Dipeptidyl Peptidase Research Articles

Identification of promising dipeptidyl peptidase-4 and protein tyrosine phosphatase 1B inhibitors from selected terpenoids through molecular modeling.

Investigating novel drug-target interactions is crucial for expanding the chemical space of emerging therapeutic targets in human diseases. Herein, we explored the interactions of dipeptidyl peptidase-4 and protein tyrosine phosphatase 1B with selected terpenoids from African antidiabetic plants. Using molecular docking, molecular dynamics simulations, molecular mechanics with generalized Born and surface area solvation-free energy, and density functional theory analyses, the study revealed dipeptidyl peptidase-4 as a promising target. Cucurbitacin B, 6-oxoisoiguesterin, and 20-epi-isoiguesterinol were identified as potential dipeptidyl peptidase-4 inhibitors with strong binding affinities. These triterpenoids interacted with key catalytic and hydrophobic pockets of dipeptidyl peptidase-4, demonstrating structural stability and flexibility under dynamic conditions, as indicated by dynamics simulation parameters. The free energy analysis further supported the binding affinities in dynamic environments. Quantum mechanical calculations revealed favorable highest occupied molecular orbital and lowest unoccupied molecular orbital energy profiles, indicating the suitability of the hits as proton donors and acceptors, which likely enhance their molecular interactions with the targets. Moreover, the terpenoids showed desirable drug-like properties, suggesting their potential as safe and effective dipeptidyl peptidase-4 inhibitors. These findings may pave the way for the development of novel antidiabetic agents and nutraceuticals based on these promising in silico hits. Not applicable.

Comparative Effectiveness of Oral Hypoglycemic Agents for Glycemic Control and Glycemic Variability in Patients with Type 2 Diabetes Mellitus: Using Flash Glucose Monitoring.

The study aimed to compare the effectiveness of oral hypoglycemic agents (OHAs) as monotherapy, dual and quadruple therapy for glycemic control (GC) and glycemic variability (GV) in patients with type 2 diabetes (T2DM) using flash glucose monitoring system (FGM). Diabetes management largely relies on HbA1c monitoring. Glycemic variability has been an evolving glycemic target for preventing complications related to type 2 diabetes mellitus. The purpose of the study was to compare glycemic control measures and glycemic variability measures among study groups and to study the relationships between GC and GV indices. Retrospectively, FGM data were collected from 50 T2DM patients. The patients were classified based on prescribed number of OHAs as monotherapy [group 1: Dipeptidyl peptidase- 4 (DPP-4) inhibitors (n=10), group 2: Sodium-glucose co-transporter-2 (SGLT2) inhibitors (n=10), group 3: Sulphonylureas (n=10), group 4: Dual therapy (n=10), and group 5: Quadruple therapy (n=10)]. Measures of GC and GV were evaluated. Significant differences between study groups were observed in GC and GV measurements. The SGLT2 inhibitors monotherapy group demonstrated optimal GC [eA1c (%): 6.5 ± 2.2; MBG: 140.80 ± 63.94; TIR: 60.60 ± 19.96] and GV (SD: 42.38 ± 34.57; CV: 27.85 ± 6.68; MAGE: 96.76 ± 52.47; MODD: 33.96 ± 22.91) in comparison to other study groups. On using Pearson correlation analysis, mean blood glucose (MBG) and mean amplitude of glycemic excursion (MAGE) showed moderate correlation (r = 0.742)(r2 = 0.551), depicting distinct glucose variabilities at the same mean blood glucose levels. The monotherapy group of SGLT2 inhibitors demonstrated glucose-lowering effects with reduced glycemic variability. Hence, optimum glycemic control is associated with decreased glycemic variability.

Identification and characterization of two novel dipeptidyl peptidase-IV inhibitory peptides from the simulated gastrointestinal digestion of Tartary buckwheat proteins.

This study analyzed dipeptidyl peptidase-IV (DPP-IV) inhibitory peptides from Tartary buckwheat (Fagopyrum tataricum) protein hydrolysates, known for managing chronic diseases. Simulated gastrointestinal digestion enhanced the inhibitory activity of DPP-IV. Using anion-exchange resin DEAE-52, reverse high-performance liquid chromatography, and LC-MS/MS, eight novel peptides were identified. Among them, the peptides LAGQS (LA5) and LREIDDADK (LR9) exhibited the strongest inhibition in both competitive and noncompetitive modes. Molecular docking revealed electrostatic, hydrogen bond, and hydrophobic interactions for both peptides, with LR9 also engaging in π-cation interactions. Based on the Caco-2 model, the in situ DPP-IV inhibitory effect of LR9 was superior to that of LA5, likely because of LR9's greater stability during hydrolysis. Moreover, LA5 could not be transported through the Caco-2 monolayer, and LR9 demonstrated moderate transportability. These findings highlight Tartary buckwheat protein's potential for application in high-value plant-based products, including functional foods and pharmaceuticals targeting blood glucose regulation using DPP-IV inhibitory peptides.

Linagliptin: A comprehensive profile.

Linagliptin (LINA) is the first dipeptidyl peptidase IV (DPP-IV) inhibitor that could be administered orally to control hyperglycemia. It is indicated for controlling adult blood sugar levels that are diagnosed with diabetes mellitus type II. The current chapter provides a complete review of LINA including nomenclature, physiochemical characteristics, synthesis, and thermal analysis. Additionally, different analytical techniques used for quantitative and qualitative determination of LINA are presented.

Current practices in prevention, screening, and treatment of diabetes in kidney transplant recipients: European survey highlights from the ERA DESCARTES Working Group.

Although post-transplant diabetes mellitus (PTDM) is a common complication after kidney transplantation, there are few data on prevention, optimal screening, and treatment strategies. The European Renal Association's DESCARTES working group distributed a web-based survey to European transplant centres to gather information on risk assessment, screening procedures, and management practices for preventing and treating PTDM in kidney transplant recipients. Answers were obtained from 121/241 transplant centres (50%) across 15 European countries. Screening practices for diabetes mellitus during the transplant work-up varied, with only 13% of centres using the recommended oral glucose tolerance test (OGTT) and 14% not screening at all. At transplantation, 19% of centres tailored the immunosuppressive regimen based on perceived PTDM risk, using strategies such as cyclosporin use or early steroid withdrawal. Fifty-two percent adopted strict glycaemic control with basal insulin in the first days post-transplant. Sixty-eight percent had defined screening protocols for early PTDM (45 days-6 months), primarily based on fasting glycaemia and/or HbA1c, while only a minority (7%) incorporated an OGTT. Changes in immunosuppression were considered by 41% in cases of early hyperglycaemia (<45 days) and by 58% in established PTDM (>45 days). Besides insulin therapy, dipeptidyl peptidase-4 (DPP4) inhibitors and metformin were most frequently used to manage early hyperglycaemia (<45 days) and PTDM (>45 days). The use of SGLT2 inhibitors and GLP-analogues increased >45 days post-transplantation. This European survey underscores the significant variation in PTDM prevention, screening, and treatment practices, emphasizing the imperative for more explicit guidance in approaching this complication.

Betagenin ameliorates diabetes by inducing insulin secretion and β-cell proliferation.

Recent success with the use of glucagon-like peptide-1 (GLP-1) receptor analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of patients with diabetes has highlighted the role of the intestine as an endocrine organ. Gut-derived hormones, including GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and ghrelin, have important roles in the control of energy metabolism and food intake, and are associated with the metabolic syndrome. In this study, we isolated and identified a new intestine-derived hormone, betagenin, and showed that it stimulates insulin secretion and β-cell proliferation and suppresses β-cell apoptosis. Adenovirus-mediated expression of betagenin restored the blood glucose concentrations and hemoglobin A1c (HbA1c) levels of mice with streptozotocin (STZ)-induced diabetes to normal and increased their β-cell mass. Transgenic mice overexpressing betagenin exhibited more than three-fold higher β-cell mass than wild-type mass, whereas that of knockout mice was four-fold lower. A synthetic peptide representing the sequence of purified and secreted betagenin enhanced glucose-dependent insulin secretion in human and mouse pancreatic islets and stimulated the proliferation of the pancreatic β-cell line MIN6 through extracellular signal-regulated kinase (ERK) 1/2-dependent signaling. The intravenous administration of this peptide to STZ mice stimulated the proliferation of pancreatic β-cells in vivo, and the intraperitoneal administration of betagenin ameliorated diabetes and restored β-cell mass. These results indicate that betagenin may reduce blood glucose concentration and induce β-cell regeneration in patients with diabetes.

Dipeptidyl peptidase-4 inhibitor linagliptin reduces inflammatory response, ameliorates tissue edema formation, and improves survival in severe sepsis.

Excessive inflammation in sepsis causes microvascular dysfunction associated with organ dysfunction and high mortality. The present studies aimed to examine the therapeutic potential of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor in a clinically relevant polymicrobial sepsis model in mice. Sepsis was induced by cecal ligation and puncture (CLP). Mice were grouped into: Sham control+vehicle; Group 2: CLP+vehicle; Group 3: CLP+dexamethasone (10 mg/kg, s.c.) given 6 h after CLP; Group 4: CLP+linagliptin (1 mg/kg, s.c.) given 6 h after CLP. The experiment was terminated 24 hours after CLP in two experimental sets. Seven-day survival following CLP was determined in a third experimental set. Treatment with linagliptin inhibited DPP-4 activity, increased the levels of active forms of endogenous gastric inhibitory polypeptide and glucagon-like peptide-1, without affecting the blood glucose levels in CLP mice. Compared to vehicle treatment, administration of linagliptin reduced sepsis-induced tissue hyper permeability as evidenced by a reduction in vascular Evans blue leakage, prevented edema formation in the lung, heart, liver and kidney. Furthermore, linagliptin or dexamethasone reduced sepsis-induced proinflammatory cytokine and chemokine production, such as IL-1β, IL-2, IL-10, IL-23, IL-27, VCAM-1, eotaxin, MDC, MCSF1, GCP-2, and NGAL. Importantly, administration of linagliptin improved the 7-day survival rate following CLP in mice. RNA sequencing in lung and heart revealed that linagliptin attenuated key inflammatory pathways including TNF alpha (via NFκB) and IL6/JAK/STAT3 signaling and activated interferon signaling in the heart. Linagliptin treatment can attenuate the inflammatory response, protect against severe sepsis-induced vascular hyperpermeability, reduce multiorgan injury, and most importantly, improve the survival.

Analysis of the Endocrine Responses to Anti-Diabetes Drugs: An Issue of Elevated Plasma Renin Concentration in Sodium-Glucose Co-Transporter 2 Inhibitor.

Glucose metabolism is associated with several endocrine disorders. Anti-diabetes drugs are crucial in controlling diabetes and its complications; nevertheless, few studies have been carried out involving endocrine function. This study aimed to investigate the association between anti-diabetes drugs and endocrine parameters. We performed a study of 180 consecutive patients with type 2 diabetes who attended a medical center. Laboratory measurements of metabolic values and endocrine parameters were assessed after a stable treatment regimen of more than 12weeks. The differences in various endocrine parameters were compared between subjects with or without certain anti-diabetes drugs, with the administrated anti-diabetes drugs being analyzed to find independent risks associated with elevated endocrine parameters. After maintaining stable treatment, acceptable glycemic control was noted with an average HbA1c of 7.55% in females and 7.43% in males. Participants taking sulfonylurea (55.8 vs 26.34 ng/L, P=0.043), dipeptidyl peptidase-4 inhibitor (DPP4i) (47.14 vs 32.26 ng/L, P=0.096), or sodium-glucose co-transporter 2 inhibitor (SGLT2i) (64.58 vs 28.11 ng/L, P=0.117) had higher plasma renin concentrations compared to those without this drug but the aldosterone levels did not differ, as well as for other adrenal tests and thyroid function. Under linear regression modeling, SGLT2i was found to be independently associated with a risk of high renin level (beta coefficient: 30.186, 95% confidence interval: 1.71─58.662, P=0.038), whereas sulfonylurea only had borderline associations (B: 21.143, 95% CI: -2.729─45.014, P=0.082). Additionally, renin-angiotensin-aldosterone system (RAAS) blockade (B: 36.728, 95% CI: 12.16─61.295, P=0.004) or diuretics (B: 47.847, 95% CI: 2.039─93.655, P=0.041) was also independently associated with increased renin levels. SGLT2i was the only class of anti-diabetes drugs independently associated with elevated renin levels, with results similar to RAAS blockade and diuretics. Although SGLT2i appears to protect reno- and cardio-function, the clinical impact of increased renin warrants further precise study for verification.

Orally administered prednisolone decreases plasma arginine vasopressin and serum copeptin concentrations in healthy dogs.

The pathophysiology of polyuria and polydipsia secondary to exogenous glucocorticoid excess is incompletely understood. Investigate plasma AVP (pAVP) and serum CoP (sCoP) concentrations in healthy dogs before, during, and after abrupt discontinuation of a long-term course of orally administered prednisolone. Eight healthy neutered young adult research Beagles. In our prospective longitudinal study, Beagles were treated with a placebo PO q24h for 15 days (baseline), followed by a 35-day course of prednisolone (2.35-2.75 mg/kg PO q24h) and then abrupt discontinuation of prednisolone. Serial pAVP and sCoP concentrations, urine specific gravity (USG) and calculated plasma osmolality (pOsmcalculated) were determined during placebo and prednisolone administration, and up to 4 weeks after prednisolone discontinuation. Paired plasma samples for pAVP measurement were obtained in EDTA tubes with (pAVPP800) and without (pAVPEDTA) a proprietary combination of protease, esterase, and dipeptidyl peptidase-IV inhibitors (BD Biosciences P800). Mean pAVPP800 and sCoP concentrations were significantly lower at the end of the prednisolone course (25.8 ± 8.1 pg/mLand 166 pg/mL, range, 131-223) vs baseline (34.1 ± 5.4 pg/mL and 243 pg/mL, range, 157-336; P = .02, P = .02, respectively). Correlations between pAVPP800 and sCoP (r = .77, P = .001) and pAVPP800 and USG (r = .61, P = .02) were positive, despite no correlation between pAVPP800 and pOsmcalculated, sCoP and pOsmcalculated, and sCoP and USG. On paired samples, mean pAVPEDTA was significantly lower (5.0 ± 2.5 pg/mL) than mean pAVPP800 (34.1 ± 5.4 pg/mL; P < .0001). Orally administered prednisolone led to markedly decreased plasma AVP and serum CoP concentrations despite increased calculated plasma osmolality and stable systolic blood pressure.

Glucagon-Like Peptide 1 Receptor Agonists and Chronic Lower Respiratory Disease Among Type 2 Diabetes Patients: Replication and Reliability Assessment Across a Research Network.

The aim of this study is to use observational methods to evaluate reliability of evidence generated by a study of the effect of glucagon-like peptide 1 receptor agonists (GLP-1RA) on chronic lower respiratory disease (CLRD) outcomes among Type-2 diabetes mellitus (T2DM) patients. We independently reproduced a study comparing effects of GLP-1RA versus dipeptidyl peptidase-4 inhibitors (DPP4-i) on CLRD outcomes among patients with T2DM and prior CLRD. We reproduced inputs and outputs using the original study data (national administrative claims) and evaluated the robustness of results in comparison to alternate design/analysis decisions. To evaluate generalizability, we applied an analysis protocol and conducted a meta-analysis across a research network that includes a diverse array of populations and data sources. We also produced additional analyses evaluating individual drugs within the GLP-1RA class and CLRD outcomes. We confirmed alignment of study inputs and outputs and closely reproduced effect estimates and sensitivity analyses. Adjusted effect estimates were robust to empirical calibration. Network meta-analysis confirmed original findings but indicated weaker effects than originally published. Meta-analysis of drugs within the GLP-1RA class against DPP4-i provided evidence that effects vary within the GLP-1RA class, indicating stronger effects for exenatide and weaker effects of dulaglutide. This study supports and establishes the reliability of the original study by (1) producing consistent findings in a range of alternate databases and populations, (2) demonstrating effects for multiple drugs within the GLP-1RA class, and (3) independently confirming the reproducibility of the original study and its findings. This reliability evaluation provides the beginnings of a broader framework for using standardized tools and distributed data networks to systematically interrogate the reliability of findings generated using observational data.

Lifestyle and Pharmacologic Approaches to Prevention of Metabolic Dysfunction-associated Steatotic Liver Disease-related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major concern for public health. Fatty liver disease, related to alcohol misuse or metabolic syndrome, has become the leading cause of chronic liver disease and HCC. The strong association between type 2 diabetes mellitus and HCC can be partly attributed to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). There is a strong interest in strategies that may mitigate HCC risk and reduce HCC incidence in this growing population of at-risk individuals. In this review, we describe the pathogenesis of HCC in patients with MASLD and discuss potential emerging pharmacological and lifestyle interventions for MASLD-related HCC. HCC risk has been observed to be lower with healthy lifestyle behaviors, such as healthy dietary patterns (eg, high consumption of vegetables, whole grains, fish and poultry, yogurt, and olive oil, and low consumption of red and processed meats and dietary sugar) and increased physical activity. Selecting an appropriate anti-diabetic therapy for individuals with liver disease and diabetes may also decrease the occurrence of HCC. Metformin, PPAR activators, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, aspirin, and statins have all shown promise to reduce the risk of HCC, although guidelines do not recommend their use for the sole purpose of chemoprevention at this time, given a dearth of data defining their risk-benefit ratio.

A Phase-IV, Multi-centric, Open Label, Comparative Clinical Trial to Evaluate Safety, Tolerability, and Efficacy of Oral Tablets of Fixed-dose Combination of Alogliptin and Metformin Hydrochloride versus Alogliptin in the Treatment of Indian Type-2 Diabetes Mellitus Patients: CONFIDENCE Trial

Introduction: Dipeptidyl peptidase-4 inhibitors are widely used antidiabetic drugs due to their convenient dosing, modest HbA1C reduction, and minimal risk of hypoglycemia, commonly prescribed in combination with metformin. A phase-IV, multi-centric, open-label, randomized, comparative clinical trial aimed to evaluate the safety, efficacy, and tolerability of a fixed-dose combination (FDC) of alogliptin + metformin hydrochloride versus alogliptin oral tablet in the management of Indian patients with type-2 diabetes mellitus (T2DM). Methods: This was a multi-center, randomized, open-label, comparative, parallel-group, phase IV clinical study. The study duration was 180 days, with follow-ups conducted at 30, 60, 90, and 180 days. Safety evaluations included assessing adverse events (AEs), serious adverse events (SAE), laboratory tests, and vital parameters. Parameters such as HbA1C, fasting plasma glucose (FPG), and postprandial glucose (PPG) were analyzed at baseline and at the end of the study. The trial was registered at ClinicalTrials.gov: CTRI/2021/11/038226. Results: Out of 362 enrolled patients, 344 completed the study; 166 received the FDC of alogliptin + metformin and 178 received alogliptin only. After 6 months, the mean reduction in HbA1C from baseline was − 2.07 (P &lt; 0.001) in the FDC of alogliptin + metformin group and − 1.29 (P &lt; 0.001) in the alogliptin group. Mean FPG decreased significantly in both groups, with a greater reduction observed in the FDC of alogliptin + metformin group (−103.65, P &lt; 0.001). Similarly, there was a significant reduction in mean PPG in both groups, with a greater reduction observed in the FDC of alogliptin + metformin group (−143.11, P &lt; 0.001). Out of 166, 25 (15.10%) patients experienced 10 AE in the FDC of alogliptin + metformin group and 23 out of 178 (12.90%) patients experienced 10 AE in the alogliptin group. All the reported AE were mild in severity and resolved completely. No serious adverse events were reported in either treatment group. Conclusions: In this study, alogliptin and the FDC of alogliptin + metformin were well tolerated, without any serious adverse events reported. These findings suggest that both treatment options are promising for managing Indian T2DM patients in terms of safety, efficacy, and tolerability.

Fixed-dose Combination of Dapagliflozin and Linagliptin in Individuals with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: A Randomized Double-blind Multicenter Trial

Abstract Context: Combining dipeptidyl peptidase 4 inhibitors and sodium-glucose cotransporter-2 inhibitors in therapy could be beneficial for those with metformin intolerance or not achieving adequate control. Aims: To evaluate the efficacy, safety, and tolerability of a fixed-dose combination (FDC) of dapagliflozin plus linagliptin in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. Settings and Design: It is a phase III, prospective, randomized, double-blind, multicenter study. Materials and Methods: Patients with T2DM, with a stable dose of metformin ≥1000 mg/day as monotherapy for at least 3 months before screening, with inadequate glycemic control at screening were randomly assigned to either arm A (dapagliflozin 10 mg + linagliptin 5 mg) or arm B (linagliptin 5 mg) in a 1:1 ratio. Statistical Analysis Used: The primary and secondary efficacy endpoint analyses were done using repeated measures analysis of covariance or a two-sample t test. All safety parameters were analyzed using a two-sample t test and descriptive statistics. Results: A total of 232 patients were randomized in arm A (n = 112) and arm B (n = 110). At week 16, arm A showed a significant mean reduction in glycated hemoglobin (HbA1c) than arm B (−1.35% vs. −0.92%; P≤0.0001). Similarly, the mean reductions in fasting plasma glucose (−26.13 mg/dL vs. −22.59 mg/dL; P = 0.0492), 2-h postprandial plasma glucose (−52.29 mg/dL vs. −30.35 mg/dL; P≤0.0001), and body weight (−1.32 kg vs. −0.42 kg; P≤0.0001) were significantly higher in arm A than in arm B. Arm A had a higher proportion of patients achieving HbA1c &lt;7.0% (42.24% vs. 22.41%; P = 0.0012). Adverse events were comparable between study arms. Conclusions: The FDC of dapagliflozin and linagliptin was superior in terms of improvement in glycemic control and a higher proportion of patients achieving target HbA1c level, with both treatment arms being well-tolerated.

Therapeutic potential inhibitor for dipeptidyl peptidase IV in diabetic type 2: in silico approaches.

Diabetes mellitus (DM)is a metabolic disease marked by an excessive rise in blood sugar (glucose) levels caused by a partial or total absence of insulin production, combined with alterations in the metabolism of proteins, lipids, and carbohydrates. The International Diabetes Federation estimates that 425 million individuals globally had diabetes in 2017 which will be 629 million by 2045. Several medications are used to treat DM, but they have limitations and side effects including weight gain, nausea, vomiting, and damage to blood vessels and kidneys. Therefore, it is essential to identify anti-diabetic drugs that have lessor no side effects. Hence, the current study employed in silico approaches to discover new DPP-IV inhibitors that might be associated with diabetes. Thirty-four (34) co-crystalized DPP-IV enzymes were found from the protein data bank and the co-crystal ligands were docked into the active-site 6B1E protein to find out the hit compounds. From the docking results, we found two hit compounds (5T4E and 4J3J) which were used to find out the analogs from the experimental drug database using the DrugRep software. According to the results, twenty (20) analogs were found from the experimental drug database with the similarity score of ≥ 0.790 and docked once again into the active site of the DPP-IV (PDB ID: 6B1E) enzyme. Interestingly, DB02226 showed the best binding affinity (-10.3kcal/mol) and prime MM/GBSA (-68.73kcal/mol) compared to the reference drug (co-crystal ligand; -7.4kcal/mol and -47.49kcal/mol, respectively). Additionally, DB02226 has shown excellent reactivity, efficacy, and structural stability in the binding region of target proteins in studies using MD simulation, MM/GBSA, DFT, and MESP analysis. These findings can be utilized to support further in vitro, in vivo, pre-clinical and clinical research rather than definitively confirming anti-diabetic effectiveness.

Uncovering Potential Novel Antidiabetic Compounds from African Traditional Medicinal Plants: A Computer-Aided Study

Background: The prevalence of type 2 diabetes mellitus (T2DM) has increased markedly in recent years. Although traditional medicinal plants and natural products offer promising candidates for antidiabetic drugs, their full potential remains largely underexplored. Objectives: This study aimed to identify antidiabetic phytocompounds from a database of African plant-derived compounds, which were screened against four key antidiabetic targets: alpha-amylase 1 (AMY1A), α-glucosidase (MGAM), Protein Tyrosine Phosphatase 1B (PTP1B), and dipeptidyl peptidase IV (DPP-IV). Methods: The compounds were initially filtered for drug-likeness and subsequently screened using molecular docking. The top candidates underwent molecular dynamics (MD) simulations. During these simulations, the binding energies were calculated using the Molecular Mechanics Generalized Born Surface Area (MMGBSA) method. Additionally, several structural parameters such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (rGyr), polar surface area (PSA), molecular surface area (MolSA), and solvent accessible surface area (SASA) were analyzed. Results: A total of 43 unique compounds belonging to several chemical classes (i.e., flavonoids, terpenoids, alkaloids, iridoids, and xanthones) were identified, exhibiting docking scores comparable to known controls. The results were as follows: docking scores of -7.4 to -8.7 kcal/mol (control: -9.7) for AMY1A, -6.8 to -8.0 kcal/mol (control: -8.2) for MGAM, -8.1 to -9.6 kcal/mol (control: -9.3) for DPP4, and -5.9 to -6.8 kcal/mol (control: -9.1) for PTP1B. MD simulations indicated that AMY1A-101679366 and DPP4-393472 complexes are negative and notably lower (-65.3 kcal/mol and -54.1 kcal/mol, respectively) than their respective controls. Furthermore, the MD simulations revealed relatively stable RMSD and RMSF profiles for the complexes, with fluctuations below 2.0 Å. The rGyr, PSA, MolSA, and SASA analyses further confirmed the stability of the protein-ligand complexes. Conclusion: The findings unveiled several compounds with promising antidiabetic potential, establishing a basis for further in vitro and in vivo studies to explore their therapeutic applications in T2DM treatment. Additionally, these compounds may serve as scaffolds for enhanced drug development.

Middle East respiratory syndrome coronavirus (MERS-CoV) internalization does not rely on DPP4 cytoplasmic tail signaling

AbstractMiddle East respiratory syndrome coronavirus (MERS-CoV) infects respiratory epithelial cells in humans and camels by binding to dipeptidyl peptidase 4 (DPP4) as its entry receptor. DPP4 is a multifunctional type II membrane protein with a long ectodomain and a short six-amino-acid (aa) cytoplasmic tail. MERS-CoV is known to bind to the ectodomain of DPP4 to gain entry into the host cell. However, the role of the cytoplasmic tail in the entry process remains unclear. Here, we show that mutating or deleting individual aa residues or the entire cytoplasmic tail of DPP4 (ΔcytDPP4) does not completely prevent DPP4 from being inserted into the membrane or from allowing the binding of the MERS-CoV spike protein and pseudovirus infection. Although two mutants, ΔcytDPP4, and a single aa deleted DPP4 (ΔK6DPP4) displayed less surface presentation than wtDPP4, the spike protein could still bind and localize on different DPP4 mutants. The reduced surface expression of ΔK6DPP4 might be due to the extended transmembrane domain, which is altered by the hydrophobic tryptophan (W) residue adjacent to the deleted K6. Furthermore, HEK293T cells transiently expressing DPP4 mutants were permeable to MERS-CoV pseudovirus infection. Not only transiently expressing cells but also cells stably expressing the ΔcytDPP4 mutant were susceptible to MERS-CoV pseudoviral infection, indicating that the DPP4 cytoplasmic tail is not required for MERS-CoV entry. Overall, these data suggest that, although MERS-CoV binds to DPP4, other host factors may need to interact with DPP4 or the spike protein to trigger internalization.

A comprehensive study on sitagliptin in the treatment of Type-II Diabetes

Sitagliptin is an oral antihyperglycemic drug classified as a dipeptidyl peptidase-4 (DPP-4) inhibitor; commonly used in the treatment of type 2 diabetes. It works by promoting insulin secretion and decreasing glucagon levels through the inhibition of incretin degradation in a glucose-dependent manner. As of 2013; it was the second-highest selling medication in the United States. This review highlights various analytical techniques for the quantification of sitagliptin; either alone or in combination with other agents. These methods include spectrometry; high-performance liquid chromatography (HPLC); liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS); liquid chromatography-mass spectrometry (LC-MS); capillary electrophoresis (CE); ultra-performance liquid chromatography (UPLC); high-performance thin-layer chromatography (HPTLC); and gas chromatography-mass spectrometry (GC-MS).

High-Throughput Screening of DPPIV Inhibitors Antagonizing GLP-1 Degradation Using an Enzymatic Activated Fluorescent Probe.

Dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) is an exopeptidase widely expressed on various cell surfaces that selectively cleaves N-terminal dipeptides from diverse substrates. In recent years, DPPIV inhibitors have been extensively utilized in the treatment of hepatitis mellitus (DM). In this study, we designed a far-red fluorescent probe, DBX-AP, through molecular docking simulations and by leveraging the functional characteristics of DPPIV. This probe enables rapid, highly selective, and real-time monitoring of DPPIV activity both in vitro and in vivo. Using DBX-AP, we developed a visual high-throughput screening technique for the detection of DPPIV inhibitors. From a library of 4828 compounds, three inhibitors (K784-2660, 6484-0066, and E699-0153) were identified for their strong inhibitory effects on DPPIV. These inhibitors not only suppressed DPPIV activity in the ileum of mice, thereby reducing GLP-1 degradation, but also effectively inhibited DPPIV activity in gut microbiota. The successful application of DBX-AP in visual detection technology highlights its potential for evaluating DPPIV activity and identifying novel DPPIV inhibitors for diabetes mellitus treatment.

Dynamic gastrointestinal digestion of tilapia (Oreochromis mossambicus) skin gelatin: changes of hydrolysate properties and dipeptidyl peptidase IV inhibitory activity.

It is important to study the physicochemical properties of tilapia (Oreochromis mossambicus) skin gelatin and the changes in dipeptidyl peptidase IV (DPP-IV) inhibition activity during gastrointestinal digestion in order to understand and exploit the potential of tilapia as a source of DPP-IV inhibitory peptides. The DPP-IV inhibition of fish-skin gelatin increased from 9.92 ± 0.76% to 36.75 ± 0.98%, and further to 51.06 ± 1.23%, following simulated intestinal digestion for a period of 60 min. After gastric digestion, the degree of hydrolysis (DH) was 18.19 ± 0.48%, the average molecular weight (AMW) was 219 ± 7.19 kDa, the sum of charged groups was -5.08 ± 0.32, and the surface hydrophobicity of the hydrolysate was 24.81 ± 0.25. After intestinal digestion, these values changed to 27.72 ± 0.47%, 146.56 ± 8.16 kDa, -8.09 ± 0.32, and 13.04 ± 0.53, respectively. The DH and sum of charged groups exhibited positive correlations with DPP-IV inhibition (0.94 and 0.71, respectively), but AMW showed a negative correlation (-0.96). MATLAB fit functions were applied to predict theoretical inhibition values, with the fitted equation: DPP-IV inhibition = 2.5885 × DH - 0.0983 × AMW - 1.0047 × sum of charged groups + 3.5118. The test set for the multiple linear regression model demonstrated an R2 equal to or greater than 0.8. The DH, AMW, and sum of charged groups in the hydrolysate correlated with DPP-IV inhibition, and the fitted equation predicted DPP-IV inhibition effectively in tilapia skin gelatin. © 2024 Society of Chemical Industry.

Assessing the benefit-risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials.

To comprehensively evaluate the benefits and risks of glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), and sodium-glucose cotransporter 2 inhibitors (SGLT2i). A systematic search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 2023 to identify randomized cardiovascular and kidney outcome trials that enrolled adults with type 2 diabetes, heart failure, or chronic kidney disease and compared DPP4i, GLP-1RAs, or SGLT2i to placebo. Twenty-one outcomes (e.g., major adverse cardiovascular events [MACE], stroke, and hospitalization for heart failure [HHF]) were assessed. Data were pooled using population-averaged odds ratios (ORs) with 95% CIs. Twenty-six trials enrolling 198 177 participants were included. GLP-1RAs were most effective in lowering the risks of MACE (OR, 0.85, [95% CI, 0.79 to 0.92]) and stroke (0.84 [0.77, 0.91]), but increased the risk of thyroid cancer (1.58 [1.36, 2.50]). SGLT2i showed the greatest benefits in reducing the risk of HHF (0.68 [0.64, 0.73]) and improving composite renal outcomes (0.67 [0.58, 0.77]), but increased the risk of genital infections (3.11 [2.15, 4.50]). DPP4i were associated with a lower risk of certain psychiatric disorders, Parkinson's disease (0.54 [0.32, 0.92]), and amputation (0.70 [0.86, 0.93]), but an increased risk of neuropathy (1.10 [1.02, 1.18]) and pancreatitis (1.63 [1.40, 1.91]). The weighted origami plot suggested that GLP-1RAs were more suitable for reducing macrovascular and microvascular outcomes, while DPP4i might be better for neurodegenerative diseases and cancer concerns. Given the distinct benefit-risk profiles, the selection of glucose-lowering drugs should be individualized based on patient characteristics and risk factors.