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Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display.
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.
Affiliation
  • 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.
  • Dickinson BC; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, United States.
J Am Chem Soc ; 146(34): 24053-24060, 2024 Aug 28.
Article in En | MEDLINE | ID: mdl-39136646
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: RNA, Messenger Language: En Journal: J Am Chem Soc Year: 2024 Document type: Article Affiliation country: United States Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: RNA, Messenger Language: En Journal: J Am Chem Soc Year: 2024 Document type: Article Affiliation country: United States Country of publication: United States