High-Throughput Solid-Phase Combinatorial Biocatalysis

高通量固相组合生物催化

• 批准号: 6700385
• 负责人: Jonathan S. Dordick
• 金额: $ 71.34万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-03 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700385
• 关键词: aspartic endopeptidases; biotechnology; catalyst; combinatorial chemistry; doxorubicin; drug discovery /isolation; enzyme activity; enzyme structure; enzyme substrate; glycosylation; high throughput technology; indinavir; paclitaxel; polymers; technology /technique development

DESCRIPTION (provided by applicant): Rapid developments in genomics, proteomics, and combinatorial chemistry have reshaped the field of drug discovery, providing new drug targets for selective screens and new compounds to be tested in those screens. While combinatorial methods have given rise to large libraries of compounds, typically these compounds result in improved lead candidates that must undergo further transformations by conventional medicinal chemistry to yield new drug candidates. Bioengineering, in the context of high-throughput combinatorial methodologies, has not impacted lead optimization nearly as much as it has lead discovery, mainly because of the highly selective, intricate chemistries often required to optimize lead compounds and the lack of a suitably broad high-throughput platform. Combinatorial biocatalysis can help overcome these obstacles by exploiting the exquisite selectivity and unique reactivity of enzymes and microbial biocatalysts; however, to date this technology has been limited to the derivatization of soluble substrates. We propose to expand the scope of combinatorial biocatalysis to include reactions on, and the generation of libraries from, lead molecules attached to solid and soluble polymer supports. In the process, we will develop a high-throughput, biocatalytic technology for drug discovery. The specific aims are: 1. To expand the breadth of biocatalysis on solid- and polymer-supported compounds in aqueous and nonaqueous media; 2. To develop strategies for attaching lead compounds and removing their derivatives from solid and polymeric supports; 3. To demonstrate high-throughput, combinatorial biocatalytic lead optimization of complex natural and synthetic molecules, screen resulting derivatives for biological activity, and scale up structurally and functionally interesting derivatives using biotransformations. A series of lead molecules will be used in this work, ranging from enzyme substrates that are attached onto solid and soluble polymer supports to complex compounds (the flavonoid bergenin and the current HIV-1 protease inhibitor indinavir). Successful completion of this research program will result in a powerful methodology that can be used by biomedical investigators in the search for new, more potent small molecule therapeutics.

描述（由申请人提供）：基因组学，蛋白质组学和组合化学的快速发展已重塑了药物发现领域，为在这些筛查中测试的选择性筛选和新化合物提供了新的药物靶标。虽然组合方法已引起大量化合物的文库，但通常这些化合物会改善铅候选者，这些候选者必须通过常规药物化学反应进行进一步的转化，以产生新的药物候选者。在高通量组合方法学的背景下，生物工程的影响几乎没有影响铅发现的影响，主要是因为通常需要高度选择性，复杂的化学作用来优化铅化合物，并且缺乏合适的宽阔高通量平台。组合生物催化可以通过利用酶和微生物生物催化剂的精致选择性和独特的反应性来帮助克服这些障碍。但是，迄今为止，该技术仅限于可溶性基材的衍生化。我们建议将组合生物催化的范围扩展到包含反应，以及与固体和可溶性聚合物支撑相连的铅分子的产生。在此过程中，我们将开发一种用于药物发现的高通量生物催化技术。具体目的是： 1。在水性和非水培养基中的固体和聚合物支持的化合物上扩大生物催化的广度； 2。制定策略来附着铅化合物并从固体和聚合物支持中去除其衍生物； 3。为了证明复杂的天然和合成分子的高通量，结合生物催化铅优化，筛选生物学活性的衍生物，并使用生物转化在结构和功能上有趣的衍生物扩展。这项工作将使用一系列的铅分子，范围从连接到固体和可溶性聚合物载体上的酶底物与复杂化合物（黄酮类垂体和当前的HIV-1蛋白酶抑制剂idininavir）。该研究计划的成功完成将导致一种强大的方法，生物医学研究人员可以使用，以寻找新的，更有效的小分子疗法。