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CGEN-25007
The gp96 protein, a member of the family of heat shock proteins, normally resides in the lumen of the endoplasmic reticulum, where its chaperone function plays fundamental roles vital for the proper folding of many proteins. gp96 gains extra-cellular access following cellular stress, and necrotic cell death, The gp96 protein triggers both the innate and adaptive arms of the immune system, and its involvement in inflammatory responses has been demonstrated in recent years, pointing to its potential as a target for therapeutic intervention in the treatment of inflammation and immune-related disorders. Using the DAC Blockers discovery platform (Kliger et al., 2009), Compugen has identified a novel peptide, CGEN-25007, which displays potent anti-inflammatory activity. CGEN-25007 was found to significantly reduce the secretion of pro-inflammatory cytokines when tested on human peripheral blood mononuclear cells (PBMCs) or murine splenocytes challenged with various stimuli.In mice challenged with LPS, a model of endotoxemia, CGEN-25007 exhibited profound anti-inflammatory activity, manifested in a decrease of serum levels of several inflammatory cytokines and chemokines. This peptide also protected mice from the lethal effect of IL-12+IL-18 administration, an established model of acute inflammation, and markedly attenuated the weight loss and severe diarrhea observed in this model, concomitantly with a dramatic reduction in plasma cytokine levels. The anti inflammatory activity of CGEN-25007 was further evaluated in a chronic disease model: TNBS-induced colitis, an animal model of IBD (inflammatory bowel disease). Administration of CGEN-25007 had a pronounced protective effect in this model, as manifested by the increase in survival rate and by a mild and reversible weight loss, while untreated mice showed an irreversible and fatal wasting syndrome. This protective effect was further confirmed by improved endoscopic and histological colitis scores, which were similar to those obtained with corticosteroids. |
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