DRUG DISCOVERY FOR TREATMENT OF CRYPTOCOCCAL DISEASE

这项NCDDG提案的长期目标是解决 迫切需要新的治疗策略来治疗隐球菌 艾滋病患者中的新生杆菌感染。隐球菌病是最常见的 艾滋病中常见的危及生命的真菌感染。在这些地方感染 患者通常表现为急性脑膜脑炎，通常 表现出相对较轻的神经系统症状。临床部 然而，这种表现掩盖了疾病的严重性。在此之前 两性霉素B治疗艾滋病中的隐球菌性脑膜炎 隐球菌病。然而，对新的治疗方法的需求是 停止治疗后的高复发率凸显了这一点， 对终身维持治疗的要求，以及严重的 药物毒性。 为了应对对新的治疗方式的迫切需要， 隐球菌病，我们已经组建了一个调查小组，他们的专业知识 将针对“药物发现”的创新方法。这个 科学和组织基础设施的协作性 将促进项目特定目标和计划的实现 目标。 NCDDG计划的五个项目的具体目标是：1) 检测白细胞来源的抗真菌多肽在体内的有效性 治疗实验性的隐球菌病。固相合成生产 精选的、高度特征化的多肽将提供足够的材料 对这些分子进行全面评估；2)测试新的策略 使用体外检测系统和AN增强宿主清除机制 隐球菌病的体内模型。这将需要对选定的 细胞因子，以及合成和免疫试剂 其他NCDDG项目；4)开发信息素控制的交配 新生隐球菌作为一种抑制隐球菌机制的反应 生长；5)评估隐球菌病的治疗：6)开发 提供新型抗隐球菌剂的策略。

The long term objective of this NCDDG proposal is to address the critical need for new therapeutic strategies to treat Cryptococcus neoformans infections in AIDS patients. Cryptococcosis is the most common life-threatening fungal infection in AIDS. Infection in these patients is usually manifested as acute meningoencephalitis, often presenting with relatively mils neurologic symptoms. The clinical presentation, however, belies the severity of the disease. Prior to the advent of amphotericin B therapy, cryptococcal meningitis in AIDS cryptococcosis. However, the need for new therapeutic approaches is underscored by the high rate of relapse following cessation of therapy, requirements for lifelong maintenance therapy, and problems of serious drug toxicity. In response to the urgent need for new treatment modalities for cryptococcosis, we have assembled a team of investigators whose expertise will be directed toward innovative approaches of "drug discovery". The collaborative nature of the scientific and organizational infrastructure will facilitate the attainment of project specific aims and program objectives. The specific aims of the five projects of this NCDDG program are: 1)to test the in vivo utility of leukocyte-derived antifungal peptides for treating experimental cryptococcosis. Solid phase synthetic production of selected, highly characterized peptides will provide adequate material for full evaluation of these molecules; 2) to test new strategies for enhancing host clearance mechanisms using in vitro assays systems and an in vivo model of cryptococcosis. This will entail evaluation of selected cytokines, as well as synthetic and immunologic reagents generated by other NCDDG projects; 4) to exploit the pheromone-controlled mating response of C. neoformans as a mechanism for arresting cryptococcal growth; 5) to evaluate the therapeutic of cryptococcosis: 6) to develop strategies for delivering new anticryptococcal agents.