Novel peptide inhibitor of dipeptidyl peptidase IV (Tyr-Pro-D-Ala-NH2) with anti-inflammatory activity in the mouse models of colitis

• Published in: Peptides (New York, N.Y. : 1980) Vol. 108; pp. 34 - 45
• Main Authors: Salaga, M, Binienda, A, Draczkowski, P, Kosson, P, Kordek, R, Jozwiak, K, Fichna, J
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2018
• Subjects: Colitis; DPP IV inhibitor; IBD; Inflammation; TNFα; DMSO; DPP; NSAID; HRP; IBD; HTAB; MPO; UC; AMC; i.c; PBS; CD; GI; GLP-1; IL; DSS; GLP2R; DIP; Inflammation; TNBS; EM-2; PETIR; Colitis; DPP IV inhibitor; GLP-2; GAPDH
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2018.08.011

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•Protease inhibition is a new approach in the inflammatory bowel disease therapy.•Dipeptidyl peptidase IV is a pharmacological target for anti-inflammatory drugs.•We designed a novel inhibitor of dipeptidyl peptidase IV, Tyr-Pro-D-Ala-NH2 – DI-1.•DI-1 inhibits degradation of colonic glucagon-like peptide 2.•DI-1 blocks dipeptidyl peptidase IV in vitro and attenuates colitis in vivo.
Protease inhibition has become a new possible approach in the inflammatory bowel disease (IBD) therapy. A serine exopeptidase, dipeptidyl peptidase IV (DPP IV) is responsible for 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, EMDB-1 (Tyr-Pro-D-ClPhe-Phe-NH2) is a potent blocker of DPP IV and exhibits an anti-inflammatory activity in vivo. The aim of this study was to design, synthesize and characterize the therapeutic activity and mechanism of action of a series of novel EMDB-1 analogs. The inhibitory potential of all peptides was evaluated using the fluorometric screening assay employing Gly-Pro-Aminomethylcoumarin (AMC) to measure DPP IV activity. Consequently, one compound, namely DI-1 was selected and its therapeutic activity evaluated using mouse models of experimental colitis (induced by TNBS and DSS). Macro- and microscopic score, ulcer score, colonic wall thickness as well as myeloperoxidase activity were measured. We showed that DI-1 blocks DPP IV in vitro (IC50 = 0.76 ± 0.04 nM) and attenuates acute, semichronic and relapsing TNBS- as well as DSS-induced colitis in mice after topical administration. Its anti-inflammatory action is associated with the increase of colonic GLP-2 but not GLP2 receptor or DPP IV expression. Our results validate DPP IV as a pharmacological target for the anti-IBD drugs and its inhibitors, such as DI-1, have the potential to become valuable anti-inflammatory therapeutics.