Development of Sequence-Specific Bioorthogonal Reactions

该奖项资助纽约州立大学布法罗分校的生命过程化学项目资助林青博士使用基于噬菌体的方法来进化序列特定的钯介导的与芳基碘试剂的交叉偶联反应所需的含炔基肽，以及用于与含腈的小分子探针进行缩合反应的含半胱氨酸的多肽。通过利用噬菌体展示等生物技术，可以研究多达6000亿个含有独特化学功能基团的多肽底物的反应活性。将研究氨基酸序列对上述多肽反应性的影响。利用动力学和核磁共振方法对两个生物正交反应的结构基础和机理进行了探讨。这项拟议的研究旨在为重要的生物学问题的研究带来新的化学工具。该项目解决了在生命系统内应用的有机反应开发中的重要挑战，即在多肽和蛋白质中特定氨基酸的反应的适度反应速度和特异性。这项研究将加强我们对生物环境中化学反应活性的基本理解，特别是作为多肽序列的函数。研究结果将被纳入林博士教授的课程。该项目将通过与纽约州大学科技入门计划的长期合作，为纽约州立大学布法罗分校的本科生提供跨学科的研究机会，包括一些在STEM职业生涯中代表性不足的群体。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Qing Lin from State University of New York at Buffalo to use a phage-based method to evolve the alkyne-containing peptides for sequence-specific palladium-mediated cross-coupling reactions with aryl iodide reagents, as well as the cysteine-containing peptides for condensation reactions with nitrile-containing small-molecule probes. By exploiting biological techniques such as phage display, the reactivity of up to 600 billion peptide substrates containing unique chemical functional groups can be interrogated. The effect of the sequence of amino acids on the reactivity of the aforementioned peptides will be studied. The structural basis and mechanism of the two bioorthogonal reactions will be probed using kinetic and nuclear magnetic resonance (NMR) methods. The proposed research seeks to bring new chemical tools to the study of important biological problems. This project addresses important challenges in the development of organic reactions for applications inside living systems, namely the modest reaction rates and specificity of reactions at specific amino acids within peptides and proteins. The research will enhance our fundamental understanding of chemical reactivity in the biological environment, particularly as a function of the sequence of the peptides. The results of the research will be incorporated in courses taught by Dr. Lin. The project will provide interdisciplinary research opportunities to the undergraduate students at State University of New York at Buffalo, including some from the groups underrepresented in STEM careers, through a long-standing collaboration with the New York State Collegiate Science and Technology Entry Program.