“Sleeping Beauty” Phenomenon: SuFEx-Enabled Discovery of Selective Covalent Inhibitors of Human Neutrophil Elastase

Abstract

<div> <div> <div> <p>Sulfur-Fluoride Exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled approach exploiting the “sleeping beauty” phenomenon of sulfur fluoride compounds in the context of the serendipitous discovery of selective covalent human neutrophil elastase (hNE) inhibitors. Evaluation of an ever-growing collection of SuFExable compounds toward various biological assays unexpectedly yielded a selective and covalent hNE inhibitor, benzene-1,2-disulfonyl fluoride. Derivatization of the initial hit led to a better agent, 2- triflyl benzenesulfonyl fluoride, itself made through a SuFEx trifluoromethylation process, with IC50 = 1.1 μM and ~200-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized probe only modified active hNE and not its denatured form, setting another example of the “sleeping beauty” phenomenon of sulfur fluoride capturing agents for the discovery of covalent medicines. </p> </div> </div> </div>

Development of an Enzyme‐Inhibitor Reaction Using Cellular Retinoic Acid Binding Protein II for One‐Pot Megamolecule Assembly

“…[8] This sulfur fluoride exchange (SuFEx) click reaction was activated by two proximal arginine residues (Arg112 and Arg133) that electrostatically stabilized the reactive sulfur fluoride bond through the formation of a sulfate ester, lowering the pK a of the nucleophile and accelerating the inhibition reaction. [8][9][10][11] The rate of reaction with this inhibitor, however, was not well-suited for megamolecule assembly. Hence, we incorporated a synthetic retinoid described by Whiting, Pohl, and coworkers.…”

Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors

“…6). This ability to refine the electrophilicity of a reactive covalent group is highly desirable for drug discovery applications, and in-principle, should facilitate the design of covalent agents that are capable of selectively modifying target proteins through a "Sleeping Beauty" event, a perfect matchmaking with complete selectivity observed for living, but not denatured, biotargets (45). Through screening our library of novel ligands against hNE, we demonstrate the matched pair discovery of a new class of irreversible covalent inhibitors of hNE.…”