Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display
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.
Authors
- Bryan C. Dickinson (ORCID: https://orcid.org/0000-0002-9616-1911)
- Aleksandar Radakovic (ORCID: https://orcid.org/0000-0003-3794-3822)
- Matthew S. Bogyo (ORCID: https://orcid.org/0000-0003-3753-4412)
- Xiyuan Yao (ORCID: https://orcid.org/0000-0002-2331-0023)
- Tongyao Wei (ORCID: https://orcid.org/0000-0002-0602-6979)
- S. Lovell (ORCID: https://orcid.org/0000-0002-9627-5679)
- Tong Lan (ORCID: https://orcid.org/0000-0003-3923-5408)
- Scott A. Snyder (ORCID: https://orcid.org/0000-0003-3594-8769)
- Anuchit Rupanya (ORCID: https://orcid.org/0009-0001-1088-4212)
- Shiyu Chen (ORCID: https://orcid.org/0000-0001-6578-561X)
- Sijie Wang (ORCID: https://orcid.org/0009-0005-8338-3303)
- Cheng Peng (ORCID: https://orcid.org/0000-0001-5680-1024)
- R. Chan
Institutions
- University of Chicago (US)
- Chan Zuckerberg Initiative (United States) (US)
- Chan Zuckerberg Biohub Chicago
- Stanford University (US)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2024-08-13
- DOI
- https://doi.org/10.1021/jacs.4c07851
- Citations
- 18
- Primary Topic
- Click Chemistry and Applications
- Type
- article
- Field-Weighted Citation Impact
- 4.50
Funders
- National Institutes of Health
- National Institute of General Medical Sciences