Proteome-wide covalent ligand discovery in native biological systems

By Keriann M. Backus, Bruno E. Correia, Kenneth M. Lum, Stefano Forli, Benjamin D. Horning, G. González-Páez, Sandip Chatterjee, Bryan R. Lanning, J. Teijaro, Arthur J. Olson and 2 more. Nature, 2016

775 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Organic Chemistry, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/018da1a6d6db1d39dd24e2dcb11e9d439c584dcc

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Citations in the corpus

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “Although human CASP10 shares some degree of substrate specificity with CASP8 [317] and possibly contributes to extrinsic apoptosis in primary T cells [318], rodents including mice and rats lack a functional Casp10 gene, and the precise role of this caspase in death receptor-driven apoptosis in human”
Target identification with quantitative activity based protein profiling (ABPP) (2017, methodology): “…was applied on a global level in a recent study by Backus et al., which used isoTOP-ABPP screening of a large constructed library of fragment electrophiles to identify ligandable cysteines in MDA-MB-231 (human breast cancer cell) and Ramos Cell (human B lymphocyte cell) human cancer proteomes [83].”