Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display

Tong Lan, Cheng Peng, Xiyuan Yao, Rachel Shu Ting Chan, Tongyao Wei, Anuchit Rupanya, Aleksandar Radakovic, Sijie Wang, Shiyu Chen, Scott Lovell, Scott A Snyder, Matthew Bogyo, Bryan C Dickinson

Research output: Contribution to journalArticlepeer-review

1 Citation (SciVal)

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.

Original languageEnglish
Pages (from-to)24053-24060
Number of pages8
JournalJournal of the American Chemical Society
Volume146
Issue number34
Early online date13 Aug 2024
DOIs
Publication statusPublished - 28 Aug 2024

Funding

This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health NIH (R35 GM119840 to B.C.D). We thank S. Ahmadiantehrani for editing assistance and Y. Cao and R. Sinnott for technical assistance. We thank the University of Chicago Comprehensive Cancer Center DNA Sequencing and Genotyping Facility for sequencing services.

FundersFunder number
National Institute of General Medical Sciences
National Institutes of HealthR35 GM119840

    Keywords

    • RNA, Messenger/antagonists & inhibitors
    • Cyclization
    • Sulfides/chemistry
    • Peptides, Cyclic/chemistry
    • Macrocyclic Compounds/chemistry
    • Sulfones/chemistry
    • Drug Discovery
    • Protease Inhibitors/pharmacology
    • Molecular Structure

    ASJC Scopus subject areas

    • Catalysis
    • General Chemistry
    • Biochemistry
    • Colloid and Surface Chemistry

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