Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display.

Autor:	Lan T; Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States., Peng C; Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States., Yao X; Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States., Chan RST; Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States., Wei T; Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States., Rupanya A; Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States., Radakovic A; Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States., Wang S; Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, United States., Chen S; Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, United States., Lovell S; Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, United States., Snyder SA; Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States., Bogyo M; Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, United States.; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, United States., Dickinson BC; Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States.; Chan Zuckerberg Biohub, Chicago, Illinois 60642, United States.
Jazyk:	angličtina
Zdroj:	Journal of the American Chemical Society [J Am Chem Soc] 2024 Aug 28; Vol. 146 (34), pp. 24053-24060. Date of Electronic Publication: 2024 Aug 13.
DOI:	10.1021/jacs.4c07851
Abstrakt:	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.
Databáze:	MEDLINE
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