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

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

Author information

1
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
2
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
3
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.
4
La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, VIC 3086, Australia.
5
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037; wolan@scripps.edu sharples@scripps.edu.
6
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; wolan@scripps.edu sharples@scripps.edu.

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.

KEYWORDS:

SuFEx; agnostic; click chemistry; covalent inhibitor; elastase

PMID:
31484779
PMCID:
PMC6754619
[Available on 2020-03-04]
DOI:
10.1073/pnas.1909972116

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