Diverse Molecular Libraries from Unique Endosymbiotic Fungi

来自独特内共生真菌的多样化分子文库

• 批准号: 8119134
• 负责人: LESLIE GUNATILAKA
• 金额: $ 29.75万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-02 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119134
• 关键词: Affect; Biological; Biological Factors; Biological Process; Chemicals; Collection; Diamines; Disease; Goals; High Pressure Liquid Chromatography; Hydrazine; Lead; Libraries; Life; Microbiology; Molecular Bank; Natural Products Chemistry; Nature; Organism; Pharmaceutical Preparations; Process; Public Health; Reaction; Reagent; Recording of previous events; Signaling Pathway Gene; Source; Structure; United States National Institutes of Health; analog; cellular targeting; combinatorial; drug development; fungus; human disease; innovation; microbial; new therapeutic target; novel; public health relevance; repository; response; small molecule; success; tool

DESCRIPTION (provided by applicant): Fungi, especially those which live in symbiotic association with other organisms, are rich sources of small-molecule natural products representing novel structures and eliciting diverse biological responses, but to date they remain underexplored. The goal of this project is to generate molecular libraries derived from a unique collection of carefully identified and curated endophytic and endolichenic fungal strains from four diverse U.S. eco-zones. In Specific Aim 1, selected strains of fungal species which have never been investigated previously for their secondary metabolites will be cultured in small-scale and subjected to HPLC analysis, LC-MS and 13C-NMR dereplication to select high-yielding strains producing new, rare, and/or carbonyl-containing compounds. In Aim 2, promising fungal strains will be cultured on large-scale and processed to isolate natural products new to the NIH Molecular Libraries Small-Molecule Repository (MLSMR). Aim 3 will focus on an innovative approach of chemically diversifying CO-containing natural products prevalent among fungal secondary metabolites in a high-yielding reaction with the diamine reagent, hydrazine. This will result in analogs containing N-N moieties very rare in nature but common among "drug-like" combinatorial and synthetic molecules. During the course of this project compounds possessing unique structural features and occupying biologically-relevant chemical space hitherto not represented in the MLSMR will be generated and submitted to the MLSMR, which constitutes Aim 4 of this proposal. The major strengths of this application are: (i) availability of a collection of a unique, geno-typed endosymbiotic fungal strains not previously investigated for their secondary metabolites; (ii) biological relevance of structures to be generated that are poorly represented in the MLSMR; (iii) the track record of the group in microbiology and natural products chemistry, as well as (iv) the success the group has had in converting carbonyl-containing fungal metabolites into their N-N bond-containing analogs, many with unprecedented structures and potential bioactivities. Thus, the likelihood of discovering activities relevant to human diseases and/or affecting the functions of genes, signaling pathways, and disease-related biological processes will be greater within these libraries due to their natural product origin and/or "drug-like" structures. PUBLIC HEALTH RELEVANCE: Microbial natural products have a rich history for their utility as tools for identification of novel therapeutic targets for human diseases and as lead structures for drug development. This project proposes to generate diverse molecular libraries from endosymbiotic fungi with potential to interact with cellular targets and serve as lead molecules for drug development and therefore will have a great impact on public health.

描述（由申请人提供）：真菌，尤其是与其他生物体共生关联的真菌，是代表新型结构并引起多种生物学反应的小型天然产品的丰富来源，但迄今为止，它们仍然尚未被倍增。该项目的目的是生成来自独特的识别和策划的内生内生和内醇的真菌菌株的独特集合的分子库，这些库来自四种不同的美国生态区。在特定的目标1中， 以前从未研究过其继发代谢物的真菌物种的选定菌株将在小型中进行培养，并经过HPLC分析，LC-MS和13C-NMR的消除，以选择可产生新的，稀有的，稀有和/或含羰基的化合物。在AIM 2中，有希望的真菌菌株将在大规模上进行培养，并处理以隔离NIH分子库小分子存储库（MLSMR）的新天然产品。 AIM 3将重点介绍一种与二氨基试剂（二氨基试剂）的高产反应中，在真菌二级代谢产物中普遍存在的化学多样化的共同含有自然产物的创新方法。这将导致含有非常罕见的N-N部分的类似物，但在“药物样”组合和合成分子中很常见。在该项目的过程中，将生成并提交给MLSMR的MLSMR，具有具有独特的结构特征并占据尚未在MLSMR中尚未代表的生物学的化学空间，该化学空间构成了本提案的目标4。该应用的主要优势是：（i）以前未针对其二级代谢物研究的独特，型内共生真菌菌株的收集； （ii）在MLSMR中代表不当的结构的生物学相关性； （iii）微生物学和天然产物化学中该组的往绩记录，以及（iv）该组在将含羰基的真菌代谢物转化为含N-N键的类似物中所取得的成功，许多人具有前所未有的结构和潜在的生物活性。因此，发现与人类疾病相关的活动和/或影响基因，信号通路和与疾病相关的生物学过程的功能的可能性更大，因为它们的天然产物起源和/或类似“药物样”结构。 公共卫生相关性：微生物天然产品具有丰富的历史，因为它们的效用是识别人类疾病的新型治疗靶标和药物开发的铅结构的工具。该项目建议从内共生真菌产生各种分子文库，并有可能与细胞靶标相互作用并充当药物开发的铅分子，因此将对公共卫生产生重大影响。