Pilot-Scale Libraries of Marine Cyanobacterial Natural Products

海洋蓝藻天然产物中试规模文库

• 批准号: 7693209
• 负责人: HENDRIK LUESCH
• 金额: $ 20万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7693209
• 关键词: Affect; Antineoplastic Agents; Aquaculture; Biological; Biological Assay; Biological Factors; Chemicals; Collection; Condition; Cyanobacterium; Disease; Environment; Enzymes; Florida; Fractionation; Fresh Water; Generations; Genetic; Genetic Variation; Genome; Goals; Growth; Guam; Habitats; High Pressure Liquid Chromatography; Hybrids; Iron; Laboratory culture; Lead; Libraries; Life; Light; Location; Marines; Mass Spectrum Analysis; Metabolism; Methodology; Methods; Modification; Nitrogen; Nutrient; Oceans; Organism; Peptides; Phosphorus; Population; Production; Protocols documentation; Public Health; Purpose; Rate; Reproducibility; Research; Seasonal Variations; Secondary to; Site; Source; Structure; Substrate Specificity; Techniques; Testing; Water; Work; analog; base; cytotoxicity; day; drug discovery; novel; scaffold; success

DESCRIPTION (provided by applicant): Cyanobacteria are among the most ancient organisms on Earth and their ubiquitous presence to this day in terrestrial, freshwater and marine environments is indication for their success in competitive situations. Many cyanobacteria produce an array of different secondary metabolites, and it is estimated that some of these life forms devote up to 10% of their genome to secondary metabolism, presumably for defense purposes to gain competitive advantages. Cyanobacterial secondary metabolites (natural products) isolated so far have only been tested in very few assays, yet hit rates in cytotoxicity or target-based assays towards anticancer drug discovery have been quite high. Yet relatively little explored, secondary metabolites produced by marine cyanobacteria are privileged structures that are already well-optimized to interact with biological targets. The overall goal of this proposed research is to isolate known and to discover new natural products from benthic marine cyanobacteria that will possess unique structural features and will occupy biologically relevant chemical space not yet represented in the MLSMR. Furthermore, efforts will be undertaken to determine the best methods for culturing marine benthic cyanobacteria that optimize production of targeted compounds and also provide sustainable compound supply. First, "superproducing" cyanobacteria with proven rich secondary metabolite content will be re-collected from several locations in US waters in the Pacific and Florida and structurally diverse metabolites re-isolated and fully characterized. Second, we will determine the best methods for culturing marine benthic cyanobacteria that optimize production of targeted compounds, which also provides sustainable compound supply. Third, yet uncharacterized cyanobacteria will be collected from several locations in the western Pacific around Guam and in Florida. Extracts will be chromatographically fractionated and analyzed by NMR for the presence of secondary metabolites, i.e., peptides and peptide-polyketide hybrids. Compounds are purified by HPLC and structures elucidated by spectroscopic techniques, particularly NMR and mass spectrometry. PUBLIC HEALTH RELEVANCE: Marine cyanobacteria produce natural products which are structurally unique, biologically active, and have not been extensively tested for their activities against disease-relevant targets. These natural products will significantly enrich the diversity of the MLSMR.

描述（由申请人提供）：蓝细菌是地球上最古老的生物之一，迄今为止，它们在陆地，淡水和海洋环境中至今无处不在，这表明它们在竞争性情况下的成功表明。许多蓝细菌产生了一系列不同的二级代谢产物，据估计，其中一些生命形式将其基因组的10％投入到次级代谢上，大概是为了获得竞争优势。到目前为止，分离出的蓝细菌次级代谢物（天然产物）仅在很少的测定中进行了测试，但是细胞毒性的命中率或基于靶标的抗癌药物发现的基于目标的测定率很高。然而，相对较少的探索，海洋蓝细菌产生的二级代谢产物是特权结构，已经被良好地优化与生物学靶标相互作用。这项拟议的研究的总体目标是隔离已知并发现底栖海蓝细菌的新天然产品，该产品将具有独特的结构特征，并将占据MLSMR中尚未代表的生物学相关的化学空间。此外，将努力确定培养海洋底栖蓝细菌的最佳方法，以优化目标化合物的生产并提供可持续的复合供应。首先，将从太平洋和佛罗里达州的美国水域的多个位置重新收集具有富含二次代谢含量的富含二级代谢物含量的“超生产”蓝细菌，并重新溶解并充分表征了结构上多样的代谢物。其次，我们将确定培养海洋底栖蓝细菌的最佳方法，该方法优化了靶向化合物的产生，这也提供了可持续的化合物供应。第三，将从关岛和佛罗里达州西太平洋的几个地点收集但未表征的蓝细菌。提取物将通过NMR进行色谱分离，并分析二次代谢产物，即肽和肽 - 聚酮化合物杂交。化合物通过HPLC纯化，并通过光谱技术阐明了结构，尤其是NMR和质谱法。公共卫生相关性：海洋蓝细菌生产的天然产物在结构上是独特的，生物学上的活跃，并且没有针对与疾病相关的靶标的活动进行广泛的测试。这些天然产品将大大丰富MLSMR的多样性。