ANTI-PCP AGENTS FOR ALCOHOLIC AIDS PATIENTS

申请人摘要： 卡氏肺孢子虫肺炎是一种机会性感染。 在许多免疫功能低下的人中，最明显的是 获得性免疫缺陷综合征(艾滋病)。五烷双胺目前是一种 治疗艾滋病患者的首选药物。这种药物， 然而，它与毒副作用的高发生率有关 那就是肝炎。因为饮酒是一个主要的风险因素 对于肝硬变，酗酒的艾滋病患者患上肝炎的风险更高 死于肝毒性。因此，迫切需要 在这一人群中治疗PCP的更安全和肝毒性较低的药物 爱滋病患者。目前，黄曲霉毒素的分子作用机制尚不清楚。 扑热息痛对卡氏肺孢子虫的杀灭效果并不牢固 已经成立了。然而，已知该药物与许多 包括病原体中的DNA在内的大分子。作为一种灵活的分子， 五烷双胺可以呈现多种可相互转化的构象。我们 假设这种构象灵活性允许五烷双胺 结合到不同的大分子上并且这可以至少部分地解释， 对于药物的治疗和毒性作用。它可能 因此有可能分离出五烷双胺的治疗作用 从构象-生物活性关系看其毒性作用 学习。为了验证这一假设并实现该项目的目标， 我们计划进行以下研究：a)设计和合成 构象受限类似物，与五烷双胺有关；b) 评价所合成化合物的体外抗PCP活性 卡氏肺孢子虫培养模型；c)体内抗PCP活性评价 最有希望的化合物在动物模型中的毒性 疾病；d)研究拟议的五烷双胺类似物之间的相互作用 通过热变性和分子水平上的DNA 模特儿研究。之所以提出这一部分的研究是因为最近 研究表明，五烷双胺的抗PCP作用可能 这是由于它与致病基因组的相互作用。这些信息 所获得的信息不仅在确定相关性方面具有价值 在药物-DNA相互作用和抗PCP疗效或毒性之间存在， 但也将指导设计可能更有效和 更安全的抗PCP药物。

APPLICANT'S ABSTRACT: Pneumocystis Carinii pneumonia (PCP) is an opportunistic infection seen in many immunocompromised individuals, most notably in patients with acquired immunodeficiency syndrome (AIDS). Pentamidine is currently one of the drugs of choice in treating patients with AIDS. The drug, however, is associated with a high incidence of toxic side effects among which is hepatitis. Since alcohol consumption is a major risk factor for liver cirrhosis, alcoholic AIDS patients are at a greater risk of death from hepatotoxicity. There is, therefore, an urgent need for safer and less hepatotoxic drugs for treatment of PCP in this population of AIDS patients. At present, the molecular mechanism of action of pentamidine against Pneumocystis Carinii has not been firmly established. However, the drug is known to interact with a number of macromolecules including DNA in the pathogen. Being a flexible molecule, pentamidine can assume a number of interconvertible conformations. We hypothesize that this conformational flexibility allows pentamidine 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 the therapeutic actions of pentamidine from its toxic actions via conformation-biological activity relationship studies. To test this hypothesis and achieve the goals of the project, we propose to conduct the following studies: a) design and synthesize conformationally restricted analogues related to pentamidine; b) evaluate the in vitro anti-PCP activity of the synthesized compounds in a P. carinii culture model; c) evaluate the in vivo anti-PCP activity and toxicity of the most promising compounds in an animal model of the disease; d) study the interactions of the proposed pentamidine analogues with DNA at the molecular level via thermal denaturation and molecular modeling studies. This section of the study is proposed because recent studies have indicated that the anti-PCP actions of pentamidine might be due to its interaction with the pathogenic genome. The information gained will be valuable not only in determining whether a correlation between drug- DNA interaction and anti-PCP efficacy or toxicity exist, but will also guide in the design of potentially more effective and safer anti-PCP agents.