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

doi:10.1038/s41557-023-01240-y

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

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

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 language	English
Pages (from-to)	1267-1275
Number of pages	9
Journal	Nature Chemistry
Volume	15
Issue number	9
Early online date	15 Jun 2023
DOIs	https://doi.org/10.1038/s41557-023-01240-y
State	Published - Sep 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

The work was supported by the National Science Foundation Center for Synthetic Organic Electrochemistry CHE-2002158 (exploration and development of electrochemically active functional group), National Institutes of Health grant GM-118176 (synthesis of elaborated probes for biological studies) and gifts from Merck & Co., Inc., Kenilworth, NJ, USA (synthesis of elaborated probes for biological studies). G.N.H. was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), grant numbers 419055018/HE 8427/1-1. A.F.S. was supported by the Lundbeck Foundation (grant number R208-2015-3354), E.R.-C. was supported by the Galician Programme for Research, Innovation and Growth for 2018. We thank D.-H. Huang and L. Pasternack (Scripps Research) for assistance with NMR spectroscopy; and J. Chen, B. Sanchez and E. Sturgell (Automated Synthesis Facility, Scripps Research) for purification of compounds and acquisition of HRMS data. We thank T. Wyche (Merck & Co., Inc.) for assistance with HRMS data, S. Ingale (Merck & Co., Inc.) for assistance with peptide synthesis, and J. Oh (Merck & Co., Inc.) for helpful discussions. The work was supported by the National Science Foundation Center for Synthetic Organic Electrochemistry CHE-2002158 (exploration and development of electrochemically active functional group), National Institutes of Health grant GM-118176 (synthesis of elaborated probes for biological studies) and gifts from Merck & Co., Inc., Kenilworth, NJ, USA (synthesis of elaborated probes for biological studies). G.N.H. was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), grant numbers 419055018/HE 8427/1-1. A.F.S. was supported by the Lundbeck Foundation (grant number R208-2015-3354), E.R.-C. was supported by the Galician Programme for Research, Innovation and Growth for 2018. We thank D.-H. Huang and L. Pasternack (Scripps Research) for assistance with NMR spectroscopy; and J. Chen, B. Sanchez and E. Sturgell (Automated Synthesis Facility, Scripps Research) for purification of compounds and acquisition of HRMS data. We thank T. Wyche (Merck & Co., Inc.) for assistance with HRMS data, S. Ingale (Merck & Co., Inc.) for assistance with peptide synthesis, and J. Oh (Merck & Co., Inc.) for helpful discussions.

Funders	Funder number
National Science Foundation Center for Synthetic Organic Electrochemistry	CHE-2002158
National Institutes of Health	GM-118176
Merck
Deutsche Forschungsgemeinschaft	419055018/HE 8427/1-1
Lundbeck Foundation	R208-2015-3354

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Cite this

Kawamata, Y., Ryu, K. A., Hermann, G. N., Sandahl, A., Vantourout, J. C., Olow, A. K., Adams, L. T. A., Rivera-Chao, E., Roberts, L. R., Gnaim, S., Nassir, M., Oslund, R. C., Fadeyi, O. O., & Baran, P. S. (2023). An electroaffinity labelling platform for chemoproteomic-based target identification. Nature Chemistry, 15(9), 1267-1275. https://doi.org/10.1038/s41557-023-01240-y

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abstract = "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.].",

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AU - Olow, Aleksandra K.

AU - Adams, La Tonya A.

AU - Rivera-Chao, Eva

AU - Roberts, Lee R.

AU - Gnaim, Samer

AU - Nassir, Molhm

AU - Oslund, Rob C.

AU - Fadeyi, Olugbeminiyi O.

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An electroaffinity labelling platform for chemoproteomic-based target identification

Abstract

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