Document 0780
 DOCN  M9650780
 TI    Phosphatidyl-2',3'-dideoxy-3'-thiacytidine: synthesis and antiviral
       activity in hepatitis B-and HIV-1-infected cells.
 DT    9605
 AU    Xie H; Voronkov M; Liotta DC; Korba BA; Schinazi RF; Richman DD;
       Hostetler KY; Department of Medicine, University of California, San
       Diego, La; Jolla 92093, USA.
 SO    Antiviral Res. 1995 Oct;28(2):113-20. Unique Identifier : AIDSLINE
       MED/96126404
 AB    We recently found that phosphatidyl-2',3'-dideoxycytidine
       (phosphatidyl-ddC) had substantial anti-hepatitis B virus (HBV) activity
       in vitro compared to 2',3'-dideoxycytidine (ddC) (Hostetler et al.
       (1994) Antiviral Res. 24, 59-67). Upon administration of liposomal
       phosphatidyl-ddC to mice, a 40-fold higher drug area under curve was
       observed in the liver. To evaluate the possibility of using
       liver-targeted anti-HBV nucleosides to treat woodchuck hepatitis virus,
       we wanted to find the most potent and selective lipid conjugates. It has
       been shown that 2',3'-dideoxy-3'-thiacytidine as a racemic mixture of
       the cis-isomer (cis-(+/-)-BCH-189) has much greater activity against HBV
       viruses than ddC in vitro. Recently, it was shown that the
       (-)-beta-L-enantiomer (3TC) is more active and less toxic than the
       (+)-beta-D-form ((+)-BCH-189). To determine whether phospholipid
       conjugates of 3TC retain antiviral activity in 2.2.15 cells as
       demonstrated previously with ddC, we synthesized the
       1,2-dipalmitoyl-sn-glycerol-3-phosphate conjugates of (+/-)-BCH-189 and
       3TC and assessed their anti-HBV and anti-HIV activities, in vitro.
       Phosphatidyl-3TC and phosphatidyl-BCH-189 had antiviral activity
       comparable to the respective free drugs in 2.2.15 cells which
       chronically produce HBV. In HIV-1-infected human peripheral blood
       mononuclear cells and HT4-6C cells, phosphatidyl-3TC and
       phosphatidyl-(+/-)-BCH-189 exhibited significantly lower activity than
       the corresponding free nucleosides. In view of the documented ability of
       phosphatidyl-ddC to target drug to the liver, it seems reasonable to
       expect that phosphatidyl-3TC or phosphatidyl-(+/-)-BCH-189 could be
       employed to provide greatly enhanced hepatic antiviral activity in HBV
       infection in vivo.
 DE    Antiviral Agents/CHEMISTRY/*PHARMACOLOGY  Cell Line  Hepatitis B
       Virus/*DRUG EFFECTS  Human  HIV-1/*DRUG EFFECTS  Molecular Structure
       Prodrugs/PHARMACOLOGY  Reverse Transcriptase
       Inhibitors/CHEMISTRY/*PHARMACOLOGY  Support, U.S. Gov't, Non-P.H.S.
       Support, U.S. Gov't, P.H.S.  Zalcitabine/*ANALOGS &
       DERIVATIVES/CHEMISTRY/PHARMACOLOGY  JOURNAL ARTICLE

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