PHOSPHATIDYL-2',3'-DIDEOXY-3'-THIACYTIDINE - SYNTHESIS AND ANTIVIRAL ACTIVITY IN HEPATITIS-B-INFECTED AND HIV-1-INFECTED CELLS

We recently found that phosphatidyl-2',3'-dideoxycytidine (phosphatidy l-ddC) had substantial anti-hepatitis B virus (HBV) activity in vitro compared to 2',3'-dideoxycytidine (ddC) (Hostetler et al. (1994) Antiv iral Res, 24, 59-67). Upon administration of liposomal phosphatidyl-dd C 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 nu cleosides to treat woodchuck hepatitis virus, we wanted to find the mo st 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 act ivity in 2.2.15 cells as demonstrated previously with ddC, we synthesi zed the 1,2-dipalmitoyl-sn-glycerol-3-phosphate conjugates of (+/-)-BC H-189 and 3TC and assessed their anti-HBV and anti-HIV activities, in vitro. Phosphatidyl-3TC and phosphatidyl-BCH-189 had antiviral activit y comparable to the respective free drugs in 2.2.15 cells which chroni cally produce HBV. In HIV-1-infected human peripheral blood mononuclea r 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-3TC to target drug to the liver, it seems reasonable to expect that phosphat idyi-3TC or phosphatidyl-(+/-)-BCH-189 could be employed to provide gr eatly enhanced hepatic antiviral activity in HBV infection in vivo.