A Peptidyl Inhibitor that Blocks Calcineurin-NFAT Interaction and Prevents Acute Lung Injury.
Acute Lung Injury
/ pathology
Amino Acid Sequence
Animals
Binding Sites
Calcineurin
/ chemistry
Calcineurin Inhibitors
/ chemistry
Half-Life
Humans
Lipopolysaccharides
/ toxicity
Lung
/ diagnostic imaging
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Molecular Dynamics Simulation
NFATC Transcription Factors
/ chemistry
Peptides
/ chemistry
Protein Interaction Domains and Motifs
/ drug effects
Signal Transduction
/ drug effects
Tissue Distribution
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
12 11 2020
12 11 2020
Historique:
pubmed:
20
10
2020
medline:
19
12
2020
entrez:
19
10
2020
Statut:
ppublish
Résumé
Acute respiratory distress syndrome (ARDS) is an inflammatory lung disease with a high morbidity and mortality rate, for which no pharmacologic treatment is currently available. Our previous studies discovered that a pivotal step in the disease process is the activation of the nuclear factor of activated T cells (NFAT) c3 in lung macrophages, suggesting that inhibitors against the upstream protein phosphatase calcineurin should be effective for prevention/treatment of ARDS. Herein, we report the development of a highly potent, cell-permeable, and metabolically stable peptidyl inhibitor, CNI103, which selectively blocks the interaction between calcineurin and NFATc3, through computational and medicinal chemistry. CNI103 specifically inhibited calcineurin signaling
Identifiants
pubmed: 33073986
doi: 10.1021/acs.jmedchem.0c01236
pmc: PMC8011862
mid: NIHMS1682094
doi:
Substances chimiques
Calcineurin Inhibitors
0
Lipopolysaccharides
0
NFATC Transcription Factors
0
Peptides
0
transcription factor NF-AT c3
0
Calcineurin
EC 3.1.3.16
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
12853-12872Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM110406
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137224
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122459
Pays : United States
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