OPTIMIZATION OF PRODRUGS FOR AZT/PFA RESISTANCE IN AIDS

描述（改编自摘要）：建议是一个合作 两个研究小组之间的项目，一个由K.Y. Hostetler和by J.W.梅勒斯其主要目的是开发一种有用的前药， 膦甲酸--或膦甲酸-AZT的“双重前药”--用于艾滋病， 是口服生物可利用的，有效的，并且能够克服对 膦甲酸和AZT 具体目标是： (1)合成膦甲酸和膦甲酸的最佳烷基醚类前药- AZT“双前药”，通过改变铅的结构参数 化合物已被鉴定。 (2)确定这些前药的体外活性和选择性 针对野生型HIV和一组耐药变体，包括 对膦甲酸、AZT以及这两种药物都有耐药性。 (3)评估HIV对前体药物的体外耐药性演变 膦甲酸和膦甲酸-AZT，从野生型和膦甲酸开始 和/或抗AZT的物种。 (4)确定优化前药的毒性和口服生物利用度 及其与野生型抗逆转录病毒活性的比较 小鼠SCID/HU中的HIV和膦甲酸和/或AZT抗性HIV株 模型 这些目标的总体目标是制定一个有效的组合， AZT和膦甲酸的前体药物或脂质前体药物的方案， 一种治疗艾滋病的药物膦甲酸-AZT。

DESCRIPTION (adapted from the Abstract): 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.