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

Abstract

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.

• Authors: Jing Zhao, Lei Zhang, Xiaodong Mu, Christelle Doebelin, William Nguyen, Callen Wallace, Daniel P Reay, Sara J McGowan, Lana Corbo, Paula R Clemens, Gabriela Mustata Wilson, Simon C Watkins, Laura A Solt, Michael D Cameron, Johnny Huard, Laura J Niedernhofer, Theodore M Kamenecka, Paul D Robbins
• Journal: PLoS biology (PLoS Biol) Vol. 16 Issue 6 Pg. e2004663 (06 2018) ISSN: 1545-7885 [Electronic] United States
• PMID: 29889904 (Publication Type: Journal Article)

Chemical References

• IKBKG protein, human
• Lipopolysaccharides
• Tumor Necrosis Factor-alpha
• I-kappa B Kinase

Topics

• Animals
• Biomimetic Materials (chemistry, pharmacology)
• Cell Line
• Female
• HEK293 Cells
• Humans
• I-kappa B Kinase (antagonists & inhibitors, chemistry, metabolism)
• Inflammation (drug therapy)
• Lipopolysaccharides
• Mice
• Mice, Inbred C57BL
• Muscular Dystrophy, Duchenne (drug therapy)
• Necrosis (drug therapy)
• Pneumonia (drug therapy)
• Protein Domains
• RAW 264.7 Cells
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)