NEW AGENTS FOR PNEUMOCYSTIS CARINII PNEUMONIA

卡氏肺孢子虫肺炎（PCP）是最常见的严重 获得性免疫缺陷患者的机会性感染 综合征（艾滋病）和死亡的主要原因，在这些病人。 喷他脒是广泛用于治疗 艾滋病相关PCR尽管发病率高，但有严重的副作用。 因此，迫切需要更有效和毒性更低的抗PCP 剂.喷他脒是一种灵活的分子，可以呈现出许多 可相互转化的构象抗PCP的精确机理 喷他脒的作用尚不清楚。我们假设 喷他脒的构象灵活性允许它结合不同的 大分子，这可能至少部分地解释了治疗作用。 以及药物的毒性作用。因此，有可能 通过构象-生物活性关系将这些作用分开 study.为了验证这些假设，我们建议进行以下工作： 研究：a）设计和合成新的构象限制的 B）测定与喷他脒相关的类似物的pKa值， c）评价化合物的体外抗PCP活性 在疾病的动物模型中的活性和毒性; e）研究 所提出的喷他脒类似物与DNA的相互作用， 分子模拟技术和通过测量热变性 温度获得的信息不仅在以下方面有价值： 确定喷他脒类似物的作用机制，但 也可能导致开发更有效和更安全的抗PCR 剂

Pneumocystis carinii pneumonia (PCP) is the most common serious opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS) and as a major cause of mortality in these patients. Pentamidine is one of the drugs of choice widely used for the treatment of AIDS-related PCR despite its high incidence of serious side effects. Therefore, the is a critical need for more effective and less toxic anti-PCP agents. Pentamidine is a flexible molecule and can assume a number of interconvertible conformations. The precise mechanism of anti-PCP action of pentamidine is unknown. We hypothesize that the conformational flexibility of pentamidine allows it to bind to different macromolecules and this may account at least in part, for the therapeutic as well as toxic actions of the drug. It may therefore, be possible to separate these actions by a conformation-biological activity relationship study. To test these hypothesis, we propose to conduct the following studies: a) design and synthesize new conformationally restricted analogues related to pentamidine; b) determine the pKa values of the synthesized compounds; c) evaluate the compounds for in vitro anti-PCP activity and toxicity in an animal model of the disease; e) study the interactions of the proposed pentamidine analogues with DNA using molecular modeling techniques and by measuring thermal denaturation temperatures. The information gained will be valuable not only in determining the mechanism(s) of action of the pentamidine analogues, but may also result in the development of a more effective and safer anti-PCR agent.