&#945;ß,&#945;'ß'-Diepoxyketones are mechanism-based inhibitors of nucleophilic cysteine enzymes.

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

αß,α'ß'-Diepoxyketones are mechanism-based inhibitors of nucleophilic cysteine enzymes.

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

Afiliação

de Munnik M; Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute of Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. christopher.schofield@chem.ox.ac.uk.
Lithgow J; Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute of Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. christopher.schofield@chem.ox.ac.uk.
Brewitz L; Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute of Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. christopher.schofield@chem.ox.ac.uk.
Christensen KE; Chemical Crystallography, Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Bates RH; Tres Cantos Medicines Development Campus, GlaxoSmithKline, Calle Severo Ochoa 2, Tres Cantos, Madrid, Spain.
Rodriguez-Miquel B; Tres Cantos Medicines Development Campus, GlaxoSmithKline, Calle Severo Ochoa 2, Tres Cantos, Madrid, Spain.
Schofield CJ; Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute of Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. christopher.schofield@chem.ox.ac.uk.

Chem Commun (Camb) ; 59(86): 12859-12862, 2023 Oct 26.

Article em En | MEDLINE | ID: mdl-37815791

ABSTRACT

ABSTRACT

Epoxides are an established class of electrophilic alkylating agents that react with nucleophilic protein residues. We report αß,α'ß'-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.

Assuntos

Cisteína; Mycobacterium tuberculosis; Inibidores de Proteases

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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cisteína / Mycobacterium tuberculosis Idioma: En Revista: Chem Commun (Camb) Assunto da revista: QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Reino Unido

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