Profiling Sulfur(VI) Fluorides as Reactive Functionalities for Chemical Biology Tools and Expansion of the Ligandable Proteome

Here, we report a comprehensive profiling of sulfur(VI) fluorides (S^VI-Fs) as reactive groups for chemical biology applications. S^VI-Fs are reactive functionalities that modify lysine, tyrosine, histidine, and serine sidechains. A panel of S^VI-Fs were studied with respect to hydrolytic stability and reactivity with nucleophilic amino acid sidechains. The use of S^VI-Fs to covalently modify carbonic anhydrase II (CAII) and a range of kinases was then investigated. Finally, the S^VI-F panel was used in live cell chemoproteomic workflows, identifying novel protein targets based on the type of S^VI-F used. This work highlights how S^VI-F reactivity can be used as a tool to expand the liganded proteome.