Covalent Enzyme Inhibition through Fluorosulfate Modification of a Noncatalytic Serine Residue

• DOI: 10.1021/acschembio.7b00403
• Publication Date: 2017-07-18T13:02:16Z
• Authors: Olugbeminiyi O. F...; Lise R. Hoth; Chulho Choi; Xidong Feng; Ariamala Gopalsamy; Erik C. Hett; Robert E. Kyne; Ralph P. Robinson; Lyn H. Jones
• Keywords: Residue (chemistry)

Irreversible enzyme inhibitors and covalent chemical biology probes often utilize the reaction of a protein cysteine residue with an appropriately positioned electrophile (e.g., acrylamide) on ligand template. However, residues are not always available for site-specific labeling, therefore new approaches needed to expand toolkit appropriate electrophiles ("warheads") that target alternative amino acids. We previously described rational targeting tyrosine in active site (the mRNA decapping scavenger enzyme, DcpS) using armed sulfonyl fluoride electrophile. These subsequently enabled development clickable probe technology measure drug-target occupancy live cells. Here we describe fluorosulfate-containing inhibitor (aryl fluorosulfate (FS-p1)) excellent metabolic stability reacts selectively noncatalytic serine same DcpS as confirmed by peptide mapping experiments. Our results suggest electrophilic warheads could be suitable strategy drugs probes.