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Proteome-wide covalent ligand discovery in native biological systems
Open accessAbstract
Small molecules are powerful tools for investigating protein function and can serve as leads for new therapeutics. Most human proteins, however, lack small-molecule ligands, and entire protein classes are considered 'undruggable'. Fragment-based ligand discovery can identify small-molecule probes for proteins that have proven difficult to target using high-throughput screening of complex compound libraries. Although reversibly binding ligands are commonly pursued, covalent fragments provide an alternative route to small-molecule probes, including those that can access regions of proteins that are difficult to target through binding affinity alone. Here we report a quantitative analysis of cysteine-reactive small-molecule fragments screened against thousands of proteins in human proteomes and cells. Covalent ligands were identified for >700 cysteines found in both druggable proteins and proteins deficient in chemical probes, including transcription factors, adaptor/scaffolding proteins, and uncharacterized proteins. Among the atypical ligand-protein interactions discovered were compounds that react preferentially with pro- (inactive) caspases. We used these ligands to distinguish extrinsic apoptosis pathways in human cell lines versus primary human T cells, showing that the former is largely mediated by caspase-8 while the latter depends on both caspase-8 and -10. Fragment-based covalent ligand discovery provides a greatly expanded portrait of the ligandable proteome and furnishes compounds that can illuminate protein functions in native biological systems.
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In the citing paper
“Although human CASP10 shares some degree of substrate specificity with CASP8 [317] and possibly contributes to extrinsic apoptosis in primary T cells [318]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [318]
In the citing paper
“Covalent inhibitors have been reported to achieve high efficiency through forming covalent bonds with cysteine or other nucleophilic residues in the target protein.”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [53]
In the citing paper
“Reactive cysteine residues on proteins have high nucleophilicity, which enables covalent binding with electrophilic small molecules [53, 54].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [53]
In the citing paper
“In this study, more than 700 ligandable cysteines were identified, and information was provided about the proteome-wide selectivity of each covalent fragment in the library.”
From Advances in covalent drug discovery (2022) · cites this paper as [180]
In the citing paper
“The use of competitive isoTOP-ABPP was expanded to identify proteome-wide targets of a small covalent fragment library by competing individual acrylamide and chloroacetamide fragments against an iodoacetamide–alkyne probe180.”
From Advances in covalent drug discovery (2022) · cites this paper as [180]
In the citing paper
“showing that this approach can rapidly identify compounds that target proteins of biological interest.”
From Advances in covalent drug discovery (2022) · cites this paper as [180]
In the citing paper
“The covalent ligands discovered with this approach and their corresponding ligandable sites were used to help elucidate the role of caspase 8 and caspase 10 in extrinsic apoptosis in T cells”
From Advances in covalent drug discovery (2022) · cites this paper as [180]
In the citing paper
“We finally observed limited overlap of enantioprobe targets with proteins that demonstrated ligandability in previous chemical proteomic studies using cysteine-26,27 or lysine-reactive28 electrophilic fragments (Fig. 3b)”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [26]
In the citing paper
“prior to further processing using a well-validated method for covalent ligand target identification—isotopic tandem orthogonal proteolysis ABPP (isoTOP-ABPP) 2,17,26.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [2]
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Profiling the proteome-wide selectivity of diverse electrophilesPreprint
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Advanced approaches of developing targeted covalent drugs
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Applications of Reactive Cysteine Profiling
Backus, K. M. (2018) · Current topics in microbiology and immunology · doi:10.1007/82_2018_120 · Cited by 39
Self-citationApplications of Activity‐Based Protein Profiling (ABPP) and Bioimaging in Drug Discovery
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Bianco, G., Goodsell, D. S., & Forli, S. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.10.005 · Cited by 40
“Reactive docking was initially developed to model cysteine modifications by acrylamide and chloroacetamide warheads [36], but virtually any chemical reaction can be modeled.”
BackgroundMethodSelf-citationChemoproteomic profiling of kinases in live cells using electrophilic sulfonyl triazole probes
Huang, T., Hosseinibarkooie, S., Borne, A. L., Granade, M. E., Brulet, J. W., Harris, T. E., Ferris, H. A., & Hsu, K. (2021) · Chemical Science · doi:10.1039/d0sc06623k · Cited by 42
Identification and selectivity profiling of small-molecule degraders via multi-omics approaches
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Bringing Vibrational Imaging to Chemical Biology with Molecular Probes
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Assessing the Performance of Screening MM/PBSA in Protein–Ligand Interactions
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Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action
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Optimization of Caged Electrophiles for Improved Monitoring of Cysteine Reactivity in Living Cells
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Global substrate specificity profiling of post‐translational modifying enzymes
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“Although beyond the scope of this review, large libraries of electrophile-containing compounds and fragments have been applied for identifying PTM enzyme inhibitors.(44,45)”
Proteomics and Beyond: Cell Decision-Making Shaped by Reactive Electrophiles
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“other variants[48, 49]) used in indirect profiling, and good MSsample-processing conditions including presence (and judicious choice) of a reducing agent to preserve aggregation-prone sensor proteins and labile RES-modifications.”
BackgroundMethodTargeting allosteric regulation of cancer metabolism
Kremer, D. M., & Lyssiotis, C. A. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-00997-6 · Cited by 43
Targeted Protein Degradation through Recruitment of the CUL4 Complex Adaptor Protein DDB1
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Self-citationProteomic Ligandability Maps of Spirocycle Acrylamide Stereoprobes Identify Covalent ERCC3 Degraders
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“Chemoproteomic technologies are now frequently used to elucidate the selectivity of covalent small molecules and are being applied with increasing regularity to enable the discovery of new ligandable proteins [23,24].”
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Self-citationProfiling Cysteine Reactivity and Oxidation in the Endoplasmic Reticulum
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“Fragment screening is therefore an unique and powerful method to discover new E3 ligases and new ligands of E3 ligases that can be artificially exploited to design MGDs and degrade neosubstrates [93].”
BackgroundDe novo design of covalent bonding peptides for target protein
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“6,7,13 More recently, we reported an even broader NHS-ester-alkyne chemoproteomics-compatible reactivity-based probe that reacts primarily with lysines, but also with serines, threonines, tyrosines, and other amino acids, where we showed that the reactivity of NHS-ester-based covalent ligands can…”
Fast and Bioorthogonal Release of Isocyanates in Living Cells from Iminosydnones and Cycloalkynes
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Metadata
- Authors
- Backus, K. M., Correia, B. E., Lum, K. M., Forli, S., Horning, B. D., González-Páez, G. E., Chatterjee, S., Lanning, B. R., Teijaro, J. R., Olson, A. J., Wolan, D. W., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Backus, Keriann M.
- Cravatt, Benjamin F.
- ORCID
- Venue
- Nature
- Published
- 2016-06-15
- Volume
- 534
- Issue
- 7608
- Pages
- 570-574
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4919207
- OpenAlex
- W2430132928
- Cited by
- 940
- References
- 43
- Citations by year
- 2026: 109 · 2025: 114 · 2024: 114 · 2023: 134 · 2022: 82 · 2021: 94 · 2020: 87 · 2019: 69 · 2018: 61 · 2017: 54 · 2016: 18
- FWCI
- 31.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (CA-087660, R37CA087660, R01CA087660)
- National Institute of General Medical Sciences (GM069832, GM-090294, GM108208, R01GM090294, F32GM108208, R01GM069832)
- 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 ligands, chemical probes, undruggable proteins, transcription factors, caspase-8, caspase-10, extrinsic apoptotic pathway, T cells, protein function
- MeSH terms
- Cells, Cultured, Cysteine, Drug Evaluation, Preclinical, Enzyme Precursors, Humans, Ligands, Peptide Fragments, T-Lymphocytes, Transcription Factors, Apoptosis, Proteome, Caspase 8, Caspase 10, Small Molecule Libraries
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