SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase Academic Article uri icon

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 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.

authors

  • Zheng, Q
  • Woehl, JL
  • Kitamura, S
  • Santos-Martins, D
  • Smedley, Christopher J
  • Li, G
  • Forli, S
  • Moses, John E
  • Wolan, DW
  • Barry Sharpless, K

publication date

  • 2019