An electroaffinity labelling platform for chemoproteomic-based target identification

Yu Kawamata, Keun Ah Ryu, Gary N. Hermann, Alexander Sandahl, Julien C. Vantourout, Aleksandra K. Olow, La Tonya A. Adams, Eva Rivera-Chao, Lee R. Roberts, Samer Gnaim, Molhm Nassir, Rob C. Oslund*, Olugbeminiyi O. Fadeyi*, Phil S. Baran*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Target identification involves deconvoluting the protein target of a pharmacologically active, small-molecule ligand, a process that is critical for early drug discovery yet technically challenging. Photoaffinity labelling strategies have become the benchmark for small-molecule target deconvolution, but covalent protein capture requires the use of high-energy ultraviolet light, which can complicate downstream target identification. Thus, there is a strong demand for alternative technologies that allow for controlled activation of chemical probes to covalently label their protein target. Here we introduce an electroaffinity labelling platform that leverages the use of a small, redox-active diazetidinone functional group to enable chemoproteomic-based target identification of pharmacophores within live cell environments. The underlying discovery to enable this platform is that the diazetidinone can be electrochemically oxidized to reveal a reactive intermediate useful for covalent modification of proteins. This work demonstrates the electrochemical platform to be a functional tool for drug-target identification. [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)1267-1275
Number of pages9
JournalNature Chemistry
Issue number9
StatePublished - Sep 2023
Externally publishedYes


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