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