Natural feedstocks for diversity-oriented synthesis

用于多样性合成的天然原料

• 批准号: 7109033
• 负责人: Dennis L. Wright
• 金额: $ 51.72万
• 依托单位: PROMILIAD BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7109033
• 关键词: bioengineering /biomedical engineering; biological products; biomimetics; chemical kinetics; chemical registry /resource; chemical structure function; chemical synthesis; cheminformatics; combinatorial chemistry; fermentation; genetic recombination; ketoacid; macrolide antibiotics; technology /technique development; terpenes

DESCRIPTION (provided by applicant): This Phase II STTR application is a continuation of a previous Phase I award between the Wright group at Dartmouth College and Promiliad Biopharma. The goal of this application is to continue our efforts to develop novel chemical libraries with the diversity and complexity common to natural products as a marketable product to the pharmaceutical industry. Key to our strategy is the use of fermentation derived natural products and recombinant non-natural variants as high complexity feedstock materials for diversity oriented synthesis. Unlike analog generation, these recombinant natural products are specifically designed to allow chemical diversification. Our approach differs substantially from combinatorial biosynthesis in that only a few, well-defined compounds are needed from fermentation sources. By only requiring a limited set of recombinant compounds from the organism, careful optimization can be conducted to ensure high yields of material. While this strategy relies on nature to construct a high degree of the complex features of the library, diversity-oriented strategies are utilized to generate large libraries that cover vast areas of structural space. Under the Phase I award, we have developed a number of direct and efficient strategies for converting a recombinant building block (nonactate) into several unique molecular architectures. This Phase award will allow our efforts to transition from the methods stage to Phase III, large-scale production and marketing of compound libraries. Under this award we will (1) prepare moderate sized libraries of highly diverse and complex molecules from nonactate, (2) develop new methods for scaffolds generation from the polyketides methymycin, pikromycin and spinosyn and (3) develop two new recombinant natural feedstocks, pikrodiene and spinosene. Through these efforts, Promiliad will be in a position to become a major supplier of new chemical entities to the pharmaceutical industry.

描述（由申请人提供）：此II阶段的STTR应用程序是达特茅斯学院与Promiliad Biopharma的Wright Group之间I阶段奖的延续。该应用程序的目的是继续我们的努力，以开发新型化学图书馆，其自然产品具有多样性和复杂性作为制药行业的可销售产品。我们策略的关键是使用发酵衍生的天然产物和重组非天然变体作为高复杂性原料材料，用于多样性的综合。与类似物的产生不同，这些重组天然产物是专门设计的，以允许化学多样化。我们的方法与组合生物合成有很大不同，因为从发酵源中只需要少数几种明确的化合物。通过仅需要有限的重组化合物，可以进行仔​​细的优化，以确保材料的高收益。尽管这种策略依赖于自然界来构建图书馆的复杂特征的高度，但采用以多样性为导向的策略来产生覆盖大量结构空间领域的大型图书馆。在第一阶段奖项下，我们开发了许多直接有效的策略，用于将重组构建块（非动态）转换为几个独特的分子体系结构。该阶段奖项将使我们的努力从方法阶段过渡到第三阶段，大规模生产和化合物库的营销。在该奖项下，我们将（1）制备来自非肌酸的高度多样化和复杂分子的中等尺寸的文库，（2）开发了从聚酮化合物甲基霉素，pikromycin和spinosyn和（3）开发两种新的重组天然原料，Pikrodiene，Pikrodiene和Pactosone的新方法。通过这些努力，Promiliad将有能力成为制药行业新化学实体的主要供应商。