Details

Autor(en) / Beteiligte

• 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
• Khosla, Chaitan

Titel

Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation

Ist Teil von

• PLoS biology, 2018-06, Vol.16 (6), p.e2004663-e2004663

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2018

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.