Issue 12, 2022

Advanced approaches of developing targeted covalent drugs

Abstract

In recent years, the development of targeted covalent inhibitors has gained popularity around the world. Specific groups (electrophilic warheads) form irreversible bonds with the side chain of nucleophilic amino acid residues, thus changing the function of biological targets such as proteins. Since the first targeted covalent inhibitor was disclosed in the 1990s, great efforts have been made to develop covalent ligands from known reversible leads or drugs by addition of tolerated electrophilic warheads. However, high reactivity and “off-target” toxicity remain challenging issues. This review covers the concept of targeted covalent inhibition to diseases, discusses traditional and interdisciplinary strategies of cysteine-focused covalent drug discovery, and exhibits newly disclosed electrophilic warheads majorly targeting the cysteine residue. Successful applications to address the challenges of designing effective covalent drugs are also introduced.

Graphical abstract: Advanced approaches of developing targeted covalent drugs

Article information

Article type
Review Article
Submitted
08 srp 2022
Accepted
20 ruj 2022
First published
11 lis 2022

RSC Med. Chem., 2022,13, 1460-1475

Advanced approaches of developing targeted covalent drugs

C. Gai, S. J. Harnor, S. Zhang, C. Cano, C. Zhuang and Q. Zhao, RSC Med. Chem., 2022, 13, 1460 DOI: 10.1039/D2MD00216G

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