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 language | English |
---|---|
Pages (from-to) | 24053-24060 |
Number of pages | 8 |
Journal | Journal of the American Chemical Society |
Volume | 146 |
Issue number | 34 |
Early online date | 13 Aug 2024 |
DOIs | |
Publication status | Published - 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.
Funders | Funder number |
---|---|
National Institute of General Medical Sciences | |
National Institutes of Health | R35 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