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Advanced approaches of developing targeted covalent drugs

Lookup NU author(s): Dr Suzannah HarnorORCiD, Dr Celine CanoORCiD



This is the authors' accepted manuscript of an article that has been published in its final definitive form by Royal Society of Chemistry, 2022.

For re-use rights please refer to the publisher's terms and conditions.


© 2022 RSC. 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.

Publication metadata

Author(s): Gai C, Harnor SJ, Zhang S, Cano C, Zhuang C, Zhao Q

Publication type: Article

Publication status: Published

Journal: RSC Medicinal Chemistry

Year: 2022

Volume: 13

Issue: 12

Pages: 1460-1475

Print publication date: 01/12/2022

Online publication date: 11/10/2022

Acceptance date: 20/09/2022

Date deposited: 12/12/2022

ISSN (electronic): 2632-8682

Publisher: Royal Society of Chemistry


DOI: 10.1039/d2md00216g

ePrints DOI: 10.57711/s4jc-b767


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