Activity-Based Hydrazine Probes for Protein Profiling of Electrophilic Functionality in Therapeutic Targets
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Most known probes for activity-based protein profiling (ABPP) use electrophilic groups that tag a single type of nucleophilic amino acid to identify cases in which its hyper-reactivity underpins function. Much important biochemistry derives from electrophilic enzyme cofactors, transient intermediates, and labile regulatory modifications, but ABPP probes for such species are underdeveloped. Here, we describe a versatile class of probes for this less charted hemisphere of the proteome. The use of an electron-rich hydrazine as the common chemical modifier enables covalent targeting of multiple, pharmacologically important classes of enzymes bearing diverse organic and inorganic cofactors. Probe attachment occurs by both polar and radicaloid mechanisms, can be blocked by molecules that occupy the active sites, and depends on the proper poise of the active site for turnover. These traits will enable the probes to be used to identify specific inhibitors of individual members of these multiple enzyme classes, making them uniquely versatile among known ABPP probes.
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Hydrazine-based probes have been used to identify and characterize ligands for proteins with electrophilic cofactors or post-translational modifications.
“Hydrazine-based probes have also been used to help identify and characterize ligands for proteins with electrophilic cofactors or post-translational modifications198,199.”
From Advances in covalent drug discovery (2022) · cites this paper as [199]
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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 · see citing works
Discovery of Potent and Selective Inhibitors against Protein-Derived Electrophilic Cofactors
Wang, X., Lin, Z., Bustin, K. A., McKnight, N. R., Parsons, W. H., & Matthews, M. L. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.1c12748 · Cited by 31 · see citing works
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- Authors
- Lin, Z., Wang, X., Bustin, K. A., Shishikura, K., McKnight, N. R., He, L., Suciu, R. M., Hu, K., Han, X., Ahmadi, M., Olson, E. J., Parsons, W. H., & Matthews, M. L.
- Affiliations
- University of Pennsylvania (US)
- Zenagem, LLC , , ,
- Scripps Research Institute (US)
- University of Massachusetts Chan Medical School (US)
- St. Jude Children's Research Hospital (US)
- Oberlin College (US)
- Corresponding author
- Matthews, Megan L.
- ORCID
- Venue
- ACS Central Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-08-19
- Volume
- 7
- Issue
- 9
- Pages
- 1524-1534
- ISSN
- 2374-7943 (ISSN-L)
- 2374-7951
- PMC
- PMC8461768
- OpenAlex
- W3195309302
- Cited by
- 43
- References
- 56
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 11 · 2023: 12 · 2022: 5 · 2021: 2
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- ACS Central Science (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Drug Abuse (1DP1DA051620)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- activity-based protein profiling, enzyme cofactors, covalent modification, polar mechanism, enzyme inhibitors, therapeutic target
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