       Document 0154
 DOCN  M9640154
 TI    Antiviral, metabolic, and pharmacokinetic properties of the isomeric
       dideoxynucleoside
       4(S)-(6-amino-9H-purin-9-yl)tetrahydro-2(S)-furanmethanol.
 DT    9604
 AU    Nair V; St. Clair MH; Reardon JE; Krasny HC; Hazen RJ; Paff MT; Boone
       LR; Tisdale M; Najera I; Dornsife RE; et al; Department of Chemistry,
       University of Iowa, Iowa City 52242,; USA.
 SO    Antimicrob Agents Chemother. 1995 Sep;39(9):1993-9. Unique Identifier :
       AIDSLINE MED/96050731
 AB    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)
 DE    Adenosine Deaminase/METABOLISM  Animal  Antibody-Dependent Cell
       Cytotoxicity  Antiviral Agents/METABOLISM/*PHARMACOLOGY/PHARMACOKINETICS
       Cells, Cultured  Dideoxyadenosine/*ANALOGS &
       DERIVATIVES/METABOLISM/PHARMACOLOGY/  PHARMACOKINETICS  Drug Resistance,
       Microbial  DNA Polymerases/ANTAGONISTS & INHIB  DNA, Viral/ANALYSIS
       Erythroid Progenitor Cells/PHYSIOLOGY  Hepatitis B Virus/DRUG EFFECTS
       Human  HIV-1/DRUG EFFECTS  HIV-2/DRUG EFFECTS  Phosphorylation  Plaque
       Assay  Polymerase Chain Reaction  Rats  Support, U.S. Gov't, P.H.S.
       JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

