SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase.
basic_science · Level V
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- Record sourced from PubMed, PMID 31484779.
- Also identified by DOI 10.1073/pnas.1909972116 and PMC identifier 6754619.
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Abstract
Sulfur fluoride exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled, agnostic approach for the discovery and optimization of covalent inhibitors of human neutrophil elastase (hNE). Evaluation of our ever-growing collection of SuFExable compounds toward various biological assays unexpectedly revealed a selective and covalent hNE inhibitor: benzene-1,2-disulfonyl fluoride. Synthetic derivatization of the initial hit led to a more potent agent, 2-(fluorosulfonyl)phenyl fluorosulfate with IC<sub>50</sub> 0.24 μM and greater than 833-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized, yet simple benzenoid probe only modified active hNE and not its denatured form.
Medical subject headings
- Fluorides
- Leukocyte Elastase
- Serine Proteinase Inhibitors
- Sulfur Compounds