Natural Products for Treatment of Emergent AIDS-Related Pathogens

描述（由申请人提供）：艾滋病毒/艾滋病感染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疾病的破坏。治疗耐唑真菌病原体和中枢神经系统难治性感染的新药是非常需要的。海洋天然产物表现出非凡的化学多样性，使它们成为培养细胞试验中针对念珠菌、隐球菌和其他真菌病原体的新打击的理想来源。该提案扩展了海洋无脊椎动物抗真菌先导物的发现，结构阐明和生物学特性的成功项目，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演变为新的目标方向，特别是发现紧急病原体抗真菌药物的方法，例如，加蒂隐球菌，新生C.和加蒂C.，重点是克服黑化生长阶段的耐药性。本研究提出的技术方法的特点包括基于微低温探针核磁共振、质谱、圆二色性和有机合成的集成，在亚微摩尔尺度上完善强大的结构解析工具，以及一种新的深层化学多样性“自下而上”（cd - bu）方法，用于发现新的化学实体。预期的结果包括鉴定抗真菌药物开发的重要非唑先导物，特别是针对病原体加蒂隐球菌和格鲁比隐球菌，具有提高艾滋病毒/艾滋病患者生活质量的潜在有益结果。

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.