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

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.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Carvalho LAR,Almeida VT,Brito JA,Lum KM,Oliveira TF,Guedes RC,Gonçalves LM,Lucas SD,Cravatt BF,Archer M,Moreira R

doi

10.1021/acschembio.0c00090

subject

Has Abstract

pub_date

2020-04-17 00:00:00

pages

878-883

issue

4

eissn

1554-8929

issn

1554-8937

journal_volume

15

pub_type

杂志文章

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