Backus, K.M. et al. Nature 534, 570–574 (2016).

Small molecules are useful for studying protein function, but the vast majority of human proteins lack specific probes. Backus et al. report a covalent screening approach allowing one to target these 'undruggable' proteins by treating cells with compounds containing a cysteine-reactive group and blocking other, unreacted cysteines in the proteome with a broadly reactive molecule containing a click chemistry group. Biotin tags labeled with either light or heavy stable isotopes are then clicked onto experimental and dimethylsulfoxide-treated control samples, respectively, to enrich proteins on streptavidin beads before digestion and analysis by quantitative liquid chromatography–mass spectrometry. This process reveals cysteine residues that were bound specifically by the cysteine-reactive compounds. The authors identified covalent ligands for more than 700 cysteines in the proteome, including many for previously undruggable proteins.