Natural feedstocks for diversity-oriented synthesis

描述（由申请人提供）：这个第二阶段的STTR申请是达特茅斯学院赖特小组和Promiliad生物制药公司之前的第一阶段奖励的延续。这个应用程序的目标是继续我们的努力，以开发新的化学文库的多样性和复杂性共同的天然产品作为一个可销售的产品到制药工业。我们策略的关键是利用发酵衍生的天然产物和重组的非天然变体作为多样性合成的高复杂性原料。与模拟产物不同，这些重组天然产物是专门设计用于化学多样化的。我们的方法与组合生物合成有很大的不同，因为从发酵来源中只需要少量的、定义明确的化合物。只需从生物体中提取有限的重组化合物，就可以进行仔细的优化，以确保材料的高产量。这种策略依赖于自然来构建高度复杂的图书馆特征，而以多样性为导向的策略则用于生成覆盖大面积结构空间的大型图书馆。根据第一阶段的奖励，我们已经开发了一些直接和有效的策略，将重组构建块（非乳酸）转化为几种独特的分子结构。这个阶段的奖励将使我们的努力从方法阶段过渡到第三阶段，即化合物库的大规模生产和营销。根据该奖项，我们将(1)从非乳酸中制备高度多样化和复杂分子的中等规模文库，(2)开发从聚酮类化合物甲霉素、匹克霉素和斯宾诺辛中生成支架的新方法，以及(3)开发两种新的重组天然原料，匹克二烯和斯宾诺辛。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。

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.