Natural Products for Treatment of Emergent AIDS-Related Pathogens

描述(由申请人提供)：艾滋病毒/艾滋病患者容易受到一系列有害的机会性感染，并经常死于传播性真菌病的蹂躏。治疗耐唑真菌病原体和中枢神经系统难治性感染的新药非常受欢迎。海洋天然产物表现出非凡的化学多样性，使其成为培养细胞检测中对抗念珠菌、隐球菌属的理想来源。和其他真菌病原体。该提案扩展了一项在海洋无脊椎动物抗真菌线索的发现、结构阐明和生物学特性方面的成功计划，重点是基于机制的筛选、功能分析和作用机制。过去的研究成果已经朝着新的目标发展，特别是发现新出现的病原体的抗真菌药物的方法学，例如隐球菌Gatti、新生隐球菌和C.Gatti，重点是克服黑化生长阶段的耐药性。这项研究的技术方法的特点包括完善了基于微冷探针核磁共振、质谱学、圆二色谱和有机合成的亚微摩尔尺度结构解析的强大工具，以及用于发现新化学实体的新的深层化学多样性‘自下而上’(DCD-BU)方法。预期的结果包括确定用于抗真菌药物开发的重要的非唑类先导化合物，特别是针对病原体隐球菌Gatti和C.gRubbi，这可能对艾滋病毒/艾滋病患者的生活质量产生有益的结果。

DESCRIPTION (provided by applicant): Persons living with HIV/AIDS are vulnerable to a range of pernicious opportunistic infections and frequently succumb to the ravages of disseminated fungal disease. New drugs to treat azole-resistant fungal pathogens and refractory infections in the central nervous system are highly desirable. Marine natural products exhibit an extraordinary chemical diversity making them ideal as sources of novel hits in cultured cell assays against Candida spp., Cryptococcus sp. and other fungal pathogens. The proposal expands a successful program in discovery, structure elucidation and biological characterization of antifungal leads from marine invertebrates with emphasis on mechanism-based screens, functional assays and mechanism of action. Achievements from the past investigations have evolved into directions towards new goals, particularly methodology for discovery of antifungal agents for emergent pathogens, for example, Cryptococcus gatti, C. neoformans, and C. gatti, with emphasis on overcoming drug resistance in the melanized growth phase. Features of the technical approaches of this proposed research include refinement of powerful tools for structure elucidation at sub- micromole scale based on integration of microcryoprobe NMR, mass spectrometry, circular dichroism and organic synthesis, and a new deep-chemical diversity 'bottom-up' (DCD-BU) approach for discovery of new chemical entities. The expected results include identification of important non-azole leads for antifungal drug development, in particular against the pathogens Cryptococcus gatti and C. grubbi, with potential of beneficial outcomes in quality of life for patients living with HIV/AIDS.