THERAPIES FOR AIDS-RELATED OPPORTUNISTIC INFECTIONS

这一小组工作的总体目标是确定有前途的药物 用于治疗卡氏肺孢子虫肺炎的候选物， 艾滋病患者的播散性真菌感染。 我们建议实现 通过研究作用机制和结构来实现这一目标 已经证明有效的新先导化合物的活性关系 针对目标O 1病原体。 这些原型化合物具有 显示出理想的生物活性，但几乎没有SAR和/或 作用机制信息可用于指导未来的发展 努力 因此，我们建议调查的作用机制（S） 筛选新型杀菌剂并研究构效关系 三类抗肺孢子虫药物的研究和/或 抗真菌活性 该小组的研究目标是： . 研究选定原型的作用机制（MOA） 杀菌天然产物。 . 研究体外试验在寻找新型药物方面的效用 对潜在的新目标进行攻击 . 研究伯氨喹结合蛋白在MOA中的作用， 8-氨基喹啉类及其他抗肺孢子虫药物的临床应用。 . 探索8-氨基喹啉类抗肺孢子虫药物的SAR。 . 探索两种原型杀真菌抗生素的SAR。 因此，该小组将把作用的分子基础知识与 合成努力以制备改进的类似物。 此外，作为 对选定抗真菌剂的MOA进行研究的结果， 很可能会发现新的分子靶点。 的一部分 为此，我们还建议开发快速、可靠和方便的 设计用于检测新的选择性抗真菌活性的体外试验， 具体作用机制。 成功完成项目 应提供; . 作为新疗法开发的特定候选药物 艾滋病相关的PCP和播散性真菌病 . 确定潜在的新目标 . 在未来寻找新的选择性治疗的新方法。

The overall goal of this group effort is to identify promising drug candidates for the therapy of Pneumoycstis carinii pneumonia and disseminated fungal infections in AIDS patients. We propose to accomplish this goal by investigating the mechanism(s) of action and structure activity relationships of new lead compounds already shown to be effective against the target Ol pathogens. These prototype compounds have demonstrated desirable biological activitaies, but virtually no SAR and/or mechanism of action information is available to direct future development efforts. Thus, we propose to investigate the mechanism(s) of action of selected novel fungicidal agents and pursue structure-activity relationship studies for three classes of agents with anti-Pneumocystis and/or antifungal activity. The research objectives of the Group are; . Investigate the mechanism(s) of action (MOA) of selected prototype fungicidal natural products. . Investigate the utility of in vitro assays to search for novel agents that act at potential new targets. . Investigate the role of primaquine-binding proteins in the MOA and clinical utility of 8-aminoquinolines and other antiPneumocystis drugs. . Explore the SAR of 8-aminoquinolines as anti-Pneumocystis agents. . Explore the SAR of two prototype fungicidal antibiotics. Thus, the Group will couple knowledge of the molecular basis of action with synthetic efforts to prepare improved analogs. Additionally, as a consequence of the investigation of the MOA of selected antifungal agents, it is likely that new molecular targets will be identified. As part of this effort, we also propose to develop rapid, reliable and convenient in vitro assays designed to detect novel selective antifungal activity based on specific mechanism(s) of action. Successful completion of the project should provide; . specific drug candidates for development as new therapies for treatment of AIDS related PCP and disseminated mycoses . identification of potential new targets . novel means of searching for new selective therapies in the future.