Novel Nuclear Factor-KappaB Targeting Peptide Suppresses β-Amyloid Induced Inflammatory and Apoptotic Responses in Neuronal Cells

Abstract

In the central nervous system (CNS), activation of the transcription factor nuclear factor-kappa B (NF-κβ) is associated with both neuronal survival and increased vulnerability to apoptosis. The mechanisms underlying these dichotomous effects are attributed to the composition of NF-κΒ dimers. In Alzheimer’s disease (AD), β-amyloid (Aβ) and other aggregates upregulate activation of p65:p50 dimers in CNS cells and enhance transactivation of pathological mediators that cause neuroinflammation and neurodegeneration. Hence selective targeting of activated p65 is an attractive therapeutic strategy for AD. Here we report the design, structural and functional characterization of peptide analogs of a p65 interacting protein, the glucocorticoid induced leucine zipper (GILZ). By virtue of binding the transactivation domain of p65 exposed after release from the inhibitory IκΒ proteins in activated cells, the GILZ analogs can act as highly selective inhibitors of activated p65 with minimal potential for off-target effects.

Mechanisms of a sustained anti-inflammatory drug response in alveolar macrophages unraveled with mathematical modeling

“…It has been shown previously that Dexa, after binding to GR, interacts with NF-κB and promotes enhanced export of the p65 subunit from the nucleus, peaking at 20 min [30]. The sustained response observed in the current study may include GR-induced expression of additional proteins such as Glucocorticoid-induced leucine zipper (GILZ), that both bind and inhibit p65 as well and further stimulates increased export of p65 out of the nucleus [31,32].…”

Mechanisms of NF-κB p65 and strategies for therapeutic manipulation

“…In this context, steric blockade of p65-TAD using GILZ mimetics or mimics of the p65:Smad4 interface appears to be a promising strategy to selectively inhibit activated p65. 91 , 100 , 131 Targeted intracellular delivery in a context- and tissue-specific manner is another drawback that impedes development of effective p65 inhibitors. It is anticipated that advances in nanotechnology-based delivery systems will assist in not only improving the pharmacokinetic profile but also facilitate contextual delivery of drugs and drug-like agents.…”

“…89 GILZ has been shown to physically bind the p65 TAD via its proline-rich region and inhibit NF-κB signaling. 90 , 91 In protein interfaces, proline-rich regions that adopt extended polyproline type II helical conformation constitute excellent drug templates with the specificity of the interaction determined by the residues adjacent to the interacting moieties in each partner. 60 , 92 Synthetic peptide mimics of the p65 binding motif of GILZ suppressed nuclear translocation of p65, inflammation, and apoptosis.…”

Geniposide protects PC12 cells from lipopolysaccharide-evoked inflammatory injury via up-regulation of miR-145-5p

“…In central nervous system, several stimuli such as LPS can induce the activation of NF-jB and JNK pathways [30,31]. The activated signalling triggers the production of proinflammatory cytokines and thereby induces inflammatory response and increases vulnerability to apoptosis [32,33]. Apart from inflammation, these two signalling pathways are also critical in regulating neuron survival and death [33,34].…”