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

被引：2

作者：

de Munnik, Mariska ^{[1
,2
]}

Lithgow, Jasper ^{[1
,2
]}

Brewitz, Lennart ^{[1
,2
]}

Christensen, Kirsten E. ^{[3
]}

Bates, Robert H. ^{[4
]}

Rodriguez-Miquel, Beatriz ^{[4
]}

Schofield, Christopher J. ^{[1
,2
]}

机构：

[1] Univ Oxford, Dept Chem, Chem Res Lab, 12 Mansfield Rd, Oxford OX1 3TA, England

[2] Univ Oxford, Ineos Oxford Inst Antimicrobial Res, 12 Mansfield Rd, Oxford OX1 3TA, England

[3] Univ Oxford, Dept Chem, Chem Res Lab, Chem Crystallog, 12 Mansfield Rd, Oxford OX1 3TA, England

[4] GlaxoSmithKline, Tres Cantos Med Dev Campus, Calle Severo Ochoa 2, Madrid, Spain

来源：

CHEMICAL COMMUNICATIONS | 2023年 / 59卷 / 86期

关键词：

IRREVERSIBLE INHIBITORS; PROTEASOME INHIBITOR; BETA-LACTAMASE; INACTIVATION; LDT(MT2); BINDING; DISCOVERY; PROTEINS; REVEALS;

D O I：

10.1039/d3cc02932h

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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

引用

页码：12859 / 12862

页数：4

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