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: 7944686
• 负责人: LESLIE GUNATILAKA
• 金额: $ 26.75万
• 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/7944686
• 关键词: Affect; Biological; Biological Factors; Biological Process; Chemicals; Collection; Diamines; Disease; Goals; High Pressure Liquid Chromatography; Hydrazine; Hydrazines; 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; gene function; 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(申请人提供)：真菌，特别是那些与其他生物共生的真菌，是代表新结构和引发不同生物反应的小分子天然产物的丰富来源，但到目前为止，它们仍未得到充分开发。该项目的目标是从来自美国四个不同生态区的精心鉴定和精选的内生和内生真菌菌株的独特集合中产生分子文库。在具体目标1中， 选择以前从未研究过次生代谢物的真菌菌株将进行小规模培养，并进行高效液相分析、LC-MS和13C-核磁共振去复制，以选择产生新的、稀有的和/或含有羰基化合物的高产菌株。在目标2中，将大规模培养有希望的真菌菌株，并对其进行加工，以分离出NIH分子库小分子资源库(MLSMR)新的天然产物。目标3将重点放在一种创新的方法上，在与二胺试剂联氨的高产率反应中，对真菌次生代谢物中普遍存在的含CO的天然产物进行化学多样化。这将导致含有在自然界中非常罕见的N-N部分的类似物，但在“类药物”组合和合成分子中很常见。在这一项目过程中，将产生具有独特结构特征并占据生物相关化学空间的化合物，这些化合物在MLSMR中尚未出现，并将提交给MLSMR，这构成了本提案的目标4。这一应用的主要优势是：(1)获得了一批以前没有研究过次级代谢物的独特的、遗传型的内共生真菌菌株；(2)待产生的结构具有生物学相关性，而这些结构在MLSMR中的代表性很差；(3)该小组在微生物学和天然产品化学方面的记录，以及(4)该小组在将含有羰基的真菌代谢物转化为含有N-N键的类似物方面取得的成功，其中许多具有前所未有的结构和潜在的生物活性。因此，由于这些文库的天然产物来源和/或类似药物的结构，在这些文库中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活动的可能性将更大。 与公共健康相关：微生物天然产物作为确定人类疾病新的治疗靶点的工具和药物开发的先导结构，有着丰富的历史。该项目建议从内生真菌中建立多种分子文库，这些分子文库具有与细胞靶标相互作用的潜力，并作为药物开发的先导分子，因此将对公众健康产生重大影响。