Synthesis and Discovery Through DNA-Templated Chemistry

通过 DNA 模板化学进行合成和发现

• 批准号: 6729776
• 负责人: DAVID R LIU
• 金额: $ 36.71万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729776
• 关键词: Diels Alder reaction; alcohols; amines; chemical addition; chemical binding; chemical group; chemical reaction; chemical registry /resource; chemical structure function; chemical synthesis; combinatorial chemistry; cyclic compound; drug design /synthesis /production; drug discovery /isolation; hepatitis C; hepatitis C virus; molecular biology information system; organic chemicals; polymerase chain reaction; porphyrins; protease inhibitor; protein binding; thiols

DESCRIPTION (provided by applicant): Two of the most ubiquitous challenges in chemistry are how to control chemical reactivity and how to discover molecules with optimal properties from many possible structures. My laboratory has initiated a program to develop a new approach to addressing these two challenges that differs from the approaches most frequently taken by chemists. Our approach combines powerful aspects of natural biosynthesis and molecular evolution with the flexibility of synthetic organic chemistry. We discovered that DNA duplex formation exerts remarkable control over the effective molarity of DNA-linked reactants without structural requirements. The surprising generality of DNA-templated organic synthesis has enabled us to subject synthetic molecules to translation, selection, and amplification that parallel the molecular evolution of biological molecules in Nature. This proposal seeks to develop our initial studies in a direction that will further reveal the principles that underlie DNA-templated synthesis and, using these principles, further expand our synthetic capabilities. I believe that this approach to creating synthetic molecules already merits an early stage effort to couple DNA-templated organic synthesis with selection methods for discovering molecules with functional properties. As a result, I also propose to develop true selections (as opposed to screens) based on iterative rounds of protein binding, and to apply these selections to our first DNA-templated small molecule libraries. The development of these new areas may lead to the discovery of new functional synthetic molecules as research tools for probing biological functions or as leads for new therapeutics.

描述（申请人提供）：化学中最普遍的两个挑战是如何控制化学反应性以及如何从许多可能的结构中发现具有最佳特性的分子。我的实验室已经启动了一项计划，以开发一种新的方法来解决这两个挑战与化学家最常采用的方法不同的挑战。我们的方法结合了自然生物合成和分子进化的强大方面，以及合成有机化学的灵活性。我们发现，DNA双链体的形成对无结构要求的DNA连接反应物的有效摩尔性产生了明显的控制。 DNA-模拟有机合成的一般普遍性使我们能够对合成分子进行翻译，选择和放大，这与自然界生物分子的分子进化相似。该提案旨在朝着我们的初步研究朝着一个方向发展，该研究将进一步揭示DNA-构成合成的原则，并使用这些原理进一步扩大我们的合成能力。我认为，这种创建合成分子的方法已经值得早期的努力，将DNA模拟的有机合成与发现具有功能特性的分子的选择方法。结果，我还建议基于迭代蛋白结合的迭代回合开发真实的选择（而不是筛选），并将这些选择应用于我们的第一个DNA模拟的小分子库。这些新领域的发展可能导致发现新功能合成分子作为探测生物学功能或作为新疗法的铅的研究工具。