Identification of highly selective covalent inhibitors by phage display.

ABSTRACT: Molecules that covalently bind macromolecular targets have found widespread applications as activity-based probes and as irreversibly binding drugs. However, the general reactivity of the electrophiles needed for covalent bond formation makes control of selectivity difficult. There is currently no rapid, unbiased screening method to identify new classes of covalent inhibitors from highly diverse pools of candidate molecules. Here we describe a phage display method to directly screen for ligands that bind to protein targets through covalent bond formation. This approach makes use of a reactive linker to form cyclic peptides on the phage surface while simultaneously introducing an electrophilic 'warhead' to covalently react with a nucleophile on the target. Using this approach, we identified

SUBMITTER: Chen S 

PROVIDER: S-EPMC8043995 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature