| First Author | Zhao J | Year | 2018 |
| Journal | PLoS Biol | Volume | 16 |
| Issue | 6 | Pages | e2004663 |
| PubMed ID | 29889904 | Mgi Jnum | J:263686 |
| Mgi Id | MGI:6187813 | Doi | 10.1371/journal.pbio.2004663 |
| Citation | Zhao J, et al. (2018) Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-kappaB activation. PLoS Biol 16(6):e2004663 |
| abstractText | Nuclear factor kappaB (NF-kappaB) is a transcription factor important for regulating innate and adaptive immunity, cellular proliferation, apoptosis, and senescence. Dysregulation of NF-kappaB and its upstream regulator IkappaB kinase (IKK) contributes to the pathogenesis of multiple inflammatory and degenerative diseases as well as cancer. An 11-amino acid peptide containing the NF-kappaB essential modulator (NEMO)-binding domain (NBD) derived from the C-terminus of beta subunit of IKK, functions as a highly selective inhibitor of the IKK complex by disrupting the association of IKKbeta and the IKKgamma 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 alpha (TNF-alpha)- and lipopolysaccharide (LPS)-induced NF-kappaB activation by blocking the interaction between IKKbeta 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. |
