Tong Lan, Cheng Peng, Xiyuan Yao, Rachel Shu Ting Chan, Tongyao Wei, Anuchit Rupanya, Aleksandar Radakovic, Sijie Wang, Shiyu Chen, Scott Lovell, Scott A. Snyder, Matthew Bogyo, and Bryan C. Dickinson
Journal of the American Chemical Society 2024
DOI: 10.1021/jacs.4c07851
Macrocyclic peptides are promising scaffolds for the covalent ligand discovery. However, platforms enabling the direct identification of covalent macrocyclic ligands in a high-throughput manner are limited. In this study, we present an mRNA display platform allowing selection of covalent macrocyclic inhibitors using 1,3-dibromoacetone-vinyl sulfone (DBA-VS). Testcase selections on TEV protease resulted in potent covalent inhibitors with diverse cyclic structures, among which cTEV6-2, a macrocyclic peptide with a unique C-terminal cyclization, emerged as the most potent covalent inhibitor of TEV protease described to-date. This study outlines the workflow for integrating chemical functionalization─installation of a covalent warhead─with mRNA display and showcases its application in targeted covalent ligand discovery.
