NEW DRUGS FOR OI--NATURAL PRODUCT MODELS

治疗 OI 的新药——天然产品模型

• 批准号: 2457763
• 负责人: ALICE M. CLARK
• 金额: $ 19.07万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2457763
• 关键词: AIDS; Candida albicans; Cryptococcus neoformans; DNA topoisomerases; Mycobacterium intracellulare; alkaloids; antifungal agents; chemical models; chemical structure function; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; laboratory mouse; microorganism disease chemotherapy; nuclear magnetic resonance spectroscopy; opportunistic infections; pharmacokinetics; tissue /cell culture

DESCRIPTION (Adapted from the Investigator's Abstract): Acquired Immunodeficiency Syndrome (AIDS) is characterized by a breakdown in the immune system that manifests itself in the form of serious, life-threatening oppor-tunistic infections (OI). Therapy of AIDS-related OI is inadequate due to a number of factors, among the most important of which is the absence of any truly effective antibiotics. As part of other projects to discover novel prototype antibiotics for AIDS-related OI, two natural products (eupolauridine and liriodenine) were discovered to exhibit promising in vitro activity against the major AIDS-related fungal and bacterial OI pathogens, as well as in vivo efficacy in animal models of disseminated mycoses. The proposed project is aimed at determining the structure-activity-relationships (SAR) of one of these prototype natural products, eupolauridine, which has demonstrated activity against Cryptococcus neoformans, Candida albicans, Aspergillus species, and Mycobacterium intracellulare, as well as selective inhibition of yeast topoisomerase I. Toward this goal it is proposed to: (1) synthesize a series of rationally designed structural analogs of topoisomerase I eupolauridine for antifungal SAR studies; (2) evaluation in vitro activities of compounds against the opportunistic pathogens Cryptococcus neoformans, Candida albicans, and Mycobacterium intracellulare; (3) evaluate the inhibition of yeast and mammalian topisomerase I; (4) assess the selectivity of activity of the most active compounds from Specific Aims 1 and 2 by eval-uating their toxicities to mammalian cell culture (Vero and H9) to resident peritoneal macrophages and by evaluating them for gerotoxicity; (5) select the most promising candidates(s) for further study and to evaluate the efficacy of such candidates in appropriate animal models of disseminated infection; and (6) select and prioritize the most efficacious compound(s) for further derivatization to improve administration and delivery to the site of infection (i.e., bioavailability and pharmacokinetics).

描述（改编自研究者的摘要）：获得 免疫缺陷综合症（艾滋病）的特点是免疫系统崩溃 免疫系统以严重的、危及生命的形式表现出来 机会性感染（OI）。 艾滋病相关成骨不全的治疗不充分 由于多种因素，其中最重要的是缺乏 任何真正有效的抗生素。 作为其他项目的一部分来发现 用于治疗艾滋病相关成骨不全症的新型抗生素原型，两种天然产物 （eupolauridine 和 Liriodenine）被发现在 针对与艾滋病相关的主要真菌和细菌 OI 的体外活性 病原体以及传播性动物模型的体内功效 真菌病。 拟议项目旨在确定 这些原型自然之一的结构-活动-关系（SAR） 产品，Eupolauridine，已被证明具有对抗 新型隐球菌、白色念珠菌、曲霉属和 胞内分枝杆菌，以及酵母的选择性抑制 拓扑异构酶 I。为了实现这一目标，建议：（1）合成 系列合理设计的拓扑异构酶 I 结构类似物 用于抗真菌 SAR 研究的 eupolauridine； (2)体外活性评价 对抗机会性病原体新型隐球菌的化合物， 白色念珠菌和胞内分枝杆菌； (3) 评估 抑制酵母和哺乳动物拓扑异构酶 I； (4) 评估选择性 具体目标 1 和 2 中最活跃的化合物的活性 评估它们对哺乳动物细胞培养物（Vero 和 H9）的毒性，以 驻留腹腔巨噬细胞并评估其老年毒性； (5) 选择最有前途的候选人进行进一步研究和评估 此类候选药物在适当的传播性动物模型中的功效 感染; (6) 选择并优先考虑最有效的化合物 进一步衍生化以改善管理和交付 感染部位（即生物利用度和药代动力学）。