DNA AS TARGET FOR ANTIPNEUMOCYSTIS CARINII AGENTS

描述：(改编自申请人摘要)。的长期目标是 这一领域的提议是为了阐明抗-HBs的分子靶点。 卡氏肺孢子虫对芳香二胺的活性，并用此 开发新的化疗药物的知识。短期目标 的建议是确定芳香族化合物的活性 二胺是通过序列选择性结合到小沟槽上而介导的 关于DNA的。扑热息痛是治疗的首选药物之一。 卡氏肺孢子虫肺炎(PCP)，其发病率在60%-80%之间 美国艾滋病患者的几何异构体已被合成为 半刚性同系物戊二胺的作用机理研究 药物的作用。体外DNA结合研究和足迹研究 研究表明，顺式异构体与dna的亲和力比 反式异构体和结合亲和力是否与 体外抗P.隆突活动。然而，这些化合物是 在五氯苯酚体内模型中具有等效性。基于这些结果，它是 假设：i)DNA是抗P。脊椎动物 芳香二胺的活性；以及ii)几何异构体是 受立体选择性药代动力学过程的影响，导致 更大的体内暴露于反式异构体和等同的疗效 与顺式异构体相比。这些假设将通过以下方式进行验证 合成与DNA具有不同结合亲和力的化合物。这个 体外和体内抗P。Carinii的活动将被确定。 将进行药代动力学研究并对结果进行分析 确定在统计上是否存在显著的相关性 体外DNA结合亲和力、体外抗P.Carinni活动，以及 体内暴露和抗P。芳香二胺的Carinii活性 将DNA确定为他们的分子作用目标。

DESCRIPTION: (Adapted from Applicant's Abstract). The long term goal of this AREA proposal is to elucidate the molecular target for the anti- Pneumocystis carinii activity of aromatic diamidines, and to use this knowledge to develop new chemotherapeutic agents. The short term goal of the proposal is to determine if the activity of the aromatic diamidines is mediated by sequence-selective binding to the minor groove of DNA. Pentamidine is one of the drugs of choice for treating Pneumocystis carinii pneumonia (PCP) which afflicts between 60 - 80% of AIDS patients in the U. S. Geometric isomers have been synthesized as semirigid congeners of pentamidine for investigating the mechanism of action of the drug. In vitro DNA-binding studies and footprinting studies showed that the cis isomer binds with higher affinity to DNA than does the trans isomer and that the binding affinity correlates with the in vitro anti-P. carinii activity. These compounds were, however, equipotent in an in vivo model of PCP. Based on these results it is hypothesized that: i) DNA is the molecular target for the anti-P. carinii activity of aromatic diamidines; and ii) the geometric isomers are subject to stereoselective pharmacokinetic processes resulting in greater in vivo exposure to the trans isomer and equipotent efficacy as compared to the cis isomer. These hypotheses will be tested by synthesizing compounds with varying binding affinities for DNA. The invitro and invivo anti-P. carinii activities will be determined. Pharmacokinetic studies will be carried out and the results analyzed to determine if there is a statistically significant correlation between in vitro DNA binding affinity, in vitro anti-P. carinni activity, and in vivo exposure and anti-P. carinii activity of the aromatic diamidines to establish DNA as their molecular target of action.