SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase
2019 ◽
Vol 116
(38)
◽
pp. 18808-18814
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Keyword(s):
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.
2019 ◽
1990 ◽
Vol 33
(1)
◽
pp. 394-407
◽
1983 ◽
Vol 364
(2)
◽
pp. 1297-1302
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Keyword(s):
Keyword(s):
1991 ◽
Vol 50
(6)
◽
pp. 568-579
◽
Keyword(s):
Keyword(s):