ANTI-PCP AGENTS FOR ALCOHOLIC AIDS PATIENTS

申请人摘要： 卡氏肺孢子虫肺炎（PCP）是一种机会性感染， 在许多免疫功能低下的个体中，最明显的是在患有 获得性免疫缺陷综合症（艾滋病）。喷他脒目前是一种 治疗艾滋病的药物选择。药物， 然而，与高发生率的毒副作用， 也就是肝炎由于饮酒是一个主要的风险因素 对于肝硬化，酒精性艾滋病患者有更大的风险， 死于肝毒性。因此，迫切需要 在该人群中使用更安全、肝毒性更低的药物治疗PCP 艾滋病患者。目前，分子机制的作用， 喷他脒对卡氏肺孢子虫的作用还不稳定， 确立了习然而，已知该药物与许多 包括DNA在内的大分子。作为一种灵活的分子， 喷他脒可以呈现许多可相互转化的构象。我们 假设这种构象柔性允许喷他脒 与不同的大分子结合，这可能至少部分地解释了， 药物的治疗作用和毒性作用。可能 因此可以将喷他脒的治疗作用 通过构象-生物活性关系从其毒性作用 问题研究为了验证这一假设并实现项目的目标， 我们建议进行以下研究：a）设计和合成 与喷他脒相关的构象受限的类似物; B） 评价合成的化合物的体外抗PCP活性， a卡氏肺孢子虫培养模型; c）评价体内抗PCP活性 和毒性的最有前途的化合物在动物模型的 疾病; d）研究拟议的喷他脒类似物的相互作用 在分子水平上通过热变性和分子 建模研究。之所以提出这一部分研究，是因为最近 研究表明，喷他脒的抗PCP作用可能 是由于它与致病基因组的相互作用。的信息 获得的信息不仅在确定相关性是否 药物- DNA相互作用与抗PCP的疗效或毒性之间存在着联系， 而且还将指导设计可能更有效的， 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.