Arylfluorosulfate‐Based Electrophiles for Covalent Protein Labeling: A New Addition to the Arsenal

Abstract

Selective covalent modification of a targeted protein is a powerful tool in chemical biology and drug discovery, with applications ranging from identification and characterization of proteins and their functions to the development of targeted covalent inhibitors. Most covalent ligands contain an affinity motif and an electrophilic warhead that reacts with a nucleophilic residue of the targeted protein. Because the electrophilic warhead is prone to react and modify off-target nucleophiles, its reactivity should be balanced carefully to maximize target selectivity. Arylfluorosulfates have recently emerged as latent electrophiles for selective labeling of context-specific tyrosine and lysine residues in protein pockets. Here, we review the recent but intense introduction of arylfluorosulfates into the arsenal of available warheads for selective covalent modification of proteins. We highlight the untapped potential of this functional group for use in chemical biology and drug discovery.

An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mproinhibitor

“…Fig 1), on a subset of kinases from our database, showing an increase in the number of structures that can be covalentized. New covalent 'warheads', including reversible covalent warheads, such as cyanoacrylamides 60 , and clorofluoroacetamides 61 become available, both for cysteine residues 62 , but also for other amino acids [63][64][65] . These can be incorporated with little effort into the covalentizer pipeline.…”

Covalent Small Molecules as Enabling Platforms for Drug Discovery

“…Furthermore, the electrophiles are appended to scaffolds of intermediate and “lead‐like” complexity, offering starting points for drug discovery programmes. Aryl fluorosulfate warheads were used for this study, as they have been reported to covalently bind to Lys and Tyr residues with enhanced chemical and metabolic stability relative to the related sulfonyl fluoride warhead . Their reactivity is postulated to occur within specific protein structures where nearby amino acids catalyse a sulfur fluoride exchange (SuFEx) reaction .…”

The Application of Fluorine‐Containing Reagents in Structural Proteomics

“…Although sulfonyl fluorides (SFs;F igure 4) can be traced back 100 years in Germany for applications in dyes [21] their application has been revitalized as sulfur(VI) fluoride exchange (SuFEx) reagents by Sharpless and co-workers. [22] These exchange reactions were reviewed [23] and may be emerging as the next click reaction in chemical biology.T he SuFEx reaction includes several important reagent types-SFs,s ulfonimidoyl fluorides,f luorosulfates,a nd sulfamoyl fluoride-which show specific reactivity to several amino acids (e.g.T yr, Ser,T hr, His,L ys,and Cys). SFs have at least four features: [22] 1) resistance to reduction, 2) thermodynamic stability,3)nearly exclusive reactivity at sulfur,and 4) strong hydrogen bonding to fluorine.S ulfonimidoyl fluorides,a n imino sibling of SFs,possess similar click properties but with an additional "handle" at the nitrogen atom for tuning the chemical properties.F luorosulfates and the analogous sulfamoyl fluorides are even less reactive than SFs.…”