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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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Julio, A. R., Shikwana, F., Truong, C. C., Burton, N. R., Dominguez, E. R., Turmon, A. C., Cao, J. X., & Backus, K. M. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01760-9 · Cited by 23
“The presence of many putative ligandable cysteines in nsp14 was unexpected, as previous studies had revealed that generally only a small fraction of proteinaceous cysteines in a given protein sequence are ligandable 2,5,7 .”
Self-citationGibaut, Q. M. R., Bush, J. A., Tong, Y., Baisden, J. T., Taghavi, A., Olafson, H. R., Yao, X., Childs‐Disney, J. L., Wang, E. T., & Disney, M. D. (2023) · ACS Central Science · doi:10.1021/acscentsci.2c01223 · Cited by 24
Wan, C., Yang, D., Song, C., Liang, M., An, Y., Lian, C., Dai, C., Ye, Y., Yin, F., Wang, R. Y., et al. (2024) · Chemical Science · doi:10.1039/d3sc05766f · Cited by 24
Machine Learning Models to Interrogate Proteome-Wide Covalent Ligandabilities Directed at Cysteines
Liu, R., Clayton, J., Shen, M., Bhatnagar, S., & Shen, J. (2024) · JACS Au · doi:10.1021/jacsau.3c00749 · Cited by 23
Roberts, L. S., Yan, P., Bateman, L. A., & Nomura, D. K. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.6b01159 · Cited by 23
Discovery of covalent enzyme inhibitors using virtual docking of covalent fragments
Chowdhury, S. R., Kennedy, S., Zhu, K., Mishra, R. K., Chuong, P., Nguyen, A.-U., Kathman, S. G., & Statsyuk, A. V. (2018) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2018.11.019 · Cited by 23
Epigenetic regulation by endogenous metabolite pharmacology
Kulkarni, R. A., Montgomery, D. C., & Meier, J. L. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.02.002 · Cited by 24
Covalent Kinase Inhibitors: An Overview
Gehringer, M. (2020) · Topics in medicinal chemistry · doi:10.1007/7355_2020_103 · Cited by 24
Profiling the proteome-wide selectivity of diverse electrophilesPreprint
Zanon, P. R. A., Yu, F., Musacchio, P. Z., Lewald, L., Zollo, M., Krauskopf, K., Mrdović, D., Raunft, P., Maher, T. E., Cigler, M., et al. (2021) · doi:10.33774/chemrxiv-2021-w7rss-v2 · Cited by 24
Kidd, S. L., Fowler, E., Reinhardt, T., Compton, T., Mateu, N., Newman, H., Bellini, D., Talon, R., McLoughlin, J., Krojer, T. J., et al. (2020) · Chemical Science · doi:10.1039/d0sc01232g · Cited by 21
Inverse Drug Discovery identifies weak electrophiles affording protein conjugates
Kline, G. M., Nugroho, K., & Kelly, J. W. (2022) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2021.102113 · Cited by 22
Technologies for Direct Detection of Covalent Protein–Drug Adducts
Mons, E., Kim, R. Q., & Mulder, M. P. C. (2023) · Pharmaceuticals · doi:10.3390/ph16040547 · Cited by 23
“ABPP has a prominent role in covalent drug discovery [178,187,188]: not only for identification of new covalent hits in covalent (fragment) screening [189] but also to identify cellular/in vivo covalently modified (off-target) proteins, thereby derisking covalent inhibitor development [2,190].”
BackgroundInfluentialCobley, J. N. (2023) · BioEssays · doi:10.1002/bies.202200248 · Cited by 25
Burton, N. R., Polasky, D. A., Shikwana, F., Ofori, S., Yan, T., Geiszler, D. J., Veiga Leprevost, F. D., Nesvizhskii, A. I., & Backus, K. M. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c05797 · Cited by 22
Self-citationTjin, C. C., Otley, K. D., Baguley, T. D., Kurup, P. K., Xu, J., Nairn, A. C., Lombroso, P. J., & Ellman, J. A. (2017) · ACS Central Science · doi:10.1021/acscentsci.7b00486 · Cited by 22
Exploring protein lipidation by mass spectrometry-based proteomics
Tsumagari, K., Isobe, Y., Imami, K., & Arita, M. (2023) · The Journal of Biochemistry · doi:10.1093/jb/mvad109 · Cited by 21
“…probe-modified peptides in combination with quantitative proteomics enables global identification of target proteins of these electrophilic molecules as well as their modification sites by quantifying the inhibition of probe-modified peptides in response to the electrophilic molecules (45, 46) .”
BackgroundAn allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes
Zhang, Y., Liu, Z., Hirschi, M., Brodsky, O., Johnson, E., Won, S. J., Nagata, A., Bezwada, D., Petroski, M. D., Majmudar, J. D., et al. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01738-7 · Cited by 27
“…and potentially generalizable in that it does not require prior structural information but instead leverages large chemical proteomic datasets 25,26,64–69 containing many covalently liganded paralog-restricted cysteines (for example, >60 such cysteines are described in a previous study 27 ).”
Self-citationNeocarzilin A Is a Potent Inhibitor of Cancer Cell Motility Targeting VAT-1 Controlled Pathways
Gleissner, C. M.-L., Pyka, C. L., Heydenreuter, W., Gronauer, T. F., Atzberger, C., Korotkov, V. S., Cheng, W., Hacker, S. M., Vollmar, A. M., Braig, S., et al. (2019) · ACS Central Science · doi:10.1021/acscentsci.9b00266 · Cited by 21
Palafox, M. F., Desai, H. S., Arboleda, V. A., & Backus, K. M. (2021) · Molecular Systems Biology · doi:10.15252/msb.20209840 · Cited by 19
“Several residues, including K386 and C294 were not identified by our reactivity studies but were labeled in our studies aimed at identifying small molecule ligands(Backus et al , 2016; Hacker et al , 2017).”
InfluentialSelf-citationTargeting the ubiquitin system by fragment-based drug discovery
Kennedy, C. R., McPhie, K. A., & Rittinger, K. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.1019636 · Cited by 21
“A novel method, using broadly reactive electrophilic scout fragments (Backus et al., 2016; Bar-Peled et al., 2017) as E3 ligase recruiters in PROTAC molecules, identified two novel CRL4 E3 ligases, DCAF16 and DCAF11, for TPD purposes.”
MethodFacilitating the development of molecular glues: Opportunities from serendipity and rational design
Jiang, W., Jiang, Y., Luo, Y., Qiao, W., & Yang, T. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115950 · Cited by 22
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Opportunities and challenges for the development of covalent chemical immunomodulators
Backus, K. M., Cao, J. X., & Maddox, S. M. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.05.050 · Cited by 21
Self-citationDefining the Cell Surface Cysteinome Using Two-Step Enrichment Proteomics
(2023) · doi:10.1021/jacsau.3c00707 · Cited by 21
Self-citationProteome-wide Ligand and Target Discovery by Using Strain-Enabled Cyclopropane Electrophiles
Liu, Y., Yu, Z., Li, P., Yang, T., Ding, K., Zhang, Z., Tan, Y., & Li, Z. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c04695 · Cited by 21
Fragment-based screening: A new paradigm for ligand and target discovery
Knight, S., Gianni, D., & Hendricks, A. (2022) · SLAS DISCOVERY · doi:10.1016/j.slasd.2021.10.011 · Cited by 20
“This has enabled proteome wide ligandability profiling by oving from small sets of broadly reactive “scout fragments ” [19] , [4] to uch larger sets of fragments [19] .”
Jung, Y., Noda, N., Takaya, J., Abo, M., Toh, K., Tajiri, K., Cui, C., Zhou, L., Sato, S., & Uesugi, M. (2022) · ACS Chemical Biology · doi:10.1021/acschembio.1c00824 · Cited by 20
Triazine-pyridine chemistry for protein labelling on tyrosine
Jiang, H., Zhang, Q., Zhang, Y., Feng, H., Jiang, H., Pu, F., Yu, R., Zhong, Z., Wang, C., Fung, Y. M. E., et al. (2022) · Chemical Communications · doi:10.1039/d2cc01528e · Cited by 20
HCovDock: an efficient docking method for modeling covalent protein–ligand interactions
Wu, Q., & Huang, S. (2022) · Briefings in Bioinformatics · doi:10.1093/bib/bbac559 · Cited by 21
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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