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Identification of Inhibitors of NOD1-Induced Nuclear Factor-κB Activation.

ABSTRACT: NOD1 (nucleotide-binding oligomerization domain 1) protein is a member of the NLR (NACHT and leucine rich repeat domain containing proteins) protein family, which plays a key role in innate immunity as a sensor of specific microbial components derived from bacterial peptidoglycans and induction of inflammatory responses. Mutations in NOD proteins have been associated with various inflammatory diseases that affect NF-κB (nuclear factor κB) activity, a major signaling pathway involved in apoptosis, inflammation, and immune response. A luciferase-based reporter gene assay was utilized in a high-throughput screening program conducted under the NIH-sponsored Molecular Libraries Probe Production Center Network program to identify the active scaffolds. Herein, we report the chemical synthesis, structure-activity relationship studies, downstream counterscreens, secondary assay data, and pharmacological profiling of the 2-aminobenzimidazole lead (compound 1c, ML130) as a potent and selective inhibitor of NOD1-induced NF-κB activation.

SUBMITTER: Khan PM

PROVIDER: S-EPMC3193285 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Identification of Inhibitors of NOD1-Induced Nuclear Factor-κB Activation.

Khan Pasha M PM Correa Ricardo G RG Divlianska Daniela B DB Peddibhotla Satyamaheshwar S Sessions E Hampton EH Magnuson Gavin G Brown Brock B Suyama Eigo E Yuan Hongbin H Mangravita-Novo Arianna A Vicchiarelli Michael M Su Ying Y Vasile Stefan S Smith Layton H LH Diaz Paul W PW Reed John C JC Roth Gregory P GP

ACS medicinal chemistry letters 20110805 10

NOD1 (nucleotide-binding oligomerization domain 1) protein is a member of the NLR (NACHT and leucine rich repeat domain containing proteins) protein family, which plays a key role in innate immunity as a sensor of specific microbial components derived from bacterial peptidoglycans and induction of inflammatory responses. Mutations in NOD proteins have been associated with various inflammatory diseases that affect NF-κB (nuclear factor κB) activity, a major signaling pathway involved in apoptosis ...[more]

PMID: 22003428

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Project description:ObjectivesAlthough mechanical ventilation is a life-saving measure for patients in respiratory failure, prolonged mechanical ventilation results in diaphragmatic weakness attributable to fiber atrophy and contractile dysfunction. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragmatic weakness is important. In this context, it is established that oxidative stress is required for mechanical ventilation-induced diaphragmatic weakness to occur. Numerous redox-sensitive signaling pathways exist in muscle including the transcription factor nuclear factor-κB. Although it has been suggested that nuclear factor-κB contributes to proteolytic signaling in inactivity-induced atrophy in locomotor muscles, the role that nuclear factor-κB plays in mechanical ventilation-induced diaphragmatic weakness is unknown. We tested the hypothesis that nuclear factor-κB activation plays a key signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is required for nuclear factor-κB activation.DesignCause and effect was determined by independently treating mechanically ventilated animals with either a specific nuclear factor-κB inhibitor (SN50) or a clinically relevant antioxidant (curcumin).Measurements and main resultsInhibition of nuclear factor-κB activity partially attenuated both mechanical ventilation-induced diaphragmatic atrophy and contractile dysfunction. Further, treatment with the antioxidant curcumin prevented mechanical ventilation-induced activation of nuclear factor-κB in the diaphragm and rescued the diaphragm from both mechanical ventilation-induced atrophy and contractile dysfunction.ConclusionsCollectively, these findings support the hypothesis that nuclear factor-κB activation plays a significant signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is an upstream activator of nuclear factor-κB. Finally, our results suggest that prevention of mechanical ventilation-induced oxidative stress in the diaphragm could be a useful clinical strategy to prevent or delay mechanical ventilation-induced diaphragmatic weakness.

Dataset Information

Identification of Inhibitors of NOD1-Induced Nuclear Factor-κB Activation.

Publications

Identification of Inhibitors of NOD1-Induced Nuclear Factor-κB Activation.

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