Proceedings of the National Academy of Sciences - PNAS, 2019-09, Vol.116 (38), p.18808-18814
2019
Details
- Autor(en) / Beteiligte
- Titel
- SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2019-09, Vol.116 (38), p.18808-18814
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1909972116Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6754619
- Format
- –
- Schlagworte
- Benzene, Cathepsin G, Chemical synthesis, Click Chemistry, Covalence, Elastase, Enzyme Activation - drug effects, Fluorides, Fluorides - chemistry, Homology, Humans, Inhibitors, Inhibitory Concentration 50, Leukocyte Elastase - antagonists & inhibitors, Leukocyte Elastase - chemistry, Leukocyte Elastase - metabolism, Molecular Structure, Neutrophils, Optimization, Organic chemistry, Physical Sciences, Protein Binding, Protein Folding, Selectivity, Serine, Serine proteinase, Serine Proteinase Inhibitors - chemical synthesis, Serine Proteinase Inhibitors - chemistry, Serine Proteinase Inhibitors - pharmacology, Sulfinic Acids - chemical synthesis, Sulfinic Acids - chemistry, Sulfinic Acids - pharmacology, Sulfur, Sulfur Compounds - chemistry, Sulfur fluorides