A Peptidyl Inhibitor that Blocks Calcineurin–NFAT Interaction and Prevents Acute Lung Injury
| Autor: | Manjula Karpurapu, Jessica K Lukowski, Amritendu Koley, John W. Christman, Sangwoon Chung, Patrick G Dougherty, Dehua Pei, Ziqing Qian, Amanda B. Hummon, Hao W Li, Teja Srinivas Nirujogi, Luiza Rusu |
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| Rok vydání: | 2020 |
| Předmět: |
Lipopolysaccharides
ARDS NFATC3 Acute Lung Injury Calcineurin Inhibitors Phosphatase Molecular Dynamics Simulation Pharmacology Lung injury 01 natural sciences Article Mice 03 medical and health sciences In vivo Drug Discovery medicine Animals Humans Protein Interaction Domains and Motifs Tissue Distribution Amino Acid Sequence Lung 030304 developmental biology Mice Inbred BALB C 0303 health sciences Binding Sites NFATC Transcription Factors Chemistry Calcineurin NFAT medicine.disease 0104 chemical sciences Mice Inbred C57BL 010404 medicinal & biomolecular chemistry medicine.anatomical_structure Molecular Medicine Peptides Half-Life Signal Transduction |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 in vitro and in vivo and exhibited a favorable pharmacokinetic profile, broad tissue distribution following different routes of administration, and minimal toxicity. Our data indicate that CNI103 is a promising novel treatment for ARDS and other inflammatory diseases. |
| Databáze: | OpenAIRE |
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