Boronic Acid Methods for Chemical Manipulation of Biomacromolecules

William Marsh Rice University, Houston TX

Investigators

Abstract

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.