DRUG DISCOVERY FOR TREATMENT OF CRYPTOCOCCAL DISEASE

本NCDDG的长期目标 建议是解决 迫切需要新的治疗策略来治疗隐球菌 艾滋病患者中的新型病毒感染。 隐球菌病是最 艾滋病中常见的致命真菌感染。 感染在这些 患者通常表现为急性脑膜脑炎， 表现出相对轻微的神经系统症状 临床 然而，这种表现掩盖了疾病的严重性。 之前 艾滋病隐球菌性脑膜炎的新疗法--阿替霉素B治疗 隐球菌病 然而，需要新的治疗方法， 由于停止治疗后复发率高， 终身维持治疗的要求，以及严重的 药物毒性 为了满足对新的治疗方法的迫切需要， 隐球菌病，我们已经组建了一个调查小组， 将致力于“药物发现”的创新方法。 的 科学和组织基础设施的协作性质 将促进项目具体目标和计划的实现 目标. 该NCDDG计划的五个项目的具体目标 （1）至 测试白细胞衍生的抗真菌肽的体内效用， 治疗实验性隐球菌病 固相合成生产 选择的，高度表征的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， 使用体外测定系统增强宿主清除机制， 隐球菌病体内模型。 这将需要对选定的 细胞因子，以及合成和免疫试剂产生的 其他NCDDG项目; 4）开发信息素控制的交配 C的反应。新型隐球菌作为抑制隐球菌的机制 生长; 5）评估隐球菌病的治疗：6）开发 提供新的抗隐球菌剂的策略。

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.