TY - JOUR
T1 - Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation
AU - Zhao, Jing
AU - Zhang, Lei
AU - Mu, Xiaodong
AU - Doebelin, Christelle
AU - Nguyen, William
AU - Wallace, Callen
AU - Reay, Daniel P.
AU - McGowan, Sara J.
AU - Corbo, Lana
AU - Clemens, Paula R.
AU - Wilson, Gabriela Mustata
AU - Watkins, Simon C.
AU - Solt, Laura A.
AU - Cameron, Michael D.
AU - Huard, Johnny
AU - Niedernhofer, Laura J.
AU - Kamenecka, Theodore M.
AU - Robbins, Paul D.
N1 - Publisher Copyright:
© 2018 Zhao et al. http://creativecommons.org/licenses/by/4.0/
PY - 2018/6
Y1 - 2018/6
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pbio.2004663
DO - 10.1371/journal.pbio.2004663
M3 - Article
C2 - 29889904
AN - SCOPUS:85049371521
SN - 1544-9173
VL - 16
JO - PLoS biology
JF - PLoS biology
IS - 6
M1 - e2004663
ER -