3‑Oxo-β-sultam as a Sulfonylating Chemotype for Inhibition of Serine Hydrolases and Activity-Based Protein Profiling

3-Oxo-β-sultams
are four-membered ring ambident electrophiles
that can react with nucleophiles either at the carbonyl carbon or
at the sulfonyl sulfur atoms, and that have been reported to inhibit
serine hydrolases via acylation of the active-site serine residue.
We have developed a panel of 3-oxo-β-sultam inhibitors and show,
through crystallographic data, that they are regioselective sulfonylating
electrophiles, covalently binding to the catalytic serine of human
and porcine elastases through the sulfur atom. Application of 3-oxo-β-sultam-derived
activity-based probes in a human proteome revealed their potential
to label disease-related serine hydrolases and proteasome subunits.
Activity-based protein profiling applications of 3-oxo-β-sultams
should open up new opportunities to investigate these classes of enzymes
in complex proteomes and expand the toolbox of available sulfur-based
covalent protein modifiers in chemical biology.