Natural Products for Treatment of Emergent AIDS-Related Pathogens

用于治疗新出现的艾滋病相关病原体的天然产物

• 批准号: 8442243
• 负责人: Tadeusz F Molinski
• 金额: $ 36.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442243
• 关键词: AIDS/HIV problem; Achievement; Acquired Immunodeficiency Syndrome; Antifungal Agents; Azole resistance; Biological; Biological Assay; Biological Factors; Candida; Chemicals; Circular Dichroism; Complex; Cryptococcus; Cultured Cells; Cyanobacterium; Disease; Drug resistance; Evaluation; Exhibits; Fluconazole resistance; Goals; Growth; Immunocompromised Host; In Vitro; Infection; Investigation; Lead; Life; Marine Invertebrates; Marines; Mass Spectrum Analysis; Methodology; Modeling; Mus; Mycoses; Neuraxis; Opportunistic Infections; Organic Synthesis; Outcome; Patients; Persons; Pharmaceutical Preparations; Phase; Porifera; Predisposition; Preparation; Quality of life; Refractory; Research; Resistance profile; Source; Structure; Structure-Activity Relationship; analog; base; cellular targeting; drug development; in vivo; marine natural product; microbial; novel; pathogen; pre-clinical; programs; research clinical testing; screening; tool

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.

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病的破坏。非常需要治疗唑类抗药性真菌病原体和中枢神经系统难治性感染的新药。海洋天然产物表现出非凡的化学多样性，使其成为针对念珠菌属、隐球菌属的培养细胞检测中的新靶点的理想来源。和其他真菌病原体。该提案扩展了海洋无脊椎动物抗真菌先导物的发现、结构阐明和生物学表征方面的成功计划，重点是基于机制的筛选、功能测定和作用机制。过去研究的成果已演变成新目标的方向，特别是针对新出现的病原体（例如加蒂隐球菌、新型隐球菌和加蒂隐球菌）发现抗真菌剂的方法，重点是克服黑化生长期的耐药性。这项研究的技术方法的特点包括基于微冷冻探针核磁共振、质谱、圆二色性和有机合成的集成，改进用于亚微摩尔尺度结构阐明的强大工具，以及一种新的深层化学多样性“自下而上” (DCD-BU) 发现新化学实体的方法。预期结果包括鉴定抗真菌药物开发的重要非唑类先导化合物，特别是针对病原体加蒂隐球菌和格鲁比隐球菌，可能对艾滋病毒/艾滋病患者的生活质量产生有益的结果。