2 research outputs found
Covalent Enzyme Inhibition through Fluorosulfate Modification of a Noncatalytic Serine Residue
Irreversible enzyme
inhibitors and covalent chemical biology probes
often utilize the reaction of a protein cysteine residue with an appropriately
positioned electrophile (<i>e.g.</i>, acrylamide) on the
ligand template. However, cysteine residues are not always available
for site-specific protein labeling, and therefore new approaches are
needed to expand the toolkit of appropriate electrophiles (“warheads”)
that target alternative amino acids. We previously described the rational
targeting of tyrosine residues in the active site of a protein (the
mRNA decapping scavenger enzyme, DcpS) using inhibitors armed with
a sulfonyl fluoride electrophile. These inhibitors subsequently enabled
the development of clickable probe technology to measure drug-target
occupancy in live cells. Here we describe a fluorosulfate-containing
inhibitor (aryl fluorosulfate probe (FS-p1)) with excellent chemical
and metabolic stability that reacts selectively with a noncatalytic
serine residue in the same active site of DcpS as confirmed by peptide
mapping experiments. Our results suggest that noncatalytic serine
targeting using fluorosulfate electrophilic warheads could be a suitable
strategy for the development of covalent inhibitor drugs and chemical
probes
Introduction of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides
The design, synthesis,
and application of [4-(acetylamino)Âphenyl]Âimidodisulfuryl
difluoride (AISF), a shelf-stable, crystalline reagent for the synthesis
of sulfurÂ(VI) fluorides, is described. The utility of AISF is demonstrated
in the synthesis of a diverse array of aryl fluorosulfates and sulfamoyl
fluorides under mild conditions. Additionally, a single-step preparation
of AISF was developed that installed the bisÂ(fluorosulfonyl)Âimide
group on acetanilide utilizing an oxidative C–H functionalization
protocol