SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase

Proc Natl Acad Sci U S A. 2019 Sep 17;116(38):18808-18814. doi: 10.1073/pnas.1909972116. Epub 2019 Sep 4.


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 IC50 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.

Keywords: SuFEx; agnostic; click chemistry; covalent inhibitor; elastase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Click Chemistry
  • Enzyme Activation / drug effects
  • Fluorides / chemistry*
  • Humans
  • Inhibitory Concentration 50
  • Leukocyte Elastase / antagonists & inhibitors*
  • Leukocyte Elastase / chemistry
  • Leukocyte Elastase / metabolism
  • Molecular Structure
  • Protein Binding
  • Protein Folding
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / pharmacology
  • Sulfinic Acids / chemical synthesis
  • Sulfinic Acids / chemistry
  • Sulfinic Acids / pharmacology
  • Sulfur Compounds / chemistry*


  • Serine Proteinase Inhibitors
  • Sulfinic Acids
  • Sulfur Compounds
  • sulfur fluoride
  • sulfuryl fluoride
  • ELANE protein, human
  • Leukocyte Elastase
  • Fluorides

Associated data

  • PDB/6e69