Discovering covalent cyclic peptide inhibitors of peptidyl arginine deiminase 4 (PADI4) using mRNA-display with a genetically encoded electrophilic warhead.

ABSTRACT: Covalent drugs can achieve high potency with long dosing intervals. However, concerns remain about side-effects associated with off-target reactivity. Combining macrocyclic peptides with covalent warheads provides a solution to minimise off-target reactivity: the peptide enables highly specific target binding, positioning a weakly reactive warhead proximal to a suitable residue in the target. Here we demonstrate the direct discovery of covalent cyclic peptides using encoded libraries containing a weakly electrophilic cysteine-reactive fluoroamidine warhead. We combine direct incorporation of the warhead into peptide libraries using the flexible in vitro translation system with a peptide selection approach that identifies only covalent target binders. Using this approach, we identify potent

SUBMITTER: Mathiesen IR 

PROVIDER: S-EPMC11659602 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature