4‑Oxo-β-lactams\nas Covalent Inhibitors\nof the Mitochondrial Intramembrane Protease PARL

Rhomboid proteases play a variety of physiological roles,\nbut rhomboid\nprotease inhibitors have been mostly developed for the <i>E.\ncoli</i> model rhomboid GlpG. In this work, we screened different\nelectrophilic scaffolds against the human mitochondrial rhomboid PARL\nand found 4-oxo-β-lactams as submicromolar inhibitors. Multifaceted\ncomputations suggest explanations for the activity at the molecular\nscale and provide models of covalently bound complexes. Together with\nthe straightforward synthesis of the 4-oxo-β-lactam scaffold,\nthis may pave the way toward selective, nonpeptidic PARL inhibitors.