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，并经常死于播散性真菌病的蹂躏。治疗唑类耐药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，使其成为抗念珠菌属培养细胞测定中的新型命中物的理想来源，隐球菌属和其他真菌病原体。该提案扩大了一个成功的计划，发现，结构阐明和生物学特性的抗真菌线索从海洋无脊椎动物，重点是基于机制的屏幕，功能测定和作用机制。从过去的研究成果已经发展到新的目标，特别是方法发现的抗真菌剂的新兴病原体，如隐球菌gatti，C。neoformans和C. gatti，重点是克服黑化生长阶段的耐药性。这项拟议研究的技术方法的特点包括完善强大的工具，结构阐明在亚微摩尔规模的基础上集成的微型冷冻探针NMR，质谱，圆二色性和有机合成，和一个新的深化学多样性的“自下而上”（DCD-BU）的方法发现新的化学实体。预期的结果包括确定重要的非唑类抗真菌药物开发的领导，特别是对病原体隐球菌gatti和C。grubbi，有可能对艾滋病毒/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.