Symbiosis and Chemical Diversity Generation

共生和化学多样性的产生

基本信息

批准号：
9276439
负责人：
Eric W Schmidt
金额：
$ 50.14万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-04-30
项目状态：
已结题

项目摘要

Project Summary/Abstract This program focuses on two related scientific areas: 1) a hypothesis-based approach to discovering new biosynthetic pathways and biomedically important compounds from marine animals; and 2) understanding diversity-generating biosynthesis and applying it to synthetic biology. 1) There is a greater variety of animal life in the sea than anywhere else, including millions of diverse animal species. Many marine animals live in highly competitive environments, and therefore they or their symbiotic bacteria synthesize small molecule chemical defenses, which have found value as FDA-approved therapeutics and lead compounds. They contain chemical scaffolds found only in the oceans and nowhere else on Earth. Although many important marine animal natural products have been discovered, in reality, the biological and chemical diversity of the oceans has barely been touched. Most marine animals are simply too small, rare, or variable to provide a sufficient supply of compounds for drug discovery and development. In research that will continue through this program, we are eliminating the barriers to discovering new potential pharmaceuticals, enzymes, and biochemical pathways from animals. We will take a hypothesis-driven approach to determine who makes marine natural products (animal, symbiont, or other) and how the compounds are made biochemically. We will discover and provide novel chemicals and potential pharmaceuticals. 2) Instead of containing a single bioactive natural product, species of animals contain families of compounds, where individual animals will harbor variants of a parent structure. Underlying this chemical diversity, we have shown that several biosynthetic pathways are diversity generating, capable of synthesizing millions of derivatives. This unusual plasticity has been applied as a tool for synthetic biology. Among other applications, one of the most exciting is the ability to design compounds and then produce them in different kinds of living cells. For example, genetic libraries encoding millions of unnatural natural products have already been created. Another use would be in the creation of designed cells for cell-based therapies. By better understanding the basic science of diversity-generating biosynthesis, we are helping to set the groundwork for this future. Here, using hypothesis testing, we will ask fundamental questions about diversity-generating pathways. In the course of this work, we will immediately apply new ligands and chemical libraries for drug discovery and development.

项目摘要/摘要该计划的重点是两个相关的科学领域：1）一种基于假设的方法来发现新的方法来自海洋动物的生物合成途径和生物医学重要的化合物； 2）理解生成多样性的生物合成并将其应用于合成生物学。 1）海洋中的动物生活多于其他任何地方，包括数百万种动物物种。许多海洋动物生活在高度竞争的环境中，因此它们或他们的共生细菌合成小分子化学防御，发现值为FDA批准的治疗剂和铅化合物。它们包含仅在海洋中发现的化学脚手架，而在地球上没有其他地方。尽管已经发现了许多重要的海洋动物天然产品，但实际上是生物学和海洋的化学多样性几乎没有触及。大多数海洋动物太小，稀有或可变量为药物发现和开发提供足够的化合物供应。在研究中继续通过该计划，我们消除了发现新的潜在药物的障碍，酶和动物的生化途径。我们将采用假设驱动的方法来确定谁生产海洋天然产品（动物，共生体或其他产品）以及如何制成化合物生化。我们将发现并提供新颖的化学物质和潜在药物。 2）动物种类不含单一的生物活性天然产物，而是包含各种化合物的家族，单个动物将拥有父母结构的变体。在这种化学多样性的基础上，我们有表明几种生物合成途径是产生多样性的，能够综合数百万衍生物。这种不寻常的可塑性已被用作合成生物学的工具。在其他应用中，最令人兴奋的之一是设计化合物，然后以各种生活形式生产它们细胞。例如，已经创建了编码数百万天然产品的遗传文库。另一种用途是创建用于基于细胞的疗法的细胞。通过更好地了解多样性生物合成的基础科学，我们正在帮助为这一未来树立基础。这里，使用假设检验，我们将询问有关生成多样性途径的基本问题。在课程中在这项工作中，我们将立即将新的配体和化学库用于药物发现和开发。