Proposed is a collaborative project between two research groups, one led by K.Y. Hostetler and the by J.W. Mellors. It main objective is to develop a useful pro-drug of foscarnet--or a """"""""double pro-drug"""""""" of foscarnet-AZT--for use in AIDS, which is bioavailable orally, effective, and able to overcome resistance to foscarnet and AZT.
The specific aims are to: (1) Synthesize optimal alkyl ether pro-drugs of foscarnet and foscarnet- AZT """"""""double pro-drugs,"""""""" by varying structural parameters of the lead compounds already identified. (2) Determine the in vitro activity and selectivity of these pro-drugs against wild-type HIV and a panel of drug-resistant variants including those encoding resistance to foscarnet, AZT, and both drugs. (3) Assess the in vitro evolution of HIV resistance to pro-drugs of foscarnet and foscarnet-AZT, starting with both wild-type and foscarnet and/or AZT resistant species. (4) Determine toxicity and oral bioavailability of the optimized pro-drugs in mice and their comparative anti-retroviral activity against wild-type HIV and foscarnet and/or AZT resistant HIV strains in a murine SCID/HU model. The overall goal of these aims is to develop an effective combination of regimen of AZT and a pro-drug of foscarnet or, alternatively, a lipid pro- drug of foscarnet-AZT for therapy of AIDS.
