MECHANISM OF ACTION OF NOVEL ANTIFUNGAL COMPOUNDS

与艾滋病相关的最常见的真菌感染是隐球菌病和念珠菌病。 毒性、缺乏疗效和对现有药物的耐药性的发展 抗真菌药物决定了新疗法的必要性。的总体目标 本课题主要是：(A)研究黄连(S)的作用机理。 杀菌天然产品的原型和(B)确定和表征 具有设计新疗法潜力的分子靶点，包括 体外测试系统的开发将在 艾滋病相关治疗和预防新疗法的发现 真菌油。为实现这些总体目标，有以下具体目标 将被追查； 1.评价所选先导化合物对一般情况的影响(S) 对敏感的酵母细胞进行生化处理. 2.评价选定的原型抗真菌化合物的相互作用 以已知的抗真菌药物，即甲壳素合成酶为靶标， 葡聚糖合成酶，麦角固醇结合，麦角固醇生物合成，蛋白质 合成，或甘露聚糖结合。 3.用其他方法评价所选原型化合物的效果(S) 潜在的抗真菌靶标。即拓扑异构酶I或II，DNA结合， 多胺合成和细胞通透性。 4.对于似乎不是通过已知机制起作用的化合物，确定 并用分子、热力学、电子能谱等方法表征分子靶标。 和生化特性。 5.研究“逆转”体外检测系统的实用性 检测抑制特定真菌靶点的新型抗真菌药物 (即铁载体生产、多胺合成、分泌物生产 白色念珠菌中的蛋白水解酶、多糖膜形成和黑色素 新生隐球菌的生产)。

The most common AIDS-related fungal Ol are cryptococcosis and candidiasis. The toxicities, lack of efficacy, and development of resistance to existing antifungal agents mandate the need for new therapies. The overall goals of this project are (a) to investigate the mechanism(s) of action of selected prototype fungicidal natural products and (b) to identify and characterize molecular targets with potential for the design of new therapies, including the development of in vitro assay systems that will be useful in the discovery of new therapeutic and prophylactic treatments for AIDS-related fungal Oi. To meet these overall objectives, the following specific aims will be pursued; 1. Evaluate the effects(s) of the selected lead compounds on general biochemical processes i the susceptible yeast cells. 2. Evaluate the interaction of the selected prototype antifungal compounds with the targets of known antifungal agents, i.e., chitin synthetase, glucan synthase, ergosterol binding, ergosterol biosynthesis, protein synthesis, or mannan binding. 3. Evaluate the effect(s) of the selected prototype compounds with other potential antifungal targets. i.e., topoisomerase I or II, DNA binding, polyamine synthesis and cell permeability. 4. For compounds that do not appear to act by a known mechanism, identify and characterize the molecular targets by use of molecular, thermodynamic, and biochemical properties. 5. Investigate the utility of a "reversal" in vitro assay system for the detection of novel antifungal agents that inhibit specific fungal targets (i.e., siderophore production, polyamine synthesis, production of secreted proteinases in C. albicans, polysaccharide capsule formation and melanin production in Cryptococcus neoformans).