Sufex-Enabled, Agnostic Discovery of Covalent Inhibitors of Human Neutrophil Elastase
SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase Qinheng Zhenga,1, Jordan L. Woehlb,1, Seiya Kitamurab, Diogo Santos-Martinsc, Christopher J. Smedleyd, Gencheng Lia, Stefano Forlic, John E. Mosesd, Dennis W. Wolanb,2, and K. Barry Sharplessa,2 aDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; bDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037; cDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037; and dLa Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, VIC 3086, Australia Contributed by K. Barry Sharpless, July 23, 2019 (sent for review July 9, 2019; reviewed by Peng R. Chen and Lei Wang) Sulfur fluoride exchange (SuFEx) has emerged as the new gener- unique ensemble of factors between the naturally folded protein ation of click chemistry. We report here a SuFEx-enabled, agnostic and its correct partner probe’s latent S–F electrophilic site. approach for the discovery and optimization of covalent inhibi- When the perfect S–F probe for a given protein encounters the tors of human neutrophil elastase (hNE). Evaluation of our ever- denatured form of the latter, there is no detectable reaction (24, growing collection of SuFExable compounds toward various bio- 33). In fact, in our experience with many S–F capture probes and logical assays unexpectedly revealed a selective and covalent hNE various denatured proteins, even including entire denatured inhibitor: benzene-1,2-disulfonyl fluoride. Synthetic derivatization proteomes, is that misfolded proteins simply do not react with of the initial hit led to a more potent agent, 2-(fluorosulfonyl)phenyl S–F electrophiles at all (24).
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