Boronic Acid Methods for Chemical Manipulation of Biomacromolecules

在化学系生命过程化学（CLP）项目的支持下，莱斯大学的Zachary Ball教授正在研究复杂生物环境中的选择性化学反应。这些实验将寻求理解如何设计反应来操纵蛋白质的原子结构，使用反应设计和新型筛选方法的结合。复杂环境下的反应设计仍然具有挑战性，但化学修饰蛋白质制备方法的成功发展将有许多有益的应用。杂交或化学修饰的生物制剂是越来越重要的一类新药，这些分子被用作分子探针，以更好地了解生物功能，或作为“智能”响应软材料。该项目将整合外联工作，使当地高中生接触现代科学研究。高中科学教师科研经验是本项目的重要组成部分，有助于更广泛地传播现代化学研究的价值和激情。有了这种支持，莱斯大学的研究小组将探索硼酸的独特性质，以促进几个研究目标的选择性生物偶联。由于多肽是具有少数独特活性位点的多功能环境，因此有必要追求新的选择性方法。努力将探索新的方向，在一个正在进行的计划，设计金属催化途径与生物相容性硼酸试剂操纵蛋白质结构。首先，硼酸将作为新的C-C和C-X键形成的交叉偶联试剂进行研究，特别关注焦谷氨酸-组氨酸序列的显著和独特的反应性，使含蛋白质的大分子偶联物和纳米物体的一步构建无需二次生物偶联。其次，将研究硼酸-催化剂偶联物作为糖蛋白和多糖修饰的催化剂，基于硼酸酯与富羟基区域形成的动态共价化学到模板邻近驱动的反应性，这是一种选择含低聚糖结构的新方法。补充的推广工作旨在提高外行对这一令人兴奋和重要的跨学科研究领域的理解，并鼓励、培养和激励下一代研究人员。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professor Zachary Ball from Rice University is studying selective chemical reactions in complex biological environments. The experiments will seek to understand how to design reactions to manipulate the atomic structure of proteins, using a combination of reaction design and novel screening approaches. Reaction design in complex environments remains challenging, but successful development of methods for the preparation of chemically modified proteins would have numerous beneficial applications. Hybrid or chemically-modified biologics are increasingly important classes of new drugs, and these molecules find use as molecular probes to better understand biological function, or as “smart” responsive soft materials. The project will integrate outreach efforts to expose local high school students to modern scientific research. Research experiences for high school science teachers are an important component of this project and serve to more widely disseminate the value and excitement of modern chemical research. With this support, the Rice research team will explore the unique properties of boronic acids to facilitate selective bioconjugation in several research objectives. Because polypeptides are polyfunctional environments with few uniquely reactive sites, it becomes necessary to pursue novel approaches to selectivity. Efforts will explore new directions in an ongoing program to design metal-catalyzed pathways with biocompatible boronic acid reagents for manipulating protein structure. First, boronic acids will be examined as cross-coupling reagents for new C–C and C–X bond formation, focusing in particular on the remarkable and unique reactivity of pyroglutamate-histidine sequences to enable one-step construction of protein-containing macromolecular conjugates and nano-objects without the need for secondary bioconjugation. Second, boronic acid–catalyst conjugates will be investigated as catalysts for the modification of glycoproteins and polysaccharides, based on dynamic covalent chemistry of boronic ester formation with hydroxy-rich regions to template proximity-driven reactivity, a novel approach to selective chemistry for oligosaccharide-containing structures. Complementary outreach efforts are designed to improved lay understanding of this exciting and important field of interdisciplinary research, and also to encourage, nurture, and motivate the next generation of researchers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.