Expanding the Chemistry of Nucleic Acids for the Discovery of Molecular Function

我的研究计划的主题是开发和应用技术，利用 DNA 的力量来进化和发现能够进行分子识别和催化的新型分子。我们的研究重点是开发强大的筛选技术，以满足关键需求，例如用于生物医学研究的新型人工抗体和用于有机合成的新型催化剂。为此，我的研究小组建立了新方法，能够生成和高通量筛选大型 DNA 编码组合文库，范围从能够结合蛋白质的合成生物聚合物到能够催化化学转化的小分子。基于这些发现，该提案将研究 DNA 作为发现分子功能的工具的潜力。***该计划的首要目标是研究具有增加的化学多样性的核酸聚合物及其新功能的进化。我的实验室率先采用酶法生成具有多种化学功能的 DNA。我们将为它们的生成开发可扩展的合成方法，研究官能团对分子识别和催化的影响，改善DNA的结合和催化特性，并证明它们作为生物医学研究的受体和催化剂的进化。 ***第二个重点是，我们将开发 DNA 编码的小分子催化剂库，用于成键化学物质的高通量催化剂筛选。实现这一目标的核心是我们实验室开发的两亲性 DNA，它能够在短短 20 uL 的溶剂中编码和筛选超过 1000 万个独特的分子。在推进这项研究的过程中，我们将重点研究我们最近开发的筛选平台的局限性，包括反应范围和催化剂类型。此外，我们将开发新的合成方法来生成 DNA 编码的小分子库，这将使快速发现用于合成精细化学品（包括药物相关小分子）的催化剂成为可能。***这个核酸研究跨学科项目依赖于合成化学、高分子化学、生物化学、组合科学、催化和分子生物学方面的专业知识。如果成功，将有可能获得改进的基于核酸的人工抗体用于生物医学研究和治疗。此外，还将提供用于催化剂开发的“绿色”高通量技术。最后，这项研究旨在扩大我们对合成聚合物对各种分子功能的进化适应性的基本理解，包括实现此类分子功能所需的化学多样性和结构-活性关系。该项目将培训 19 名多学科科学家。

The encompassing theme within my research program is the development and application of technologies that harness the power of DNA toward the evolution and discovery of novel molecules capable of molecular recognition and catalysis. Our research centres on developing robust screening technologies that address critical needs such as new artificial antibodies for biomedical research and new catalysts for organic synthesis. To this end, my research group has established new methods that enable the generation and high-throughput screening of large DNA-encoded combinatorial libraries ranging from synthetic biopolymers capable of binding proteins to small-molecules capable of catalyzing chemical transformations. Building from these findings, this proposal will study the potential of DNA as a tool for the discovery of molecular function.***The first thrust of this program is the study of nucleic acid polymers with increased chemical diversity and their evolution for novel function. My lab has pioneered enzymatic methods to generate DNA with diverse chemical functionality. We will develop scalable synthetic methods for their generation, study the functional group influence on molecular recognition and catalysis, improve binding and catalytic properties of DNA, and demonstrate their evolution as receptors and catalysts for biomedical research. ***In a second thrust we will develop DNA-encoded small-molecule catalyst libraries for high-throughput catalyst screening of bond-forming chemistries. Central to achieving this is an amphiphilic DNA developed in our lab, which enables the encoding and screening of >10 million unique molecules in as little as 20 uL of solvent. In advancing this research, we will focus on studying the limitations of our recently developed screening platform, including reaction scope and catalyst type. Furthermore, we will develop new synthetic methods for the generation of DNA-encoded small-molecule libraries, which will enable the rapid discovery of catalysts for synthesis of fine chemicals including pharmaceutically-relevant small molecules.***This interdisciplinary program on nucleic acids research relies on expertise in synthetic chemistry, polymer chemistry, biological chemistry, combinatorial science, catalysis, and molecular biology. If successful, access to improved nucleic acid-based artificial antibodies for biomedical research and therapeutics will be made possible. Furthermore, ‘greener' high-throughput technologies for catalyst development will be available. Lastly, this research seeks to expand our fundamental understanding of the evolutionary fitness of synthetic polymers for various molecular function, including the chemical diversity and structure-activity relationships required to achieve such molecular function. This program will train 19 multidisciplinary scientists.