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

描述(申请人提供)：天然产品是具有生物活性的新型化学支架的极好来源。据估计，在过去20年里，在美国批准使用的90种抗菌剂中，78%的抗菌剂和79种抗癌剂中的62%来自天然产品。随着机器人技术的进步，高通量筛选(HTS)已成为全球范围内发现新的先导化合物用于药物开发和化学探针以更好地了解疾病过程的主要方法。不幸的是，天然产品提取物不容易用于使用HTS的发现计划，这导致发现新药和化学探针的机会大大减少。目前的提案试图通过创建一个独特的海洋天然产物(包括浓缩部分和纯化化合物)库来克服这一障碍，该库与HTS兼容，并可作为新的研究工具提供给生命科学研究社区。在这个为期两年的项目中，我们试图创建一个独特的海洋天然产品图书馆，命名为海港分部海洋研究所(HBOI)海洋天然产品图书馆(MNPL)，它将作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制作这样一个库，并成功地用大约150个生物体创建了一个库。通过对现有化学库的筛选，可以迅速发现许多新的结构，包括新型组蛋白脱乙酰酶抑制剂、MCL-1抑制剂、抗疟疾药物和核因子kappa B抑制剂。HBOI拥有超过14,000个冷冻海洋标本和19,000个海洋微生物分离株，可用于建立一个扩大的海洋天然产物库。在目前的提案中，我们试图通过增加分馏过程的自动化，并聘请新的毕业生和学生对HBOI冷冻生物库中的750-1250个生物和海洋微生物培养库中的250-350个生物进行化学分选，从而极大地扩大图书馆的多样性。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。 公共卫生相关性：该项目将创建一个独特的资源--HBOI海洋天然产品图书馆--用于发现生物探针和新药。这个资源将是一个从海洋生物中提取的纯净和浓缩的级分的库，将可供High Throught Screen社区进行筛查。这样的图书馆将提供获取独特化学多样性的途径，以加强美国生命科学研究企业。

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.