NIPEP-IBD; A SYNTHETIC PEPTIDE TARGETING NOVEL MOLECULE, INTEGRIN BETA 1, TO RESTITUTE INTESTINAL EPITHELIAL CELLS FOR INFLAMMATORY BOWEL DISEASE (IBD) TREATMENT

Abstract

Under Inflammatory bowel disease (IBD), impaired intestinal barrier from lumen is highly associated with ongoing IBD symptoms and it also contributes as a precursor for IBD. Current IBD therapeutics lack on mucosal regeneration, which the unmet needs could be the next first in class therapeutics for IBD. Here, we propose NIPEP-IBD, a synthetically modified peptide that promotes adhesion, migration, and differentiation of intestinal epithelial cells via interaction of integrin beta 1. From NIBEC’s specialized peptide discovery platform screening, specifically sequenced peptide has been selected for regenerative functional peptide, termed NIPEP-IBD. NIPEP-IBD selectively targeted and bound to integrin beta 1 protein, and its interaction was also verified in vitro, using immunoprecipitation and immunofluorescence assays on epithelial cells. Consequently, NIPEP-IBD increased integrin beta 1 expression, followed by phosphorylated FAK and RhoA proteins. As FAK-RhoA signaling pathway is known to modulate cytoskeletal rearrangement and maturation of epithelial cells, tight junction markers and rapid wound closure of epithelial cells was accelerated by NIPEP-IBD induction. The effect of NIPEP-IBD was further analyzed in vivo IBD model. DSS-induced colitis mouse model was used to analyze therapeutic effect of NIPEP-IBD in each IP and PO administration, and impaired mucosa layer by DSS was recovered by NIPEP-IBD, verified with H&E staining. Moreover, NIPEP-IBD treated mice showed reduced immune cell infiltration in colon tissue and reduced pro-inflammatory cytokines in plasma. In vivo fluorescence imaging system was further used to track distribution of NIPEP-IBD, and NIPEP-IBD specifically binds to impaired epithelium, co-localized with integrin beta 1 protein. The following GLP toxicity studies, ADME studies, and PK studies demonstrated that safety of NIPEP-IBD was verified as a therapeutic agent. Therefore, NIPEP-IBD is a safe and effective therapeutic peptide on IBD patients by restituting epithelial layer of colon and maintain its remission.