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

基本信息

批准号：
9014503
负责人：
Tadeusz F Molinski
金额：
$ 38.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-15 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9014503
关键词：
AIDS/HIV problem Achievement Acquired Immunodeficiency Syndrome Antifungal Agents Azole resistance Biological Biological Assay Candida Chemicals Circular Dichroism Complex Cryptococcus Cryptococcus neoformans 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 Mycoses Natural Products Neuraxis Opportunistic Infections Organic Synthesis Outcome Patients Persons 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 mouse model novel novel therapeutics pathogen pre-clinical programs research clinical testing screening tool

项目摘要

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）：患有艾滋病毒/艾滋病的人容易受到一系列有害的机会性感染的影响，并且经常屈服于传播的真菌疾病的破坏。非常需要新药来治疗抗唑的真菌病原体和难治性感染。海洋天然产品具有非凡的化学多样性，使其成为针对Candida spp。，Cryptococcus sp。的新型细胞测定中新颖的细胞测定源的理想来源。和其他真菌病原体。该提案扩大了从海洋无脊椎动物的发现，结构阐明和生物学表征的成功计划，重点是基于机制的筛选，功能分析和作用机理。过去研究的成就已经发展为实现新目标的方向，尤其是发现新兴病原体的抗真菌剂的方法，例如，加密的Gatti，C。neoformans和C. gatti，重点是在黑素化生长阶段克服耐药性。这项拟议研究的技术方法的特征包括基于微晶型NMR的整合，质谱，循环二色症和有机合成的整合，以阐明的结构阐明，并进行阐明的结构阐明，以及一种新的深层化学多样性“自下而上”（DCD-BU）（DCD-BU），以发现新的化学物质。预期的结果包括鉴定出抗真菌药物开发的重要非唑铅，尤其是针对病原体Gatti和Grubbi的病原体，对于HIV/AIDS患者而言，具有有益的生活质量效果。