Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Chemistry, Medicinal, Pharmacology & Pharmacy, activity-based protein profiling, beta-lactams, covalent inhibitors, intramembrane proteases, protease inhibitors, SERINE HYDROLASE ACTIVITIES, COMPLEX, MECHANISM, POTENT, AZETIDINE-2,4-DIONES, BENZOXAZIN-4-ONES, SPECIFICITY, DISCOVERY, CATALYSIS, INVASION, beta-Lactams, Endopeptidases, Serine Proteases, 0304 Medicinal and Biomolecular Chemistry, 0601 Biochemistry and Cell Biology, Organic Chemistry, 3101 Biochemistry and cell biology, 3404 Medicinal and biomolecular chemistry

Abstract:

Intramembrane serine proteases (rhomboid proteases) are involved in a variety of biological processes and are implicated in several diseases. Here, we report 4-oxo-β-lactams as a novel scaffold for inhibition of rhomboids. We show that they covalently react with the active site and that the covalent bond is sufficiently stable for detection of the covalent rhomboid-lactam complex. 4-Oxo-β-lactams may therefore find future use as both inhibitors and activity-based probes for rhomboid proteases.