期刊
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 88
卷 88, 期 -, 页码 365-381出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev-biochem-061516-044805
关键词
aldehyde; sulfonyl fluoride; chemoproteomics; kinase; reversible covalent
资金
- NCI NIH HHS [F31 CA214028] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007618] Funding Source: Medline
Covalent inhibitors are widely used in drug discovery and chemical biology. Although covalent inhibitors are frequently designed to react with noncatalytic cysteines, many ligand binding sites lack an accessible cysteine. Here, we review recent advances in the chemical biology of lysine-targeted covalent inhibitors and chemoproteomic probes. By analyzing crystal structures of proteins bound to common metabolites and enzyme cofactors, we identify a large set of mostly unexplored lysines that are potentially targetable with covalent inhibitors. In addition, we describe mass spectrometry-based approaches for determining proteome-wide lysine ligandability and lysinereactive chemoproteomic probes for assessing drug-target engagement. Finally, we discuss the design of amine-reactive inhibitors that form reversible covalent bonds with their protein targets.
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