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

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 Ldt Mt2 from Mycobacterium...

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Bibliographic Details
Published in:Chemical communications (Cambridge, England) England), 2023-10, Vol.59 (86), p.12859-12862
Main Authors: de Munnik, Mariska, Lithgow, Jasper, Brewitz, Lennart, Christensen, Kirsten E, Bates, Robert H, Rodriguez-Miquel, Beatriz, Schofield, Christopher J
Format: Article
Language:English
Subjects:
Alkylation
Chemistry
Cysteine
Enzymes
Inhibitors
Ring opening
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Summary: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 Ldt Mt2 from Mycobacterium tuberculosis and the main protease from SARS-CoV-2 (M pro ) reveal that following epoxide ring opening by a nucleophilic cysteine, further reactions can occur, leading to irreversible alkylation. αβ,α′β′-Diepoxyketones (DEKs) inhibit nucleophilic cysteine enzymes. DEKs react with a transpeptidase and the SARS-CoV-2 main protease via epoxide opening; retro-aldol and other reactions can then occur, enabling irreversible alkylation.
ISSN:1359-7345
1364-548X
DOI:10.1039/d3cc02932h