Site-Specific Functionalization of Peptides by Cooperative Catalysis

With the support of the Chemical Catalysis Program in the Division of Chemistry, Dr. Masayuki Wasa of Boston College is developing non-natural catalysts with the goal of mimicking protease enzyme activity and selectively cleaving peptides at specific amide bonds. The ability to predictably break specific amide bonds in complex peptide structures would be a tour de force in biomimetic catalyst development and would provide important information about the principles underlying enzymatic catalysis. Dr. Wasa and his research team have designed catalysts that can activate acidic and basic groups simultaneously without reacting with each other. In this project, they are further developing this catalytic technology to mimic the spatial differentiation of active sites in enzymes and investigating new ways to cleave amide bonds in ways that are not easily achievable with naturally occurring protease enzymes. Dr. Wasa's team seeks to achieve a generalizable solution to this challenge. Dr. Wasa and his research group are also involved in outreach activities to promote engagement with STEM disciplines among diverse populations through internship programs for students and teachers from high schools in Boston and Brookline. Dr. Masayuki Wasa and his research group are developing “frustrated” Lewis acid/Bronsted base pair catalysts for the site-selective cleavage of polyfunctional peptides to access fragments that are difficult to form by known methods and have significant biological and chemical value. “Frustrated” Lewis acid/Bronsted base catalyst systems are being targeted for these reactions because they have the unique ability to increase the acidity of the amide functionalities towards deprotonation without undergoing self-quenching and the modularity to be tuned toward site-selective alcoholysis and hydrolysis. A diverse array of cyclic and acyclic peptide substrates are being explored in these studies, including complex peptide-based natural products whose structures have not been fully elucidated. These site-selective catalyst development activities are also serving as a training ground for a diverse group of graduate, undergraduate, and high school students. 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.