CAREER: DNA-Catalyst Conjugates for Site-Selective Transformations in Biological Contexts

职业：用于生物环境中位点选择性转化的 DNA 催化剂缀合物

• 批准号: 1554814
• 负责人: David Gorin
• 金额: $ 66.19万
• 依托单位: Smith College
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1554814&HistoricalAwards=false
• 关键词: CAREER; DNA; Catalyst; Conjugates; Site

The Chemistry of Life Processes Program in the Chemistry Division is funding Dr. David J. Gorin from Smith College to develop chemical reagents that selectively modify one compound in a complex biological mixture. Currently, transforming one molecular target in a mixture with many competing molecules is a major challenge for chemical researchers. The strategy being developed relies on DNA molecules capable of folding into complex three-dimensional structures and adhering to specific targets of interest. The DNA serves as an adhesive to bring a modifying chemical structure into close proximity, resulting in selective modification of the target. These new reagents are being applied to perturb and study molecular processes in living systems, including communication within bacterial populations that are important for understanding infections. Undergraduates at Smith College, the nation's largest liberal arts college for women, are key contributors to the research. In order to increase the Science, Technology, Engineering and Mathematics (STEM) undergraduate engagement and the success of women, and especially women of color, course-based research and guest lectures by diverse STEM role models are incorporated into the introductory organic chemistry classes. The impact of these and other curricular innovations are assessed through the deployment of a competition-based assessment plan for student capacities alongside more traditional approaches for tracking student outcomes.The goal of this research is to develop reagents for the selective chemical modification of one target molecule in a complex biological mixture. A new class of selective catalysts that recognize and bind to a particular target, thereby increasing the rate of a desired reaction, are being developed. Specifically, selective and high-affinity DNA aptamers are being covalently linked to well-established low molecular weight catalysts, including organo- and transition metal-catalysts, to create DNA-small molecule catalyst conjugates (DCats). DCats enable enzyme-like selectivity with synthetic reagents, promising a fundamentally new capability to target a chemical reaction to any molecule of interest. Generality is being demonstrated in an array of reaction chemistries on both small molecules and protein substrates. In addition, a DCat is being developed to investigate N-acyl homoserine lactone chemical communication within populations of bacteria. This application demonstrates the broad potential of DCats as tools to study biological systems and other complex mixtures. Smith University undergraduates are centrally involved in the research, which represents a springboard for STEM graduate study and careers. Incorporation of the proposed research into the introductory organic chemistry laboratory class broadens the impact of the research by reaching a greater number of students, especially those who might not vigorously pursue research opportunities on their own initiative.

化学部的生命过程化学项目正在资助史密斯学院的大卫J.戈林博士开发化学试剂，选择性地改变复杂生物混合物中的一种化合物。目前，在具有许多竞争分子的混合物中转化一个分子靶标是化学研究人员的主要挑战。 正在开发的策略依赖于能够折叠成复杂的三维结构并粘附到感兴趣的特定靶标的DNA分子。DNA充当粘合剂，使修饰的化学结构紧密接近，导致靶的选择性修饰。这些新试剂正被应用于干扰和研究生命系统中的分子过程，包括对理解感染很重要的细菌群体内的通信。美国最大的女子文理学院史密斯学院的本科生是这项研究的主要贡献者。为了提高科学，技术，工程和数学（STEM）本科生的参与度和女性的成功，特别是有色人种的女性，基于课程的研究和不同STEM榜样的客座讲座被纳入有机化学入门课程。这些和其他课程创新的影响进行了评估，通过部署一个基于竞争的评估计划，学生的能力，以及更传统的方法来跟踪学生的outcomes.The本研究的目标是开发试剂的选择性化学修饰的一个目标分子在一个复杂的生物混合物。正在开发一类新型选择性催化剂，它们可以识别并结合特定目标，从而提高所需反应的速率。具体地，选择性和高亲和力DNA适体被共价连接到公认的低分子量催化剂，包括有机和过渡金属催化剂，以产生DNA-小分子催化剂缀合物（DCats）。DCats使合成试剂具有类似酶的选择性，有望实现将化学反应靶向任何感兴趣分子的全新能力。在小分子和蛋白质底物上的一系列反应化学中证明了普遍性。此外，正在开发DCat以研究细菌群体内的N-酰基高丝氨酸内酯化学通讯。该应用展示了DCats作为研究生物系统和其他复杂混合物的工具的广泛潜力。 史密斯大学的本科生主要参与这项研究，这是STEM研究生学习和职业生涯的跳板。将拟议的研究纳入有机化学实验室入门课程，通过接触更多的学生，特别是那些可能不会主动积极寻求研究机会的学生，扩大了研究的影响。

项目成果

The “pHunger Games”: Manuscript Review to Assess Graduating Chemistry Majors

“饥饿游戏”：评估化学专业毕业生的手稿审查

• DOI: 10.1021/acs.jchemed.6b00179
• 发表时间: 2016
• 期刊: Journal of Chemical Education
• 影响因子: 3
• 作者: Gorin, David J.;Jamieson, Elizabeth R.;Queeney, K. T.;Shea, Kevin M.;Spray, Carrie G.
• 通讯作者: Spray, Carrie G.