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

Mariska de Munnik, Jasper Lithgow, Lennart Brewitz, Kirsten E Christensen, Robert H Bates, Beatriz Rodriguez-Miquel, Christopher J Schofield

Chemical communications (Cambridge, England) 2023 Oct 26

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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.

Citation

Mariska de Munnik, Jasper Lithgow, Lennart Brewitz, Kirsten E Christensen, Robert H Bates, Beatriz Rodriguez-Miquel, Christopher J Schofield. αβ,α'β'-Diepoxyketones are mechanism-based inhibitors of nucleophilic cysteine enzymes. Chemical communications (Cambridge, England). 2023 Oct 26;59(86):12859-12862