Proteome-wide covalent ligand discovery in native biological systems
| Autor: | Benjamin D. Horning, Sandip Chatterjee, Bruno E. Correia, Arthur J. Olson, Gonzalo E. González-Páez, Bryan R. Lanning, Dennis W. Wolan, John R. Teijaro, Stefano Forli, Benjamin F. Cravatt, Kenneth M. Lum, Keriann M. Backus |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Scaffold protein Proteome T-Lymphocytes Drug Evaluation Preclinical Druggability Apoptosis Biology Ligands Proteomics Article Small Molecule Libraries 03 medical and health sciences Humans Chemoproteomics Cysteine Caspase 10 Cells Cultured Caspase 8 Enzyme Precursors Multidisciplinary Ligand (biochemistry) Small molecule Combinatorial chemistry Peptide Fragments 3. Good health 030104 developmental biology Biochemistry Transcription Factors |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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” 1,2. Fragment-based ligand discovery (FBLD) can identify small-molecule probes for proteins that have proven difficult to target using high-throughput screening of complex compound libraries 1,3. Although reversibly binding ligands are commonly pursued, covalent fragments provide an alternative route to small-molecule probes 4–10, including those that can access regions of proteins that are difficult to access through binding affinity alone 5,10,11. In this manuscript, we report a quantitative analysis of cysteine-reactive small-molecule fragments screened against thousands of proteins. 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. |
| Databáze: | OpenAIRE |
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