddATP was a potent inhibitor of HIV-1 reverse transcriptase, with a Ki of 16 nM. The cytotoxicity 50% inhibitory concentrations of IsoddA were greater than 100 microM for CEM, MOLT-4, IM9, and the HepG2-derived HBV-infected 2.2.15 (subclone P5A) cell lines but were 12 and 11 microM for human granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Chemistry, University of Iowa, Iowa City 52242, USA.
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Nair
M H
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St Clair
J E
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Reardon
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Krasny
R J
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Hazen
M T
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Paff
L R
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Boone
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Tisdale
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Najera
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Dornsife
D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D000998:Antiviral Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D004279:DNA, Viral / Q000032:analysis; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D015672:Erythroid Precursor Cells / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051381:Rats; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D004279:DNA, Viral; D019384:Nucleic Acid Synthesis Inhibitors; C067988:Ro 24-5098; D016048:Dideoxyadenosine; D000243:Adenosine Deaminase