Natural feedstocks for diversity-oriented synthesis

描述（由申请人提供）：这个第二阶段STTR申请是达特茅斯学院赖特集团和Promiliad Bioburma之间的前一阶段奖励的延续。本申请的目标是继续我们的努力，开发新的化学库，其多样性和复杂性与天然产品一样，是制药行业的适销产品。我们战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进行多样性定向合成。与类似物生成不同，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的不同，因为只需要发酵来源的几种定义明确的化合物。通过仅需要来自生物体的有限组的重组化合物，可以进行仔细的优化以确保材料的高产率。虽然这种策略依赖于大自然来构建高度复杂的图书馆功能，但多样性导向的策略被用来生成覆盖广阔结构空间的大型图书馆。在第一阶段的奖项，我们已经开发了一些直接和有效的策略，将重组积木（nonactate）转化为几个独特的分子结构。这一阶段的奖励将使我们的努力从方法阶段过渡到第三阶段，大规模生产和销售化合物库。在该奖项下，我们将（1）从nonactate制备高度多样化和复杂分子的中等规模的文库，（2）开发从聚酮化合物甲基霉素，pikromycin和spinosyn生成支架的新方法，以及（3）开发两种新的重组天然原料，pikrodiene和spinosyn。通过这些努力，Promiliad将能够成为制药行业新化学实体的主要供应商。

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.