Natural feedstocks for diversity-oriented synthesis

描述(由申请人提供)：这项第二阶段的STTR申请是达特茅斯学院莱特小组和Promiliad Biophma之间先前第一阶段奖项的延续。这一应用程序的目标是继续努力开发新的化学库，使其具有天然产品的多样性和复杂性，作为制药行业的适销品。我们战略的关键是使用发酵衍生的天然产物和重组的非天然变体作为面向多样性合成的高复杂性原料。与模拟产品不同，这些重组天然产品是专门为实现化学多样化而设计的。我们的方法与组合生物合成有很大的不同，因为只需要从发酵来源中提取几种定义明确的化合物。只需要从生物体中获得一组有限的重组化合物，就可以进行仔细的优化，以确保材料的高产量。虽然这一战略依赖于自然来构建高度复杂的图书馆特征，但以多样性为导向的战略被用来产生覆盖广阔结构空间区域的大型图书馆。根据第一阶段奖，我们已经开发了许多直接和有效的策略来将重组构建块(非乳酸)转化为几种独特的分子结构。这一阶段奖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销售。根据这一奖项，我们将(1)从非乳酸中制备高度多样化和复杂的中等大小的分子文库，(2)开发从聚酮类化合物甲氧霉素、吡克罗霉素和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Spinosene。通过这些努力，Promiliad将能够成为制药业新化学物质的主要供应商。

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.