Global profiling of arginine reactivity and ligandability in the human proteome
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Abstract
Despite the crucial biological functions of arginine, its reactivity and ligandability within the human proteome remain largely unexplored. Here we apply activity-based protein profiling (ABPP) with phenylglyoxal-based chemical probes to map arginine reactivity globally. Screening phenylglyoxal derivatives identified a probe with enhanced coverage and selectivity, enabling quantification of 4,606 arginine sites across human cell lines. Among these, critical residues regulate liquid-liquid phase separation. Arginine reactivity was further assessed by on-beads reductive dimethylation proteomics, revealing a subset of hyper-reactive sites. Competitive fragment screening using data-independent acquisition ABPP (DIA-ABPP) generated a ligandability map of arginine residues across 60 dicarbonyl compounds. This dataset revealed ligandable arginines that modulate protein activity, in particular protein-protein interactions, highlighting potential covalent drug targets. Together, this work provides a proteome-wide profile of arginine reactivity and ligandability, offering insights into the functional landscape of arginines and expanding the scope of covalent drug discovery to include arginine-targeting molecules.
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Chemoproteomics in covalent cancer drug discovery
Ong, J.-P., Dalziel, M., Johns, D., Zhu, J., & Bertoldo, J. B. (2026) · Drug Discovery Today · doi:10.1016/j.drudis.2026.104817
- Authors
- Wang, Y., Hu, T., Zhu, L., Xie, S., Yang, X., Xu, C., Zhai, Y., Li, Y., Huang, X., Yang, B., & Li, G.
- Affiliations
- Shenzhen Bay Laboratory (CN)
- University of Electronic Science and Technology of China (CN)
- Northwest A&F University (CN)
- Corresponding author
- Li, Gang
- Venue
- Nature Chemistry
- Published
- 2026-01-02
- Volume
- 18
- Issue
- 2
- Pages
- 374-385
- ISSN
- 1755-4330 (ISSN-L)
- 1755-4349
- OpenAlex
- W7117999367
- Cited by
- 12
- References
- 75
- Citations by year
- 2026: 12
- FWCI
- 21.33
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Chemistry (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- human proteome, activity-based protein profiling, dicarbonyl compounds, liquid-liquid phase separation, protein-protein interaction, protein function regulation
- MeSH terms
- Arginine, Humans, Ligands, Proteome, Proteomics
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