@article{5ea31673268e45c78be7e390704b23cf,
title = "SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase",
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 = "Agnostic, Click chemistry, Covalent inhibitor, Elastase, SuFEx",
author = "Qinheng Zheng and Woehl, {Jordan L.} and Seiya Kitamura and Diogo Santos-Martins and Smedley, {Christopher J.} and Gencheng Li and Stefano Forli and Moses, {John E.} and Wolan, {Dennis W.} and {Barry Sharpless}, K.",
note = "Funding Information: We are very grateful to the following coworkers for their contribution to the SuFExable compound library: Hua Wang (library manager); Larisa Krasnova; Suhua Li; Bing Gao; Grant A. L. Bare; Gerui Ren; Feng Zhou; Feng Liu; Hamid R. Safaei (Department of Chemistry); Peng Wu and his group (Department of Molecular Medicine, Scripps Research); Jiajia Dong and his group (Shanghai Institute of Organic Chemistry); the J.E.M. group (La Trobe University); Hua-Li Qin and his group (Wuhan University of Technology); En-Xuan Zhang and his group (AsymChem Inc.); Bo Qin; and Mike Petrassi (Calibr, Scripps Research). The current work was financially supported by the National Institutes of Health R01GM117145 (K.B.S.), R01GM069832 (S.F.), T32AI7354-27 (J.L.W.), The Scripps Research Institute (D.W.W.), and the ARC FT170100156 (J.E.M.). We thank Prof. Hugh Rosen and Prof. Jin-Quan Yu (Scripps Research) for access to instrumentation, Dr. Yongxuan Su of the Molecular Mass Spectrometry Facility (University of California San Diego) for atmospheric-pressure chemical ionization MS, Dr. John Cappiello (Scripps Research) for proofreading, and the staff of the Stanford Synchrotron Radiation Lightsource. Funding Information: ACKNOWLEDGMENTS. We are very grateful to the following coworkers for their contribution to the SuFExable compound library: Hua Wang (library manager); Larisa Krasnova; Suhua Li; Bing Gao; Grant A. L. Bare; Gerui Ren; Feng Zhou; Feng Liu; Hamid R. Safaei (Department of Chemistry); Peng Wu and his group (Department of Molecular Medicine, Scripps Research); Jiajia Dong and his group (Shanghai Institute of Organic Chemistry); the J.E.M. group (La Trobe University); Hua-Li Qin and his group (Wuhan University of Technology); En-Xuan Zhang and his group (AsymChem Inc.); Bo Qin; and Mike Petrassi (Calibr, Scripps Research). The current work was financially supported by the National Institutes of Health R01GM117145 (K.B.S.), R01GM069832 (S.F.), T32AI7354-27 (J.L.W.), The Scripps Research Institute (D.W.W.), and the ARC FT170100156 (J.E.M.). We thank Prof. Hugh Rosen and Prof. Jin-Quan Yu (Scripps Research) for access to instrumentation, Dr. Yongxuan Su of the Molecular Mass Spectrometry Facility (University of California San Diego) for atmospheric-pressure chemical ionization MS, Dr. John Cappiello (Scripps Research) for proofreading, and the staff of the Stanford Synchrotron Radiation Lightsource. Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All rights reserved.",
year = "2019",
month = sep,
day = "17",
doi = "10.1073/pnas.1909972116",
language = "English (US)",
volume = "116",
pages = "18808--18814",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "38",
}