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

Luís A.R. Carvalho, Vanessa T. Almeida, José A. Brito, Kenneth M. Lum, Tânia F. Oliveira, Rita C. Guedes, Lídia M. Gonçalves, Susana D. Lucas, Benjamin F. Cravatt, Margarida Archer, Rui Moreira

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)878-883
Number of pages6
JournalACS Chemical Biology
Volume15
Issue number4
DOIs
Publication statusPublished - 17 Apr 2020

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