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

Chemical probes are valuable tools to explore the function of proteins. Incorporation of electrophiles into small molecules enables covalent capture of protein interactions and provides access to powerful technologies including chemoproteomic profiling and reactive fragment screening. Current approaches have been largely limited to protein pockets containing cysteine, so establishing strategies to target other amino acid residues is essential to expanding the applicability across the proteome. Here, we profiled sulfur(VI) fluorides (SVI-F) as reactive functionalities that can modify multiple residues including Lys, Tyr, His and Ser, thus offering utility for targeting almost any protein. These studies provided an in-depth understanding of SVI-F functionalities, including hydrolytic stability, protein reactivity and utility in chemoproteomics. Such insights offer a valuable guide for the prospective design of SVI-F-containing ligands for various chemical biology workflows and illustrate the wide range of proteins that SVI-Fs can capture, thus highlighting the opportunity for SVI-Fs to expand the liganded proteome.