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

Qinheng Zheng, Jordan L. Woehl, Seiya Kitamura, Diogo Santos-Martins, Christopher J. Smedley, Gencheng Li, Stefano Forli, John E. Moses, Dennis W. Wolan, K. Barry Sharpless

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)18808-18814
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number38
DOIs
StatePublished - Sep 17 2019
Externally publishedYes

Keywords

  • Agnostic
  • Click chemistry
  • Covalent inhibitor
  • Elastase
  • SuFEx

ASJC Scopus subject areas

  • General

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