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

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

  • PLoS Biol. 2018 Jun 11;16(6):e2004663. doi: 10.1371/journal.pbio.2004663.
Jing Zhao 1 2,  Lei Zhang 1,  Xiaodong Mu 3,  Christelle Doebelin 1,  William Nguyen 1,  Callen Wallace 4,  Daniel P Reay 5,  Sara J McGowan 1,  Lana Corbo 1,  Paula R Clemens 5,  Gabriela Mustata Wilson 6,  Simon C Watkins 4,  Laura A Solt 7,  Michael D Cameron 1,  Johnny Huard 3,  Laura J Niedernhofer 1,  Theodore M Kamenecka 1,  Paul D Robbins 1
Affiliations

Affiliations

  • 1 Department of Molecular Medicine and the TSRI Center on Aging, The Scripps Research Institute, Jupiter, Florida, United States of America.
  • 2 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
  • 3 Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
  • 4 Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
  • 5 Department of Neurology, University of Pittsburgh, Pennsylvania, United States of America.
  • 6 Department of Health Informatics and Information Management, College of Nursing and Health Professions, University of Southern Indiana, Evansville, Indiana, United States of America.
  • 7 Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, United States of America.
PMID: 29889904 DOI: 10.1371/journal.pbio.2004663
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.

Figures
Products