Creation of a Marine Natural Products Library to Enhance Life Science Research

描述（由申请人提供）：天然产物是具有内在生物活性的新型化学支架的极佳来源。据估计，在过去二十年中，美国批准使用的90种抗菌剂中有78%，79种抗癌剂中有62%来源于天然产物。随着机器人技术的进步，高通量筛选（HTS）已成为世界范围内用于发现药物开发和化学探针的新先导化合物以更好地了解疾病过程的主要方法。不幸的是，天然产物提取物不容易用于使用HTS的发现项目，这导致新药和化学探针发现的机会大大减少。目前的提案旨在克服这一障碍，通过创建一个独特的海洋天然产物库（包括富集组分和纯化化合物），该库与HTS兼容，并可作为一种新的研究工具提供给生命科学研究界。在这个为期两年的项目中，我们寻求建立一个独特的海洋天然产品图书馆，命名为海港海洋研究所（HBOI）海洋天然产品图书馆（MNPL），这将成为科学界的长期资源。作为国家合作药物发现项目的一部分，HBOI在过去五年中一直致力于建立这样一个图书馆，并成功地建立了一个由大约150种生物组成的图书馆。现有化学文库的筛选允许快速发现许多新结构，包括新的组蛋白去乙酰化酶抑制剂，MCL-1抑制剂，抗疟疾剂和核因子kappa b抑制剂。HBOI拥有超过14,000个冷冻海洋标本和19,000个海洋微生物分离物的存储库，可用于扩大海洋天然产物文库的生成。在目前的提案中，我们试图通过在分离过程中增加自动化来极大地扩大图书馆的多样性，并雇用新的毕业生和学生对HBOI冷冻生物库中的750-1250种生物和海洋微生物培养收集中的250-350种生物进行化学分离。图书馆将通过材料转让协议、合作研究协议和赞助研究项目向外部合作者开放。

DESCRIPTION (provided by applicant): Natural products represent an excellent source of novel chemical scaffolds that are inherently biologically active. It has been estimated that 78% of the 90 antibacterial agents and 62% of the 79 anticancer agents approved for use in the US over the past two decades have their origins in natural products. With advances in robotics, High Throughput Screening (HTS) has become the primary approach used worldwide to discover new lead compounds for drug development and chemical probes to better understand the disease process. Unfortunately, natural products extracts are not readily amenable for use in discovery programs that use HTS which has led to a significant reduction in opportunities for new drug and chemical probe discovery. The current proposal seeks to overcome this obstacle by creating a unique library of marine natural products (both enriched fractions and purified compounds) that is compatible with HTS and is available to the Life Sciences Research Community as a new research tool. In this two year project we seek to create a unique library of marine natural products, designated as the Harbor Branch Oceanographic Institute (HBOI) Marine Natural Product Library (MNPL), which will serve as a long term resource to the scientific community. HBOI has been engaged in the production of such a library for the past five years as part of a National Cooperative Drug Discovery Project and has successfully created a library from approximately 150 organisms. Screening of the existing chemical library has allowed for the rapid discovery of many new structures including novel histone deacetylase inhibitors, MCL-1 inhibitors, anti-malarial agents and inhibitors of nuclear factor kappa B. HBOI has a repository of over 14,000 frozen marine specimens and 19,000 marine microbial isolates that could be used in generation of an expanded Marine Natural Products Library. In the current proposal we seek to greatly expand the diversity of the library through adding automation to the fractionation process and hiring new graduates and students to conduct chemical fractionation on 750-1250 organisms found in the HBOI Frozen Organism Repository and 250-350 organisms from the Marine Microbial Culture Collection. The library will be made available to external collaborators through material transfer agreements, collaborative research agreements and sponsored research projects. Public Health Relevance: This project will create a unique resource - the HBOI Marine Natural Products Library- for the discovery of biological probes and new medicines. This resource will be a library of pure and enriched fractions derived from marine organisms that will be available for screening by the High Through put Screening Community. Such a library will provide access to unique chemical diversity to enhance the US Life Science Research Enterprise.