NEW AGENTS FOR PNEUMOCYSTIS CARINII PNEUMONIA

治疗卡氏肺囊虫肺炎的新药

• 批准号: 6450665
• 负责人: TIEN L HUANG
• 金额: $ 3.85万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6450665
• 关键词: Pneumocystis carinii; Pneumocystis pneumonia; analog; antiprotozoal agents; chemical structure function; conformation; drug design /synthesis /production; drug screening /evaluation; laboratory mouse; nuclear magnetic resonance spectroscopy; pentamidine

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.

卡氏肺孢子虫肺炎(PCP)是最常见的重症 获得性免疫缺陷患者的机会性感染 综合症(艾滋病)，并成为这些患者死亡的主要原因。 扑热息痛是广泛用于治疗癌症的首选药物之一。 艾滋病相关的聚合酶链式反应尽管发病率高，但副作用严重。 因此，迫切需要更有效、毒性更低的抗PCP 探员们。五烷双胺是一种灵活的分子，可以承担许多 可相互转换的构象。抗PCP的确切机制 五烷双胺的作用尚不清楚。我们假设 五烷双胺的构象灵活性使其能够与不同的 大分子，这可能至少部分解释了，治疗 以及药物的毒性作用。因此，有可能 通过构象-生物活性关系来分离这些作用 学习。为了检验这些假设，我们建议进行以下操作 研究：a)设计和合成新的构象受限的 与五烷双胺有关的类似物；b)测定 合成化合物；c)对化合物进行体外抗PCP评价 在疾病的动物模型中的活性和毒性；e)研究 五胺类化合物与DNA相互作用的研究 分子模拟技术和通过测量热变性 温度。所获得的信息不仅在 确定了戊二胺类似物的作用机理(S)，但 也可能导致开发出更有效和更安全的抗-PCR 探员。