Abstract 1598 Targeting prolyl endopeptidase with cysteine-reactive covalent inhibitors

Prolyl endopeptidase (PREP) is a serine protease that cleaves C-terminal to proline residues and has been implicated in neurodegeneration and cancer. PREP activity is regulated by dynamics-exchanging between an open and closed conformation-that limits substrate entrance into the active site. Modulation of these dynamics presents itself as an attractive avenue for drug design. While PREP inhibitors have been reported, many are proline-containing peptide mimetics, which may potentially lead to off-target effects.