Reactive-cysteine profiling for drug discovery
Open accessAbstract
The recognition that only a small percentage of known human gene products are druggable using traditional modes of non-covalent ligand design, has led to a resurgence in targeted covalent inhibitors. Covalent inhibitors offer advantages over non-covalent inhibitors in engaging otherwise challenging targets. Reactive cysteine residues on proteins are a common target for covalent inhibitors, whereby the high nucleophilicity of the cysteine thiol under physiological conditions provides an ideal anchoring site for electrophilic small molecules. A chemical-proteomic platform, termed isoTOP-ABPP, allows for profiling cysteine reactivity in complex proteomes and is one of many techniques that can aid in two aspects of the covalent-inhibitor development process: (1) to identify functional cysteines that lead to modulation of protein activity through covalent modification; and, (2) to determine cellular targets and evaluate promiscuity of electrophilic fragments, small molecules, and natural products. Herein, we discuss recent advances in isoTOP-ABPP and potential applications of this technology in the drug-discovery pipeline.
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The isoTOP-ABPP method is limited by the range of identifiable cellular cysteines and cannot evaluate the selectivity of compound in the total cellular cysteinome.
“For example, the isoTOP-ABPP method is limited by the range of identifiable cellular cysteines and cannot evaluate the selectivity of compound in the total cellular cysteinome.”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [64]
Chemoproteomic platforms enable rapid target identification and selectivity profiling of covalent ligands.
“This ‘electrophile-first’ approach is partly facilitated by the development of chemoproteomic platforms that enable rapid target identification and selectivity profiling of covalent ligands14–18.”
From Advances in covalent drug discovery (2022) · cites this paper as [18]
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- Authors
- Maurais, A. J., & Weerapana, E.
- Affiliations
- Boston College (US)
- Corresponding author
- Weerapana, Eranthie
- Venue
- Current Opinion in Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 50
- Pages
- 29-36
- ISSN
- 1367-5931 (ISSN-L)
- PMC
- PMC6584045
- OpenAlex
- W2923145509
- Cited by
- 167
- References
- 58
- Citations by year
- 2026: 19 · 2025: 29 · 2024: 18 · 2023: 31 · 2022: 24 · 2021: 22 · 2020: 18 · 2019: 6
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Opinion in Chemical Biology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1R01GM117004, 1R01GM118431-01A1)
- 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 › Chemical Synthesis and Analysis
- Keywords
- covalent inhibitors, targeted covalent inhibitors, covalent protein modification, chemoproteomics, druggable targets, natural products, drug discovery
- MeSH terms
- Cysteine, Humans, Drug Discovery, High-Throughput Screening Assays
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