6E69

Ortho-substituted phenyl sulfonyl fluoride and fluorosulfate as potent elastase inhibitory fragments

Summary for 6E69

• Entry DOI: 10.2210/pdb6e69/pdb
• Related: 5ABW
• Descriptor: Neutrophil elastase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: neutrophil, elastase, fragment, inhibitor, sulfonyl fluoride, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 98013.42

Authors

Wolan, D.W.,Woehl, J.L.,Kitamura, S. (deposition date: 2018-07-24, release date: 2019-07-24, Last modification date: 2024-10-16)

Primary citation

Zheng, Q.,Woehl, J.L.,Kitamura, S.,Santos-Martins, D.,Smedley, C.J.,Li, G.,Forli, S.,Moses, J.E.,Wolan, D.W.,Sharpless, K.B.
SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase.
Proc.Natl.Acad.Sci.USA, 116:18808-18814, 2019

PubMed 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 IC 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.

PubMed: 31484779
DOI: 10.1073/pnas.1909972116

Experimental method

X-RAY DIFFRACTION (2.33 Å)