New Peptide Inhibitor of Dipeptidyl Peptidase IV, EMDB-1 Extends the Half-Life of GLP-2 and Attenuates Colitis in Mice after Topical Administration.

Protease inhibition has become a possible new approach in inflammatory bowel disease (IBD) therapy. A serine exopeptidase, dipeptidyl peptidase IV (DPP IV), is responsible for the inactivation of incretin hormone, glucagon-like peptide 2 (GLP-2), a potent stimulator of intestinal epithelium regeneration and growth. Recently, we showed that the novel peptide analog of endomorphin-2, Tyr-Pro-D-ClPhe-Phe-NH2 (EMDB-1) is a potent blocker of DPP IV and has an inhibitory effect on gastrointestinal (GI) smooth muscle contractility. The aim of this study was to characterize the anti-inflammatory effect and mechanism of action of EMDB-1 in the mouse GI tract. We used two models of experimental colitis (induced by TNBS and DSS). The anti-inflammatory effect of EMDB-1 was assessed by the determination of macroscopic score, ulcer score, colonic wall thickness, as well as myeloperoxidase activity. Additionally, we measured the expression of GLP-2, GLP2R, and DPP IV in the colon of control and colitic animals treated with the test compound. The expression of GLP-2 and GLP2R in the serum and colon of IBD patients and healthy control subjects has been assessed. We showed that EMDB-1 elevates the half-life of GLP-2 in vitro and attenuates acute, semichronic, and relapsing TNBS as well as DSS-induced colitis in mice after topical administration. The anti-inflammatory action of EMDB-1 is associated with changes in the level of colonic GLP-2 but not DPP IV expression. Our results validate DPP IV as a pharmacological target for the anti-IBD drugs, and its inhibitors based on natural substrates, such as EMDB-1, have the potential to become valuable anti-inflammatory therapeutic agents.