Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display

  • J Am Chem Soc. 2024 Aug 28;146(34):24053-24060. doi: 10.1021/jacs.4c07851.
Tong Lan  1 ,  Cheng Peng  1 ,  Xiyuan Yao  1 ,  Rachel Shu Ting Chan  1 ,  Tongyao Wei  1 ,  Anuchit Rupanya  1 ,  Aleksandar Radakovic  1 ,  Sijie Wang  2 ,  Shiyu Chen  2 ,  Scott Lovell  2 ,  Scott A Snyder  1 ,  Matthew Bogyo  2  3 ,  Bryan C Dickinson  1  4
Affiliations
  • 1. Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States.
  • 2. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, United States.
  • 3. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, United States.
  • 4. Chan Zuckerberg Biohub, Chicago, Illinois 60642, United States.
PMID: 39136646 DOI: 10.1021/jacs.4c07851
Abstract

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.