Document 0011
 DOCN  M9550011
 TI    Inhibition of human immunodeficiency virus type 1 reverse transcriptase
       by the 5'-triphosphate beta enantiomers of cytidine analogs.
 DT    9505
 AU    Faraj A; Agrofoglio LA; Wakefield JK; McPherson S; Morrow CD; Gosselin
       G; Mathe C; Imbach JL; Schinazi RF; Sommadossi JP; Department of
       Pharmacology, University of Alabama at Birmingham; 35294.
 SO    Antimicrob Agents Chemother. 1994 Oct;38(10):2300-5. Unique Identifier :
       AIDSLINE MED/95142567
 AB    (-)-beta-L-2',3'-Dideoxycytidine (L-ddC) and
       (-)-beta-L-2',3'-dideoxy-5-fluorocytidine (L-FddC) have been reported to
       be potent and selective inhibitors of human immunodeficiency virus type
       1 (HIV-1) and type 2 (HIV-2) in vitro. In the present study, the
       5'-triphosphates of L-ddC (L-ddCTP) and L-FddC (L-FddCTP) were
       demonstrated to competitively inhibit HIV-1 reverse transcriptase (RT),
       with inhibition constants (KiS) of 2 and 1.6 microM, respectively, when
       a poly(rI).oligo(dC)10-15 template primer was used; in comparison Ki
       values for beta-D-2',3'-dideoxycytidine 5'-triphosphate (D-ddCTP) and
       beta-D-2',3'-dideoxy-5-fluorocytidine 5'-triphosphate (D-FddCTP) were
       1.1 and 1.4 microM, respectively. Use of the mutant RT at position 184
       (substitution of methionine to valine [M184V]), which is associated with
       resistance to beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) and
       beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), resulted in
       significant increases (50- to 60-fold) in Ki values for L-ddCTP and
       L-FddCTP, whereas the elevation in Ki values for D-ddCTP and D-FddCTP
       was moderate (2-fold). L-ddCTP and L-FddCTP did not inhibit human DNA
       polymerases alpha and beta up to 100 microM. In contrast, D-ddCTP and
       D-FddCTP inhibited human DNA polymerase beta, with Ki values of 0.5 and
       2.5 microM, respectively. By using sequencing analysis, L-ddCTP and
       L-FddCTP exhibited DNA chain-terminating activities toward the parental
       HIV-1 RT, whereas they were not a substrate for the mutant M184V HIV-1
       RT.(ABSTRACT TRUNCATED AT 250 WORDS)
 DE    Antiviral Agents/*PHARMACOLOGY  Base Sequence  Cells, Cultured
       Deoxycytosine Nucleotides/*PHARMACOLOGY  DNA/METABOLISM  DNA Polymerase
       I/ANTAGONISTS & INHIB  DNA, Mitochondrial/ANALYSIS  Molecular Sequence
       Data  Reverse Transcriptase/*ANTAGONISTS & INHIB  Stereoisomers
       Support, Non-U.S. Gov't  Support, U.S. Gov't, Non-P.H.S.  Support, U.S.
       Gov't, P.H.S.  Zalcitabine/*ANALOGS & DERIVATIVES/PHARMACOLOGY  JOURNAL
       ARTICLE

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