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
收藏
页码：12859 / 12862
页数：4
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