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3-Oxo-β-sultam as a sulfonylating chemotype for inhibition of serine hydrolases and activity-based protein profiling

DOI: 10.1021/acschembio.0c00090 DOI Help

Authors: Luís A. R. Carvalho (Universidade de Lisboa) , Vanessa T. Almeida (Universidade Nova de Lisboa (ITQB NOVA)) , Jose A. Brito (Universidade Nova de Lisboa (ITQB NOVA)) , Kenneth M. Lum (The Scripps Research Institute) , Tânia F. Oliveira (Universidade Nova de Lisboa (ITQB NOVA)) , Rita C. Guedes (Universidade de Lisboa) , Lídia M. Gonçalves (Universidade de Lisboa) , Susana D. Lucas (Universidade de Lisboa) , Benjamin F. Cravatt (The Scripps Research Institute) , Margarida Archer (Universidade Nova de Lisboa (ITQB NOVA)) , Rui Moreira (Universidade de Lisboa)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: March 2020
Diamond Proposal Number(s): 20161

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 Keywords: Peptides and proteins; Monomers; Labeling; Inhibitors; Probes

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: ESRF