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: 7557625
• 负责人: HENDRIK LUESCH
• 金额: $ 34.51万
• 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/7557625
• 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体之一，至今它们在陆地、淡水和海洋环境中的普遍存在表明它们在竞争环境中取得了成功。许多蓝藻产生一系列不同的次级代谢产物，据估计，这些生命形式中的一些将其基因组的10%用于次级代谢，可能是出于防御目的以获得竞争优势。到目前为止，分离的蓝藻次级代谢产物（天然产物）仅在极少数试验中进行了测试，但在细胞毒性或基于靶点的抗癌药物发现试验中的命中率相当高。然而，相对较少探索，由海洋蓝藻产生的次级代谢产物是特权结构，已经很好地优化与生物靶标相互作用。这项拟议研究的总体目标是从底栖海洋蓝细菌中分离已知的并发现新的天然产物，这些蓝细菌将具有独特的结构特征，并将占据MLSMR中尚未表示的生物相关化学空间。此外，将努力确定培养海洋底栖蓝藻的最佳方法，以优化目标化合物的生产，并提供可持续的化合物供应。首先，将从太平洋和佛罗里达的美国沃茨的几个地点重新收集具有丰富次级代谢产物含量的“超级生产”蓝藻，并重新分离和充分表征结构多样的代谢产物。其次，我们将确定培养海洋底栖蓝藻的最佳方法，优化目标化合物的生产，这也提供了可持续的化合物供应。第三，将从关岛周围的西太平洋和佛罗里达的几个地点收集尚未定性的蓝细菌。将对浸提液进行色谱分馏，并通过NMR分析是否存在次级代谢产物，即，肽和肽-聚酮化合物杂合体。通过HPLC纯化化合物，并通过光谱技术，特别是NMR和质谱法阐明结构。公共卫生相关性：海洋蓝细菌产生的天然产物结构独特，具有生物活性，尚未对其针对疾病相关靶标的活性进行广泛测试。这些天然产物将大大丰富MLSMR的多样性。