USING LIPID LINKED AZT DRUGS TO IMPROVE HIV THERAPY

Retaining polar lipid head group identity by linking drugs to acyl chains to increase drug targeting would represent a significant accomplishment. The ability to direct material to specific locations reduces the need to saturate all pharmacological compartments to achieve therapeutic levels in one. The Phase I research proposed will determine the feasibility of delivering pharmaceutical agents linked to polar lipids with their specific head groups intact. These studies should provide statistically compelling experimental data supporting the hypothesis that AE6C(3'-Azido- 2',3',dideoxythymidine [AZT] linked to ceramide), readily crosses the blood brain barrier and exhibits superior brain and CNS accumulation, antiviral activity, and lower cellular and marrow toxicity compared to AZT. Enhanced brain and CNS accumulation of AZT is likely to be very important in combating AIDS-related dementia. Utilizing an in vitro approach, we will determine whether AE6C can establish an effective cellular reservoir capable of providing a constant drug supply. In patients, this reservoir would decrease dosage frequency and the amount of drug required for therapy, thereby reducing stress and increasing patient compliance. A second drug utilizing AZT linked to phosphotidylglycerol, AE6PG, exhibits promising structural characteristics, will be synthesized and it's pharmacological and antiviral properties evaluated.