2. Academic Validation
  3. Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display

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

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.

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