THERAPIES FOR AIDS-RELATED OPPORTUNISTIC INFECTIONS

该小组工作的总体目标是确定有前景的药物 治疗卡氏肺孢子虫肺炎和肺炎的候选药物 艾滋病患者的播散性真菌感染。我们计划实现以下目标 本文通过考察S的作用机制和结构来达到这一目的 已被证明有效的新先导化合物的活性关系 对抗目标Ol病原体。这些原型化合物具有 显示出令人满意的生物活动，但实际上没有SAR和/或 行动机制信息可用于指导未来的发展 努力。因此，我们建议对黄连的作用机制(S)进行研究。 新型杀菌剂的筛选与构效关系的追求 三类抗肺孢子虫药物的研究 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(S) 杀菌天然产品。 。研究体外试验在寻找新药物方面的应用 对潜在的新目标采取行动。 。研究伯喹结合蛋白在MOA和 8-氨基喹啉类等抗肺孢子虫药物的临床应用 。探讨8-氨基喹啉类药物作为抗肺孢子虫药物的SAR。 。探索两种原型杀菌抗生素的SAR。 因此，该小组将把行动的分子基础知识与 合成努力，以制备改进的类似物。此外，作为一项 选定的抗真菌药物的MOA调查结果， 很可能会识别出新的分子靶标。作为以下内容的一部分 在这一努力中，我们还建议开发快速、可靠和方便的 用于检测新型选择性抗真菌活性的体外试验 论具体的作用机制(S)。项目圆满完成 应提供； 。作为治疗新疗法的特定候选药物的开发 艾滋病相关肺炎和播散性霉菌病 。确定潜在的新目标 。未来寻找新的选择性疗法的新方法。

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.