التفاصيل البيبلوغرافية
| العنوان: |
Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation. |
| المؤلفون: |
Zhao, Jing, Zhang, Lei, Mu, Xiaodong, Doebelin, Christelle, Nguyen, William, Wallace, Callen, Reay, Daniel P., McGowan, Sara J., Corbo, Lana, Clemens, Paula R., Wilson, Gabriela Mustata, Watkins, Simon C., Solt, Laura A., Cameron, Michael D., Huard, Johnny, Niedernhofer, Laura J., Kamenecka, Theodore M., Robbins, Paul D. |
| المصدر: |
PLoS Biology; 6/11/2018, Vol. 16 Issue 6, p1-28, 28p, 2 Diagrams, 2 Charts, 6 Graphs |
| مصطلحات موضوعية: |
NF-kappa B genetics, DUCHENNE muscular dystrophy, ADULT respiratory distress syndrome, LABORATORY mice, IMMUNOPRECIPITATION |
| مستخلص: |
Nuclear factor κB (NF-κB) is a transcription factor important for regulating innate and adaptive immunity, cellular proliferation, apoptosis, and senescence. Dysregulation of NF-κB and its upstream regulator IκB kinase (IKK) contributes to the pathogenesis of multiple inflammatory and degenerative diseases as well as cancer. An 11–amino acid peptide containing the NF-κB essential modulator (NEMO)-binding domain (NBD) derived from the C-terminus of β subunit of IKK, functions as a highly selective inhibitor of the IKK complex by disrupting the association of IKKβ and the IKKγ subunit NEMO. A structure-based pharmacophore model was developed to identify NBD mimetics by in silico screening. Two optimized lead NBD mimetics, SR12343 and SR12460, inhibited tumor necrosis factor α (TNF-α)- and lipopolysaccharide (LPS)-induced NF-κB activation by blocking the interaction between IKKβ and NEMO and suppressed LPS-induced acute pulmonary inflammation in mice. Chronic treatment of a mouse model of Duchenne muscular dystrophy (DMD) with SR12343 and SR12460 attenuated inflammatory infiltration, necrosis and muscle degeneration, demonstrating that these small-molecule NBD mimetics are potential therapeutics for inflammatory and degenerative diseases. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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