NEW DRUGS FOR OPPORTUNISTIC INFECTIOUS DISEASES

治疗机会性传染病的新药

• 批准号: 6373148
• 负责人: ALICE M. CLARK
• 金额: $ 21.53万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6373148
• 关键词: Aspergillus flavus; Candida; Candida albicans; Cryptococcus neoformans; antifungal agents; aquatic organism; aspergillosis; biological products; biotherapeutic agent; candidiasis; chemical structure function; differential display technique; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; microarray technology; microorganism disease chemotherapy; mycosis; opportunistic infections; photosynthetic bacteria; plant extracts

DESCRIPTION: (Adapted from Applicant's abstract) The overall goal of this project is to discover prototype lead compounds for development of new treatments for the major AIDS- and cancer-related disseminated fungal infections. Our approach is to evaluate previously unexamined and unique sources of natural products for in vitro activity against specific fungal pathogens and for their ability to reverse resistance to existing antifungal drugs, fractionate active extracts to isolate and identify pure active compounds, and determine the physicochemical properties, mechanisms of action, and toxicological profiles of the isolated active compounds. The specific aims of this proposal are: 1) access a diverse and unique repository of extracts of plants, microbes, and invertebrate animals and prepare samples compatible with biological assays; 2) evaluate in vitro antifungal activity of the extracts for activity against Cryptococcus neoformans, Candida albicans, Candida glabrata, Candida kruseii and Aspergillus fumigatus, and for reversal of resistance to clinically available antifungal drugs; 3) isolate, elucidate the structures, and characterize the pharmaceutical properties of the active constituents; 4) characterize the biological properties of the active compounds using functional genomics, known antifungal enzymatic targets, and mammalian toxicological predictors. Successful completion of the proposed work will yield new prototype lead compounds that will serve as templates for development of new classes of antifungal agents, as templates for the development of new drugs to be used in combination with existing antifungal agents to reverse resistance to these agents, and as probes to identify novel mechanisms of action that can be exploited in the future search for other new derivatives.

描述：（改编自申请人的摘要） 项目是发现原型先导化合物，用于开发新的 治疗艾滋病和癌症相关的主要播散性真菌 感染.我们的方法是评估以前未经审查和独特的 抗特定真菌的体外活性天然产物的来源 病原体及其逆转现有抗真菌药物耐药性的能力 药物、中药活性成分提取物的分离和纯活性成分的鉴定 化合物，并确定理化性质，作用机制， 和分离的活性化合物的毒理学特征。具体目标 这一建议是：1）访问一个多样化的和独特的知识库的摘录， 植物、微生物和无脊椎动物，并制备与 生物学测定; 2）评价提取物的体外抗真菌活性， 对新型隐球菌、白色念珠菌、光滑念珠菌， 克氏假丝酵母和烟曲霉，以及逆转对 临床可用的抗真菌药物; 3）分离，阐明结构， 并表征活性成分的药学性质; 4） 使用官能化的方法表征活性化合物的生物学性质， 基因组学、已知的抗真菌酶靶点和哺乳动物毒理学 预测器成功完成拟议的工作将产生新的原型 先导化合物，将作为开发新类别的 抗真菌剂，作为开发新药的模板， 与现有的抗真菌药物联合使用，以逆转对这些药物的耐药性。 代理商，并作为探针，以确定新的作用机制，可以 在未来寻找其他新的衍生物。