An electroaffinity labelling platform for chemoproteomic-based target identification

• Published in: Nature chemistry Vol. 15; no. 9; pp. 1267 - 1275
• Main Authors: Kawamata, Yu, Ryu, Keun Ah, Hermann, Gary N., Sandahl, Alexander, Vantourout, Julien C., Olow, Aleksandra K., Adams, La-Tonya A., Rivera-Chao, Eva, Roberts, Lee R., Gnaim, Samer, Nassir, Molhm, Oslund, Rob C., Fadeyi, Olugbeminiyi O., Baran, Phil S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2023; Nature Publishing Group
• Subjects: 639/638/549; 639/638/92/555; Alternative technology; Analytical Chemistry; Biochemistry; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Covalence; Electrochemistry; Functional groups; Identification; Inorganic Chemistry; Labeling; Labels; Ligands; Organic Chemistry; Pharmacophores; Photoaffinity labeling; Physical Chemistry; Proteins; Target recognition; Ultraviolet radiation
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/s41557-023-01240-y

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. The covalent capture of a ligand by its target protein(s) is important for drug-target identification. Now an electrochemically active warhead—diazetidinone—can be leveraged in a chemoproteomics platform for electroaffinity labelling of a ligand’s target protein to afford target-ligand identification in live cells.