Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display

• Published in: Journal of the American Chemical Society 2024-08, Vol.146 (34), p.24053-24060
• Main Authors: Lan, Tong, Peng, Cheng, Yao, Xiyuan, Chan, Rachel Shu Ting, Wei, Tongyao, Rupanya, Anuchit, Radakovic, Aleksandar, Wang, Sijie, Chen, Shiyu, Lovell, Scott, Snyder, Scott A., Bogyo, Matthew, Dickinson, Bryan C.
• Format: Article
• Language: English
• Subjects: Cyclization; Drug Discovery; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Molecular Structure; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; RNA, Messenger - antagonists & inhibitors; Sulfides - chemistry; Sulfides - pharmacology; Sulfones - chemistry; Sulfones - pharmacology
• ISSN: 0002-7863; 1520-5126; 1520-5126
• 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.