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.
Highlights
An accumulating body of evidence suggests that a combination of age related changes in the central nervous system (CNS) with excessive or prolonged inflammatory responses contribute to the pathophysiology of neurodegeneration, synaptic dysfunction and hippocampal behavior deficits in conditions such as Alzheimer's disease (AD) [1, 2]
Molecular modeling showed that the glucocorticoid induced leucine zipper (GILZ)-COOH or a 22 residue peptide derived from the proline rich region adopted an extended polyproline type II (PPII) helical conformation and interacted with the p65-transactivation domain (TAD) exhibiting weak binding kinetics [27]
Alanine scanning mutagenesis suggested that the substitution of the 120PXXP123 motif abrogated the ability to inhibit NF-κΒ transactivation potentially due to loss of PPII conformation[24, 25]
Summary
An accumulating body of evidence suggests that a combination of age related changes in the central nervous system (CNS) with excessive or prolonged inflammatory responses contribute to the pathophysiology of neurodegeneration, synaptic dysfunction and hippocampal behavior deficits in conditions such as Alzheimer's disease (AD) [1, 2]. The pleiotropic transcription factor, nuclear factor-kappa B (NF-κΒ) is induced by many physiological and pathological stimuli in the CNS [2,3,4]. The NF-κΒ family consists of five members, p50, c-rel, p65, RelB and p52 that can diversely combine to form transcriptionally active dimers. It has been suggested that the nature of the dimers determine the effects of activated NF-κΒ. While c-rel containing dimers preferentially promote transactivation of anti-apoptotic factors, activation of p65/p50.
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