Udugamasooriya, D. Gomika

AbstractObjectiveTo discover a novel peptoid antagonist that targets the interleukin‐15 (IL‐15) receptor and to evaluate its therapeutic efficacy in the treatment of inflammation and arthritis.MethodsA new compound (IFRA3, interleukin‐15 receptor antagonist 3) was discovered using a unique on‐bead two‐colour combinatorial cell screening of a peptoid library. The interaction of IFRA3 with IL‐15 receptor was assessed by in vitro pull‐down and thermal shift assays. The efficacy of IFRA3 in treating inflammation and arthritis was evaluated in mouse models.ResultsIFRA3Q1 (a tetrameric derivative of IFRA3) inhibited the activity of IL‐15 and suppressed CTLL‐2 cell proliferation (which depends on IL‐15 activity). IFRA3Q1 exhibited strong in vivo anti‐inflammatory activity in carrageenan‐induced inflammation in mice. Furthermore, IFRA3Q1 inhibited collagen‐induced arthritis in DBA/1J mice.ConclusionBy binding to and inhibiting the function of IL‐15 receptor, IFRA3Q1 exhibited significant anti‐arthritis activity. Our findings suggest that IFRA3Q1 represents a new paradigm for arthritis therapy by targeting IL‐15 signalling.

Abstract Purpose: Various studies have shown the importance of the GAIP interacting protein, COOH-terminus (GIPC, also known as Synectin) as a central adaptor molecule in different signaling pathways and as an important mediator of receptor stability. GIPC/Synectin is associated with different growth-promoting receptors such as insulin-like growth factor receptor I (IGF-IR) and integrins. These interactions were mediated through its PDZ domain. GIPC/Synectin has been shown to be overexpressed in pancreatic and breast cancer. The goal of this study was to show the importance of GIPC/Synectin in pancreatic cancer growth and to evaluate a possible therapeutic strategy by using a GIPC-PDZ domain inhibitor. Furthermore, the effect of targeting GIPC on the IGF-I receptor as one of its associated receptors was tested. Experimental Design: The in vivo effects of GIPC/Synectin knockdown were studied after lentiviral transduction of luciferase-expressing pancreatic cancer cells with short hairpin RNA against GIPC/Synectin. Additionally, a GIPC-PDZ–targeting peptide was designed. This peptide was tested for its influence on pancreatic cancer growth in vitro and in vivo. Results: Knockdown of GIPC/Synectin led to a significant inhibition of pancreatic adenocarcinoma growth in an orthotopic mouse model. Additionally, a cell-permeable GIPC-PDZ inhibitor was able to block tumor growth significantly without showing toxicity in a mouse model. Targeting GIPC was accompanied by a significant reduction in IGF-IR expression in pancreatic cancer cells. Conclusions: Our findings show that targeting GIPC/Synectin and its PDZ domain inhibits pancreatic carcinoma growth and is a potential strategy for therapeutic intervention of pancreatic cancer.