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.

2017-10-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

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

3区 · 医学

Article

作者: Zielinska, Marta ; Malecka-Panas, Ewa ; Mokrowiecka, Anna ; Kamysz, Elzbieta ; Kordek, Radzislaw ; Salaga, Maciej ; Fichna, Jakub

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.

2012-07-01·Medicinal Chemistry Research4区 · 医学

Kinetic studies of novel inhibitors of endomorphin degrading enzymes

4区 · 医学

Article

作者: Jean Claude do-Rego ; Renata Perlikowska ; Katarzyna Gach ; Jakub Fichna ; Anna Janecka

Endomorphins (EMs), two endogenous μ-opioid receptor selective ligands, are attractive lead compounds for opioid-based pain management studies. However, these peptides are quickly degraded by peptidases, in particular by dipeptidylpeptidase IV (DPP IV) and aminopeptidase M (APM). Targeting enzymatic degradation is one approach to prolong endomorphin activity. In this study we characterized the action of two new inhibitors of similar to endomorphins structure, Tyr-Pro-Ala-NH(2) (EMDB-2) and Tyr-Pro-Ala-OH (EMDB-3), which were designed earlier in our laboratory. The presented data give evidence that EMDB-2 and EMDB-3 are potent inhibitors of enzymes responsible for endomorphin cleavage. These compounds are stable and easily synthesized. EMDB-2 and EMDB-3 are competitive inhibitors of both, DPP IV and APM, with K(i) values in micromolar range. They are less potent than diprotin A in protecting EMs against DPP IV but more potent than actinonin in protecting these peptides against APM.

项与 EMDB-1 相关的新闻（医药）

2022-12-07

·BioSpace

Lilly and Boehringer's Jardiance Racks Up Another Type 2 Diabetes Win

Cristina Arias/Getty Images In what has been a watershed year for diabetes treatment, Eli Lilly and Boehringer Ingelheim declared another victory Wednesday – this one for children and adolescents with Type 2 Diabetes. In a Phase III trial, Jardiance (empagliflozin), which pulled in $1.5B in revenue for Lilly last year, met its primary endpoint. The SGLT2 inhibitor led to a statistically significant reduction in HbA1c, a marker of average blood sugar, compared to placebo in kids 10 to 17 with T2D. According to Lilly and Boehringer, Jardiance is the first sodium-glucose co-transporter 2 (SGLT2) inhibitor to achieve this feat. When given in addition to diet, exercise, metformin and/or insulin, HbA1c was reduced by 0.84% compared with placebo at week 26. The DINAMO trial enrolled 262 children and adolescents, of which 158 were randomly assigned to be treated with Jardiance (10 or 25 mg), Boehringer’s Tradjenta (linagliptin) (5 mg) or placebo once daily. Tradjenta, an inhibitor of dipeptidyl peptidase-4 (DPP-4), did not achieve statistical significance in reducing HbA1c compared to placebo. The data were presented Wednesday at the International Diabetes Federation (IDF) World Diabetes Congress 2022. Principal study investigator Lori Laffel, M.D., chief of the pediatric, adolescent, and young adult section at the Joslin Diabetes Center and professor of pediatrics at Harvard Medical School, pointed to the importance of early intervention for T2D patients. “These findings are particularly important given the need for more therapeutic options, especially oral agents, to manage type 2 diabetes in young people as, to date, metformin is the only globally available oral treatment for youth,” Laffel said in a statement. In a secondary endpoint, Jardiance also reduced fasting plasma glucose. The overall safety data was “generally consistent with previous findings in adults with type 2 diabetes,” according to the press release. Upward Momentum The diabetes space has seen upward momentum of late, with the historic approval last month of Provention Bio’s intravenous antibody TZIELD ((teplizumab-mzwv) to delay stage 3, Type 1 Diabetes. TZIELD is the first disease-modifying drug indicated to slow disease progression. It’s been an upbeat year for the Jardiance franchise as well. In November, Jardiance met the primary endpoint in the III EMPA-KIDNEY study, lowering the risk of kidney disease progression or cardiovascular death by 28%. Lilly and Boehringer called it “the largest and broadest trial studying an SGLT2 inhibitor in chronic kidney disease.” The data positioned Jardiance to compete with AstraZeneca’s Farxiga, the current leader in the CKD space. And in June, Lilly and Boehringer presented data from a real-world study showing Jardiance decreased risk of hospitalization for heart failure by 50% in adults with T2D versus DPP-4 inhibitors. Against glucagon-like peptide 1 (GLP-1) receptor agonists, this number was 30%. Jardiance is approved to reduce the risk of cardiovascular (CV) death and hospitalization for heart failure in adults with heart failure when the heart can’t pump enough blood to the rest of the body. It is also intended to reduce the risk of CV death in adults with type 2 diabetes who also have known cardiovascular disease and to lower blood sugar, along with diet and exercise, in adults with T2D.

临床结果临床3期上市批准AHA会议

100 项与 EMDB-1 相关的药物交易

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