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αβ,α′β′-Diepoxyketones are mechanism-based inhibitors of nucleophilic cysteine enzymes

DOI: 10.1039/D3CC02932H DOI Help

Authors: Mariska De Munnik (University of Oxford) , Jasper Lithgow (University of Oxford) , Lennart Brewitz (University of Oxford) , Kirsten E. Christensen (University of Oxford) , Robert H. Bates (University of Oxford) , Beatriz Rodriguez-Miquel (GlaxoSmithKline) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Chemical Communications , VOL 59 , PAGES 12859 - 12862

State: Published (Approved)
Published: October 2023
Diamond Proposal Number(s): 23459

Open Access Open Access

Abstract: Epoxides are an established class of electrophilic alkylating agents that react with nucleophilic protein residues. We report αβ,α′β′-diepoxyketones (DEKs) as a new type of mechanism-based inhibitors of nucleophilic cysteine enzymes. Studies with the L,D-transpeptidase LdtMt2 from Mycobacterium tuberculosis and the main protease from SARS-CoV-2 (Mpro) reveal that following epoxide ring opening by a nucleophilic cysteine, further reactions can occur, leading to irreversible alkylation.

Diamond Keywords: Enzymes; COVID-19; Tuberculosis (TB); Bacteria; Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 27/11/2023 11:11

Documents:
d3cc02932h.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)