Rapid Screening and Dereplication of Marine Symbiotic Natural Products

说明(申请人提供)：大多数药品直接或间接从天然产品中提取。然而，在过去的几十年里，随着这些技术变得不太适合高通量筛选，以及寻找新的天然产品变得越来越困难，通往新天然产品的管道一直在枯竭。许多实验室在这些领域取得了实质性进展，但在技术和对天然产品来源的基本了解方面仍存在差距。在这个项目中，我们将提供新的方法和数据来帮助填补这些剩余的空白。此外，我们还将在美国国立卫生研究院和威斯康星大学建立天然产物化合物筛选文库。新方法包括更快速、自动化和集成的天然产物提取、纯化和去复制技术。利用海洋共生细菌对天然产品来源的基础研究旨在回答有关寻找新的天然产品生产商的最富有成效的地方以及获得这些有希望的细菌的方法的问题。这些生物和化学研究是协同的，将提供第一组将培养的共生细菌与整个动物的化学联系起来的大型、有序的数据集。由此产生的方法被设计成在多个实验室中广泛使用，并有助于开发广泛共享的去复制平台。由此产生的天然产物库将用于美国国立卫生研究院和威斯康星州大学建立的高通量中心的各种屏幕上。我们将寻求有希望的线索，作为潜在的新药物。 公共卫生相关性：我们将开发快速发现生物活性天然产品的新方法，并提供有关能够进行药物发现的天然产品来源的新数据。我们还将提供用于筛选的天然产品库。这些结果将对天然产物科学产生很大的影响，因为新的方法和知识。这些新方法将对人类健康产生影响，并可能来自在项目过程中发现的新的治疗性小分子。

DESCRIPTION (provided by applicant): The majority of pharmaceuticals are derived from natural products either directly or indirectly. However, the pipeline to new natural products has been drying up over the last decades as the technologies became less amenable to high- throughput screening and as finding new natural products became increasingly difficult. Substantial progress has been made in these areas by numerous labs, but there are still gaps in technology and in basic understanding of natural product sources. In this project, we will provide new methods and data to help fill these remaining gaps. In addition, we will build natural product compound libraries for screening at NIH and at the University of Wisconsin. The new methods include more rapid, automated, and integrated techniques for extraction, purification, and dereplication of natural products. Basic studies of natural product sources using marine symbiotic bacteria are aimed at answering questions about the most fruitful places to find new natural product producers and about methods to obtain these promising bacteria. These biological and chemical studies are synergistic and will provide the first large, ordered set of data linking cultivated symbiotic bacteria to chemistry in whole animals. The resulting methods are designed to be widely useful in multiple labs and to help in the development of broadly shared platforms for dereplication. The resulting libraries of natural products will be used in a variety of screens at established, high-throughput centers at NIH and U. Wisconsin. We will pursue promising leads as potential new pharmaceuticals. PUBLIC HEALTH RELEVANCE: We will develop new methods for the rapid discovery of bioactive natural products and provide new data about sources of natural products that enable drug discovery. We will also provide libraries of natural products for screening. These results will have a large impact on natural products sciences because of new methods and knowledge. The human health impact will result from these new methods and potentially from new therapeutic small molecules discovered in the course of the project.