SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase.
Click Chemistry
Enzyme Activation
/ drug effects
Fluorides
/ chemistry
Humans
Inhibitory Concentration 50
Leukocyte Elastase
/ antagonists & inhibitors
Molecular Structure
Protein Binding
Protein Folding
Serine Proteinase Inhibitors
/ chemical synthesis
Sulfinic Acids
/ chemical synthesis
Sulfur Compounds
/ chemistry
SuFEx
agnostic
click chemistry
covalent inhibitor
elastase
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
17 09 2019
17 09 2019
Historique:
pubmed:
6
9
2019
medline:
1
4
2020
entrez:
6
9
2019
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 31484779
pii: 1909972116
doi: 10.1073/pnas.1909972116
pmc: PMC6754619
doi:
Substances chimiques
Serine Proteinase Inhibitors
0
Sulfinic Acids
0
Sulfur Compounds
0
sulfur fluoride
0
sulfuryl fluoride
64B59K7U6Q
ELANE protein, human
EC 3.4.21.37
Leukocyte Elastase
EC 3.4.21.37
Fluorides
Q80VPU408O
Banques de données
PDB
['6e69']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
18808-18814Subventions
Organisme : NIAID NIH HHS
ID : T32 AI007354
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM117145
Pays : United States
Organisme : NIAID NIH HHS
ID : U54 AI150472
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM103368
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM069832
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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