DNA AS TARGET FOR ANTIPNEUMOCYSTIS CARINII AGENTS

描述：（改编自申请人摘要）。的长期目标 这个区域的建议是阐明抗- 卡氏肺孢子虫活性的芳香族二脒，并使用该芳香族二脒 开发新的化疗药物的知识。短期目标 该提案的目的是确定芳香族化合物的活性是否 联脒通过与小沟的序列选择性结合介导 的DNA。喷他脒是治疗 卡氏肺孢子虫肺炎（PCP），影响60 - 80%的 美国的艾滋病患者。S.几何异构体已被合成为 半刚性同系物的喷他脒研究机制 药物的作用。体外DNA结合研究和足迹法 研究表明，顺式异构体与DNA的结合亲和力高于 反式异构体和结合亲和力与 体外抗卡氏疟原虫活性。然而，这些化合物， 在PCP体内模型中等效。根据这些结果， 假设：i）DNA是抗卡氏肺吸虫的分子靶标 芳族二脒的活性;和ii）几何异构体是 进行立体选择性药代动力学过程， 更大的体内暴露于反式异构体和等效功效， 与顺式异构体相比。这些假设将由以下人员进行检验： 合成对DNA具有不同结合亲和力的化合物。的 将测定体外和体内抗卡氏疟原虫活性。 将进行药代动力学研究，并分析结果， 确定是否存在统计学显著相关性， 体外DNA结合亲和力、体外抗卡氏肺吸虫活性，以及 芳族二脒的体内暴露和抗卡氏肺吸虫活性 将DNA作为它们的分子作用靶点。

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.