作者: Naim, Mohd. Javed ; Jamil Ahmed, Shaikh Mohd. Aatif ; Alam, Ozair ; Parveen, Bushra ; Jha, Mukund ; Mathur, Vishal ; Chandra, Kailash ; Nazar, Shagufi ; Iliyas, Anam ; Shamim, Saniya ; Ali, Shaheen

Abstract::

Diabetes mellitus, characterized as a chronic metabolic disorder or a polygenic syndrome; is increasing at a very fast pace among every group of the population worldwide. It arises due to the inability of the body to produce enough insulin (the hormone responsible for controlling blood sugar levels) or inability to utilize the insulin, leading to hyperglycaemic condition, which, if left uncontrolled gives rise to chronic microvascular and macrovascular complications like retinopathy, neuropathy, nephropathy, coronary artery disease, cognitive impairment, etc. Several therapeutic approaches are available for the treatment of diabetes; among which dipeptidyl peptidase (DPP-IV) inhibitors (gliptins) hold a significant place. DPP-IV is a multifunctional enzyme or a serine exopeptidase that plays an imperative role in cleaving bioactive molecules. DPP-IV causes the breakdown of incretin hormone (GLP-1: Glucagon-like peptide 1 and GIP: Glucose-dependent insulinotropic peptide) that is essential for controlling glycaemic levels in the body. Inhibition of DPP-IV enzyme (DPP-IV inhibitors: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin) prevents this breakdown, thereby controlling blood glucose levels and saving the patients from deleterious effects of prolonged hyperglycaemic conditions. Triazole-based DPP-IV inhibitors are a significant class of drugs used to treat Type 2 diabetes mellitus in a dose-dependent manner. Clinical trials have demonstrated their efficacy as monotherapy or in combination with other antidiabetic agents. This review highlights the molecular docking studies and structure-activity relationship of potential synthetic derivatives that may act as lead molecules for future drug discovery and yield drug molecules with enhanced efficacy, potency and reduced toxicity profile.

2018-10-01·Peptides

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

Article

作者: Salaga, M ; Binienda, A ; Draczkowski, P ; Kordek, R ; Jozwiak, K ; Kosson, P ; Fichna, J

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·The 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 ; Fichna, Jakub ; Malecka-Panas, Ewa ; Mokrowiecka, Anna ; Kordek, Radzislaw ; Kamysz, Elzbieta ; Salaga, Maciej

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.

100 项与 EMDB-1 相关的药物交易

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