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“Sleeping Beauty” Phenomenon: SuFEx-Enabled Discovery of Selective Covalent Inhibitors of Human Neutrophil Elastase

preprint
submitted on 14.03.2019 and posted on 15.03.2019 by 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

Sulfur-Fluoride Exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled approach exploiting the “sleeping beauty” phenomenon of sulfur fluoride compounds in the context of the serendipitous discovery of selective covalent human neutrophil elastase (hNE) inhibitors. Evaluation of an ever-growing collection of SuFExable compounds toward various biological assays unexpectedly yielded a selective and covalent hNE inhibitor, benzene-1,2-disulfonyl fluoride. Derivatization of the initial hit led to a better agent, 2- triflyl benzenesulfonyl fluoride, itself made through a SuFEx trifluoromethylation process, with IC50 = 1.1 μM and ~200-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized probe only modified active hNE and not its denatured form, setting another example of the “sleeping beauty” phenomenon of sulfur fluoride capturing agents for the discovery of covalent medicines.

Funding

Sulfur(VI) Fluoride Exchange (SuFEx): new developments and biological applications

National Institute of General Medical Sciences

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AutoDock Suite: Next Generation Environment for Drug Design

National Institute of General Medical Sciences

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History

Email Address of Submitting Author

qhzheng@scripps.edu

Institution

The Scripps Research Institute

Country

United States

ORCID For Submitting Author

0000-0002-8440-8673

Declaration of Conflict of Interest

No conflict of interest

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