The DOI matches its Crossref record; 74 of the 74 references it cites were found in a registry or an index.
Profiling the Proteome-Wide Selectivity of Diverse Electrophiles
Open accessPreprint — published as 10.1038/s41557-025-01902-z
Abstract
Targeted covalent inhibitors are powerful entities in drug discovery, but their application has so far mainly been limited to addressing cysteine residues. The development of cysteine-directed covalent inhibitors has largely profited from determining their proteome-wide selectivity using competitive residue-specific proteomics. Several probes have recently been described to monitor other amino acids using this technology and many more electrophiles exist to modify proteins. Nevertheless, a direct, proteome‑wide comparison of the selectivity of diverse probes is still entirely missing. Here, we developed a completely unbiased workflow to analyse electrophile selectivity proteome‑wide and applied it to directly compare 54 alkyne probes containing diverse reactive groups. In this way, we verified and newly identified probes to monitor a total of nine different amino acids as well as the N ‑terminus proteome‑wide. This selection includes the first probes to globally monitor tryptophans, histidines and arginines as well as novel tailored probes for methionines, aspartates and glutamates.
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“A recent preprint reported the use of a chemoproteomic approach to profile the amino acid reactivity preference of 54 different electrophiles, which will prove to be a great resource for covalent ligand discovery210.”
From Advances in covalent drug discovery (2022) · cites this paper as [210]
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Self-citationA statistical model for identifying proteins by tandem mass spectrometry.
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Self-citationMSFragger: ultrafast and comprehensive peptide identification in mass spectrometry–based proteomics
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Quantitative reactivity profiling predicts functional cysteines in proteomes
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Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry
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Advances in covalent drug discovery
Boike, L., Henning, N. J., & Nomura, D. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00542-z · Cited by 823
Metadata
- Authors
- Zanon, P. R. A., Yu, F., Musacchio, P., Lewald, L., Zollo, M., Krauskopf, K., Mrdović, D., Raunft, P., Maher, T. E., Cigler, M., Chang, C., Lang, K., Toste, F. D., Nesvizhskii, A. I., & Hacker, S. M.
- Affiliations
- Technical University of Munich (DE)
- University of Michigan (US)
- University of California, Berkeley (US)
- ORCID
- Venue
- ChemRxiv
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-03-10
- ISSN
- 2573-2293 (ISSN-L)
- OpenAlex
- W3138203650
- Cited by
- 35
- References
- 74
- Citations by year
- 2025: 6 · 2024: 6 · 2023: 10 · 2022: 5 · 2021: 8
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- Royal College of Surgeons in Ireland (submittedVersion, cc-by-nc-nd)
- Funders
- American Cancer Society (PF-18-132-01-CDD)
- Deutsche Forschungsgemeinschaft (SFB 1035, Project B10, 201302640)
- École Polytechnique Fédérale de Lausanne
- Studienstiftung des Deutschen Volkes
- Technische Universität München
- National Institutes of Health
- Novartis Institutes for BioMedical Research
- National Cancer Institute (U24CA210967)
- National Institute of General Medical Sciences (R01GM139245, R01GM094231)
- National Institute of Environmental Health Sciences (R01ES028096)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- covalent inhibitors, targeted covalent inhibitors, proteome-wide profiling, tryptophan, histidine, L-arginine, methionine, aspartic acid, glutamate, N-terminus, protein modification
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