Chronic inflammation plays a major role in the onset and progression of many diseases. The transcription factor, nuclear factor-kappa B is critical for mediating inflammatory processes. The nuclear factor-kappa B is a family of five proteins; (p65, p50, p52, c-rel and Rel B) that function by dimerizing in different combinations. A disproportionate increase in activated p65:p50 nuclear factor-kappa B dimers drive the inflammatory responses that precipitate neurodegeneration in multiple central nervous system pathologies. We identified novel method to selectively suppress activated p65. Glucocorticoid induced leucine zipper (GILZ) is a nuclear factor-kappa B interactant that preferentially binds the transactivation domain of p65 exposed in activated cells. Structurally the p65 binding proline rich motif of GILZ adopts an extended polyproline type II (PPII) helical conformation. PPII helices behave as adaptable gloves in obtaining the correct orientation in the context of the binding partner which provides the specificity of the interaction. Hence PPII helical interface mimics are considered excellent candidate drugs/drug templates. We designed peptide analogs of GILZ using computational modeling. Biochemical studies suggested that select GILZ analogs exhibit similar binding kinetics with p65 transactivation domain as wild type GILZ. Functional analyses showed that the GILZ analogs suppressed cellular toxicity in human fetal brain cells induced by amyloid beta, critical plaque component in Alzheimer’s disease. Furthermore, GILZ peptide ameliorated disease progression in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. 1. Evidence-based: Increased activation of the p65 subunit of nuclear factor-kappa B upregulate inflammatory and pro-apoptotic factors and aggravate degeneration in chronic pathologies such as Alzheimer’s disease and progressive multiple sclerosis. Hence activated p65 is an excellent therapeutic target. 2. Inter/cross disciplinary: This is a collaborative research project with investigators from two IUPUI schools with expertise in immunology and peptide science (Dr. Mythily Srinivasan, School of Dentistry) and neurobiology and neurotherapeutics (Dr. Debomoy K. Lahiri, School of Medicine). 3) Goal oriented for the betterment of everyday life: The burden of neurodegenerative pathologies in increasing exponentially with an estimated 5.1 million and 400,000 Americans suffering from Alzheimer’s disease and multiple sclerosis respectively. Availability of few effective therapies and the high cost of care underscore the need for disease modifying treatments that suppress disease progression. The observed ability to suppress inflammatory responses in human mixed brain cultures and to protect mice against relapsing encephalomyelitis suggest that the GILZ peptide analogs possess significant therapeutic potential for Alzheimer’s disease and progressive multiple sclerosis and improve quality of life.