Dipeptidyl Peptidase-4 Inhibitory Activity Research Articles

Gut microbiota DPP4-like enzymes are increased in type-2 diabetes and contribute to incretin inactivation

BackgroundThe gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the same function.ResultsWe identify novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations between Parabacteroides and Porphyromonas DPP4-like genes and type 2 diabetes (T2D). We also find that the DPP4-like enzyme from the gut symbiont Parabacteroides merdae mimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) hormones in vitro. Importantly, administration of E. coli overexpressing the P. merdae DPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduces active GIP and GLP-1 levels, which is attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observe that linagliptin, saxagliptin, sitagliptin, and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme from P. merdae.ConclusionsOur findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.

Rapid Screening of Novel Dipeptidyl Peptidase-4 Inhibitory Peptides from Pea (Pisum sativum L.) Protein Using Peptidomics and Molecular Docking.

Pea protein hydrolysates (PPHs) possess good hypoglycemic effects; however, their dipeptidyl peptidase-4 (DPP-4) inhibitory activity is poorly understood, and none of the DPP-4 inhibitory peptides have been identified from PPHs. This paper aims to rapidly screen these peptides from PPHs by combining peptidomics and molecular docking. In this study, 543 peptides were identified by peptidomics, and four peptides (IPYWTY, IPYWT, LPNYN, and LAFPGSS) with DPP-4 half-maximal inhibitory concentration (IC50) values <100 μM were screened for the first time. Significantly, peptide IPYWTY exhibited the most potent DPP-4 inhibitory activity (IC50 = 11.04 μM) mainly because it formed hydrophobic interactions with the S1 pocket in DPP-4. These results indicated that combining peptidomics and molecular docking is an effective strategy for rapidly screening DPP-4 inhibitory peptides.

Synthesis of 5(S)-Methyl-L-Proline Containing Peptidomimetic Compounds and their In Vitro Evaluation for Dipeptidyl Peptidase-4 Inhibition

Background: Type 2 diabetes mellitus (T2DM), which is the epidemic of the 21st century, has affected millions of people worldwide. Traditional methods available for the treatment are associated with various side effects. Among the newer therapies, DPP-4 (Dipeptidyl peptidase-4) inhibition has been a promising therapy for the past decade with the scope of further development, especially in peptidomimetics. Objective: 5(S)-methyl-L-proline containing peptidomimetic compounds were designed in the previous work. The designed compounds were synthesized and characterized by spectral methods, such as mass spectrometry, 1H NMR, and 13C NMR (Nuclear magnetic resonance) spectroscopy. The purity of the final compounds was determined by high-performance liquid chromatography (HPLC). The synthesized compounds were in vitro evaluated for their DPP-4 inhibitory activity. Method: Compounds were peptide in nature and were synthesized using the conventional synthesis approach, where peptide synthesis was done using an acid-amine coupling reagent. They were evaluated through fluorimetric enzyme-based assay using a DPP-4 inhibitor screening kit. Moreover, the CLARIOstar microplate reader instrument was used to measure fluorescence. Results: 5(S)-methyl-L-proline containing 13 compounds were synthesized. All of them were characterized for structural integrity using spectral methods. They had HPLC purity of more than 95% and were evaluated for DPP-4 inhibition. Compounds 1, 7, 10, 11, 14 and 17 were found to have good inhibition than others. These compounds were further evaluated at different concentrations to develop a linear correlation coefficient (R2). Conclusion: Six compounds were found to have good DPP-4 inhibition, hence it further opens the possibility of developing DPP-4 inhibitor-containing 5(S)-methyl-L-proline.

3D-QSAR-based pharmacophore determination and design of novel DPP-4 inhibitors

Background/Aim: Therapy of diabetes mellitus type 2 includes drugs that act as inhibitors of dipeptidyl peptidase 4 (DPP-4) enzyme. Several DPP-4 inhibitors are marketed today and although they have favourable safety profile and tolerability, they show moderate activity in controlling glycaemia. The 3D quantitative structure-activity relationship (3D-QSAR) methodology was employed in order to find pharmacophore responsible for good DPP-4 inhibitory activity and designed new compounds with enhanced activity. Methods: For 3D-QSAR model development, 48 compounds structurally related to sitagliptin were collected from ChEMBL database. Structures of all compounds were optimised in order to find the best 3D conformations prior to QSAR modelling. To establish correlation between structure and biological activity Partial Least Squares (PLS) regression method integrated in Pentacle software was used. Results: Parameters of internal and external validation (R2 = 0.80, Q2 = 0.64 and R2 pred = 0.610) confirmed reliability of developed QSAR model. Analysis of obtained structural descriptors enabled identification of key structural characteristics that influenced DPP-4 inhibitory activity. Based on that information, new compounds were designed, of which 35 compounds had a better predicted activity, compared to sitagliptin. Conclusion: This QSAR model can be used for DPP-4 inhibitory activity prediction of structurally related compounds and resulting pharmacophore contains information useful for optimisation and design of new DPP-4 inhibitors. Finally, authors propose designed compounds for further synthesis, in vitro and in vivo testing, as new potential DPP-4 inhibitors.

Inhibitory Effect and Potential Mechanism of Lactobacillus plantarum YE4 against Dipeptidyl Peptidase-4.

This study investigated the inhibitory effect and mechanism of 12 LAB strains isolated from Chinese fermented foods on dipeptidyl peptidase-4 (DPP-4) using the Caco-2 cell model. The results showed that the inhibitory effect of cell-free extracts (CFEs) collected from each LAB strain on DPP-4 was higher than that of the cell-free excretory supernatants. The CFEs from Lactobacillus plantarum YE4 (YE4-CFE) exhibited the strongest DPP-4 inhibitory activity (24.33% inhibition). Furthermore, YE4-CFE altered the TNF and MAPK signaling pathways. Additionally, the YE4-CFE ultrafiltration fraction (<3 kDa) displayed a similar DPP-4 inhibitory activity to YE4-CFE. UHPLC-MS/MS identified 19 compounds with a relative proportion of more than 1% in the <3 kDa fraction, and adenine, acetylcholine, and L-phenylalanine were the top three substances in terms of proportion. Altogether, the inhibitory effect of YE4-CFE on DPP-4 was associated with the TNF and MAPK signaling pathways, and with the high proportion of adenine, acetylcholine, and L-phenylalanine.

A Comprehensive Review and Perspective on Natural Sources as Dipeptidyl Peptidase-4 Inhibitors for Management of Diabetes.

Type 2 diabetes mellitus (T2DM) is an increasing global public health problem, and its prevalence is expected to rise in coming decades. Dipeptidyl peptidase-4 (DPP-4) is a therapeutic target for the management of T2DM, and its inhibitors prevent the degradation of glucose-dependent insulinotropic peptide and glucagon-like peptide 1, and thus, maintain their endogenous levels and lower blood glucose levels. Various medicinal plant extracts and isolated bioactive compounds exhibit DPP-4 inhibitory activity. In this review, we discussed different natural sources that have been shown to have anti-diabetic efficacy with a particular emphasis on DPP-4 inhibition. Furthermore, the effect of DPP-4 inhibition on pancreatic beta cell function, skeletal muscle function, and the glucose-lowering mechanisms were also discussed. We believe that scientists looking for novel compounds with therapeutic promise against T2DM will be able to develop antidiabetic drugs using these natural sources.

Design, synthesis and biological evaluation of glycolamide, glycinamide, and β-amino carbonyl 1,2,4-triazole derivatives as DPP-4 inhibitors

Through modification of the skeleton of Sitagliptin and Vildagliptin, we successfully synthesized and built-up four series of 1,2,4-triazole derivatives, containing N,O-disubstituted glycolamide, N,N′-disubstituted glycinamide, β-amino ester, and β-amino amide as linkers, for the development of new dipeptidyl peptidase 4 (DPP-4) inhibitors. The synthetic strategy for glycolamides or glycinamides involved convenient two-steps reaction: functionalized transformation of 2-chloro-N-(2,4,5-triflurophenyl)acetamide 9 (hydroxylation or amination) and esterification or amidation of 1,2,4-triazole-3-carboxylic acid. On the other hand, the one-pot synthesis procedure, including substitution and deprotection, was developed for the preparation of β-amino carbonyl 1,2,4-triazoles from (1H-1,2,4-triazol-3-yl)methanol 12 or (1H-1,2,4-triazol-3-yl)methanamine 13 and Boc-(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyric acid 14. All of glycolamides, glycinamides, and β-amino carbonyl 1,2,4-triazoles were also evaluated against DPP-4 inhibitory activity. Based on the SAR study of DPP-4 inhibitory capacity, β-amino ester 5n and β-amino amide 1,2,4-triazoles 6d and 6p possessed the significant inhibition of DPP-4 (IC50 < 51.0 nM), particularly for compound 6d (IC50 = 34.4 nM). The selectivity evaluation indicated compound 5n and 6p had excellent selectivity over QPP, DPP-8, and DPP-9. In addition, the docking results revealed compounds 5n and 6p provided stronger π–π stacking interaction with residue Phe357 than 1,5-disubstituted 1,2,4-triazole 6d and Sitagliptin 1. In summary, compounds 5n and 6p could be promising lead compounds for further development of DPP-4 inhibitor.

Novel Potent and Selective DPP-4 Inhibitors: Design, Synthesis and Molecular Docking Study of Dihydropyrimidine Phthalimide Hybrids.

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as anti-hyperglycemic agents that improve glycemic control in type 2 diabetic patients, either as monotherapy or in combination with other antidiabetic drugs. Methods: A novel series of dihydropyrimidine phthalimide hybrids was synthesized and evaluated for their in vitro and in vivo DPP-4 inhibition activity and selectivity using alogliptin as reference. Oral glucose tolerance test was assessed in type 2 diabetic rats after chronic treatment with the synthesized hybrids ± metformin. Cytotoxicity and antioxidant assays were performed. Additionally, molecular docking study with DPP-4 and structure activity relationship of the novel hybrids were also studied. Results: Among the synthesized hybrids, 10g, 10i, 10e, 10d and 10b had stronger in vitro DPP-4 inhibitory activity than alogliptin. Moreover, an in vivo DPP-4 inhibition assay revealed that 10g and 10i have the strongest and the most extended blood DPP-4 inhibitory activity compared to alogliptin. In type 2 diabetic rats, hybrids 10g, 10i and 10e exhibited better glycemic control than alogliptin, an effect that further supported by metformin combination. Finally, 10j, 10e, 10h and 10d had the highest radical scavenging activity in DPPH assay. Conclusions: Hybrids 10g, 10i and 10e are potent DPP-4 inhibitors which may be beneficial for T2DM treatment.

Phytosterol supplements do not inhibit dipeptidyl peptidase-4

Background and aimsSeveral commercially available phytosterol supplements are promoted for their cholesterol-lowering effects. However, limited information is available about their potential anti-hyperglycaemic effects. This study aimed to evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitory effects of phytosterol supplements in silico and in vitro to determine their potential for anti-diabetic activity. MethodsDocking studies were carried out in silico to evaluate the potential for interactions between three major phytosterol compounds (stigmasterol, β-sitosterol, campesterol) and the DPP-4 enzyme, the enzyme that is inhibited by the anti-diabetic gliptins. Gas chromatography–tandem mass spectrometry (GC-MS/MS) was used to analyse three different supplements for phytosterol content. DPP-4 inhibitory activity was tested in vitro for these phytosterol supplements and two major phytosterol standards. ResultsIn silico calculations predicted free binding energies for DPP-4 with the phytosterols to be: stigmasterol −8.78 kcal/mol; β-sitosterol −8.70 kcal/mol; campesterol −8.40 kcal/mol. These binding energies indicated a potential for significant DPP-4 inhibition. However, these results were not supported by the in vitro studies. Stigmasterol and β-sitosterol had an IC50 > 50 mg/ml (maximum tested concentration) and the Thompson’s Cholesterol Manager® and Mega Strength Beta Sitosterol® supplements gave an IC50 > 100 mg/ml (maximum tested concentration). Blackmores Cholesterol Health® gave an IC50 value of 40 mg/ml which was attributed to β-carotene content. ConclusionsPhytosterol supplements do not appear to offer any anti-diabetic activity potential via pathways that involve the inhibition of DPP-4.

Ψ-Xenin-6 enhances sitagliptin effectiveness, but does not improve glucose tolerance.

Recent studies have characterised the biological properties and glucose-dependent insulinotropic polypeptide (GIP) potentiating actions of an enzymatically stable, C-terminal hexapeptide fragment of the gut hormone xenin, namely Ψ-xenin-6. Given the primary therapeutic target of clinically approved dipeptidyl peptidase-4 (DPP-4) inhibitor drugs is augmentation of the incretin effect, the present study has assessed the capacity of Ψ-xenin-6 to enhance the antidiabetic efficacy of sitagliptin in high fat fed (HFF) mice. Individual administration of either sitagliptin or Ψ-xenin-6 alone for 18 days resulted in numerous metabolic benefits and positive effects on pancreatic islet architecture. As expected, sitagliptin therapy was associated with elevated circulating GIP and GLP-1 levels, with concurrent Ψ-xenin-6 not elevating these hormones or enhancing DPP-4 inhibitory activity of the drug. However, combined sitagliptin and Ψ-xenin-6 therapy in HFF mice was associated with further notable benefits, beyond that observed with either treatment alone. This included body weight change similar to lean controls, more pronounced and rapid benefits on circulating glucose and insulin as well as additional improvements in attenuating gluconeogenesis. Favourable effects on pancreatic islet architecture and peripheral insulin sensitivity were more apparent with combined therapy. Expression of hepatic genes involved in gluconeogenesis and insulin action were partially, or fully, restored to normal levels by the treatment regimens, with beneficial effects more prominent in the combination treatment group. These data demonstrate that combined treatment with Ψ-xenin-6 and sitagliptin did not alter glucose tolerance but does offer some metabolic advantages, which merit further consideration as a therapeutic option for type 2 diabetes.

Phytochemicals in Garlic Extract Inhibit Therapeutic Enzyme DPP-4 and Induce Skeletal Muscle Cell Proliferation: A Possible Mechanism of Action to Benefit the Treatment of Diabetes Mellitus.

Diabetes mellitus is a severe health problem in Mexico, and its prevalence is increasing exponentially every year. Recently, DPP-4 (dipeptidyl peptidase-4) inhibitors have become attractive oral anti-hyperglycemic agents to reduce the pathology of diabetes. Gliptin’s family, such as sitagliptin, vildagliptin, and alogliptin, are in clinical use to treat diabetes mellitus but possess side effects. Therefore, there is a specific need to look for new therapeutic scaffolds (biomolecules). Garlic bulb is widely used as a traditional remedy for the treatment of diabetes. The garlic extracts are scientifically proven to control glucose levels in patients with diabetes, despite the unknown mechanism of action. The aim of the study is to investigate the antidiabetic effects of ultrasonication assisted garlic bulb extract. To achieve this, in-vitro assays such as DPP-4 inhibitory and antioxidant activities were investigated. Further, functional group analysis using FTIR and identification of phytochemicals using mass spectrometry analysis was performed. The results showed that 70.9 µg/mL of garlic bulb extract inhibited 50% DPP-4 activity. On top of that, the garlic extract exhibited a 20% scavenging activity, equivalent to 10 µg/mL of ascorbic acid. Molecular docking simulations on identified phytochemicals using mass spectrometry revealed their potential binding at the DPP-4 druggable region, and therefore the possible DPP-4 inhibition mechanism. These results suggest that prepared garlic extract contains phytochemicals that inhibit DPP-4 and have antioxidant activity. Also, the prepared extract induces skeletal muscle cell proliferation that demonstrates the antidiabetic effect and its possible mechanism of action.

Polyalthia Clerodane Diterpene Potentiates Hypoglycemia via Inhibition of Dipeptidyl Peptidase 4.

Serine protease dipeptidyl peptidase 4 (DPP-4) is involved in self/non-self-recognition and insulin sensitivity. DPP-4 inhibitors are conventional choices for diabetic treatment; however, side effects such as headache, bronchus infection, and nasopharyngitis might affect the daily lives of diabetic patients. Notably, natural compounds are believed to have a similar efficacy with lower adverse effects. This study aimed to validate the DPP-4 inhibitory activity of clerodane diterpene 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) from Polyalthia longifolia, rutin, quercetin, and berberine, previously selected through molecular docking. The inhibitory potency of natural DPP-4 candidates was further determined by enzymatic, in vitro Caco-2, and ERK/PKA activation in myocyte and pancreatic cells. The hypoglycemic efficacy of the natural compounds was consecutively analyzed by single-dose and multiple-dose administration in diet-induced obese diabetic mice. All the natural-compounds could directly inhibit DPP-4 activity in enzymatic assay and Caco-2 inhibition assay, and HCD showed the highest inhibition of the compounds. HCD down-regulated LPS-induced ERK phosphorylation in myocyte but blocked GLP-1 induced PKA expression. For in vivo tests, HCD showed hypoglycemic efficacy only in single-dose administration. After 28-days administration, HCD exhibited hypolipidemic and hepatoprotective efficacy. These results revealed that HCD performed potential antidiabetic activity via inhibition of single-dose and long-term administrations, and could be a new prospective anti-diabetic drug candidate.

Synthesis and Pharmacological Activity of Trifluoromethyl-Containing Imidazo[1,2-A]Benzimidazoles

A series of 2-(4-trifluoromethylphenyl)- and 2-trifluoromethyl-9-dialkylaminoalkylimidazo[1,2-a]benzimidazoles were synthesized for the first time by reacting 2-amino-1-dialkylaminoalkylbenzimidazoles and 2-bromo-1-[(4-trifluoromethyl)phenyl]ethanone or 1-bromo-3,3,3-trifluoroacetone and were tested for analgesic and antiplatelet activity, glycogen phosphorylase and dipeptidyl peptidase-4 inhibitory activity, and in vitro glycation of bovine serum albumin.

Citrus bioflavonoids dipeptidyl peptidase-4 inhibition compared with gliptin antidiabetic medications

This study compared dipeptidyl peptidase-4 (DPP-4) inhibitory activity of citrus bioflavonoid nutraceuticals compared with three gliptins. Citrus bioflavonoid standards and three commercially available citrus bioflavonoid supplements (Thompson's Super Bioflavonoid Complex®(SB), Ethical Nutrients Bioflavonoids Plus Vitamin C®(EN), and Country Life Citrus Bioflavonoids and Rutin®(CB)) were considered in this study. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis was undertaken to identify and quantitate the citrus bioflavonoids present in each supplement. The DPP-4 inhibitory activity was determined by fluorometric assay. All of the tested individual citrus flavonoids demonstrated DPP-4 inhibitory activity, with IC50 values ranging from 485 μM (rutin) to 5700 μM (hesperitin and eriodictyol). Similarly, the flavonoid supplements had IC50 values of 16.9 mg/mL (EN), 3.44 mg/mL (SB) and 2.72 mg/mL (CB). These values compare with gliptin IC50 values of 0.684 μM (sitagliptin), 0.707 μM (saxagliptin) and 2.286 μM (vildagliptin). The supplement flavonoid content varied from 11.98% (CB) to 5.26% (EN) and 14.51% (SB) of tablet mass, corresponding to daily flavonoid doses of around 300, 150 and 400 mg, respectively, with CB and SB containing rutin at levels of 7.0% and 7.5% of tablet mass, respectively. While our data demonstrated that citrus bioflavonoid based supplements do possess DPP-4 inhibitory activity, they are several orders of magnitude less potent than gliptins. Further studies using higher concentrations of citrus bioflavonoids, as well as investigations into antioxidant properties which may add additional benefit are warranted.

Synthesis, pharmacological evaluation and molecular docking studies of pyrimidinedione based DPP-4 inhibitors as antidiabetic agents

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of newly developed antidiabetic drugs that bock DPP-4. DPP-4 is responsible for degradation of incretins harmones such as GLP-1 (Glucagon like Peptide) and GIP (Gastric inhibitory polypeptide) that maintain blood-glucose level. Pyrimidinedione based compounds were designed and synthesized for DPP-4 inhibitory activity. These heterocycles were designed by taking Alogliptin as a reference DPP-4 inhibitors and synthesized as N-methylated and N-benzylated pyrimidinediones. These compounds were subjected to DPP-4 assay, five out of nine synthesized compounds have shown in vitro DPP-4 inhibitory activity in significant range. Further, molecular docking studies of these compounds were performed on DPP-4 subunit and compared with natural DPP-4 inhibitors like Flavone, Resveratrol, Quercetin, Diprotin A. Docking studies have led to the conclusion that there are some identical amino acid interactions as Tyr 666 and Tyr 662, seen in both synthesized compounds and natural DPP-4 inhibitors. This study completely gives a good scope for further derivatisation and optimization of synthesized compounds to get clinical candidate as DPP-4 inhibitor for antidiabetic activity.

Macrocarpal C isolated from Eucalyptus globulus inhibits dipeptidyl peptidase 4 in an aggregated form

Dipeptidyl peptidase 4 (DPP-4) inhibitors are used for the treatment of type-2 diabetes mellitus. Various synthetic inhibitors have been developed to date, and plants containing natural DPP-4 inhibitors have also been identified. Here, 13 plant samples were tested for their DPP-4 inhibitory activity. Macrocarpals A–C were isolated from Eucalyptus globulus through activity-guided fractionation and shown to be DPP-4 inhibitors. Of these, macrocarpal C showed the highest inhibitory activity, demonstrating an inhibition curve characterised by a pronounced increase in activity within a narrow concentration range. Evaluation of macrocarpal C solution by turbidity, nuclear magnetic resonance spectroscopy and mass spectrometry indicated its aggregation, which may explain the characteristics of the inhibition curve. These findings will be valuable for further study of potential small molecule DPP-4 inhibitors.

SVMDLF: A novel R-based Web application for prediction of dipeptidyl peptidase 4 inhibitors.

Dipeptidyl peptidase 4 (DPP4) is a well-known target for the antidiabetic drugs. However, currently available DPP4 inhibitor screening assays are costly and labor-intensive. It is important to create a robust in silico method to predict the activity of DPP4 inhibitor for the new lead finding. Here, we introduce an R-based Web application SVMDLF (SVM-based DPP4 Lead Finder) to predict the inhibitor of DPP4, based on support vector machine (SVM) model, predictions of which are confirmed by in vitro biological evaluation. The best model generated by MACCS structure fingerprint gave the Matthews correlation coefficient of 0.87 for the test set and 0.883 for the external test set. We screened Maybridge database consisting approximately 53,000 compounds. For further bioactivity assay, six compounds were shortlisted, and of six hits, three compounds showed significant DPP4 inhibitory activities with IC50 values ranging from 8.01 to 10.73μm. This application is an OpenCPU server app which is a novel single-page R-based Web application for the DPP4 inhibitor prediction. The SVMDLF is freely available and open to all users at http://svmdlf.net/ocpu/library/dlfsvm/www/ and http://www.cdri.res.in/svmdlf/.

Anti-diabetic and anti-inflammatory activities of commonly available cephalopods

ABSTRACTAnti-diabetic and anti-inflammatory activities of ethyl acetate-methanol extracts of cephalopods namely, Amphioctopus marginatus, Urothethis duvauceli, Sepia pharaonis, Sepiella inermis, and Cistopus indicus were evaluated. The ethyl acetate-methanol extracts of C. indicus exhibited significantly greater (p < 0.05) cyclooxygenase inhibition activities (IC90 ~ 1 mg/mL, respectively) compared to other cephalopod species. Likewise, C. indicus displayed greater 5-lipoxygenase inhibitory activity (IC90 1.69 mg/mL) compared to the other cephalopod species (IC90 > 2 mg/mL) considered in the present study. The solvent extracts derived from the members of the order Octopoda demonstrated fairly good α-amylase inhibitory activity (IC90 ≤ 2.5 mg/mL). Dipeptidyl peptidase-4 inhibitory activity of the ethyl acetate-methanol extract of C. indicus was found to be significantly greater (IC50 2.51 mg/mL) than other species of cephalopods (IC50 3.4–5.4 mg/mL; p < 0.05). The labeling of protons associated with different magnetic environments of the functional groups exhibited in the ethyl acetate-methanol extracts were analyzed by proton nuclear magnetic resonance spectroscopy that supported the in vitro anti-diabetic and anti-inflammatory results. The ethyl acetate-methanol extract of C. indicus and S. inermis displayed greater proton integrals (ΣH) of highly electronegative moieties appeared in the low-field region in the proton nuclear magnetic resonance spectroscopy spectra (C. indicus ΣHδ3.5–4.5 5.34, ΣHδ4.5–6.5 6.41; S. inermis ΣHδ3.5–4.5 6.52, and ΣHδ4.5–6.5 15.39) than other cephalopod species. A significant co-linearity was found between the electronegative groups present in the downfield position of nuclear magnetic resonance spectroscopy spectra vis-à-vis anti-diabetic and anti-inflammatory activities.

Navigating the chemical space of dipeptidyl peptidase-4 inhibitors.

This study represents the first large-scale study on the chemical space of inhibitors of dipeptidyl peptidase-4 (DPP4), which is a potential therapeutic protein target for the treatment of diabetes mellitus. Herein, a large set of 2,937 compounds evaluated for their ability to inhibit DPP4 was compiled from the literature. Molecular descriptors were generated from the geometrically optimized low-energy conformers of these compounds at the semiempirical AM1 level. The origins of DPP4 inhibitory activity were elucidated from computed molecular descriptors that accounted for the unique physicochemical properties inherently present in the active and inactive sets of compounds as defined by their respective half maximal inhibitory concentration values of less than 1 μM and greater than 10 μM, respectively. Decision tree analysis revealed the importance of molecular weight, total energy of a molecule, topological polar surface area, lowest unoccupied molecular orbital, and number of hydrogen-bond donors, which correspond to molecular size, energy, surface polarity, electron acceptors, and hydrogen bond donors, respectively. The prediction model was subjected to rigorous independent testing via three external sets. Scaffold and chemical fragment analysis was also performed on these active and inactive sets of compounds to shed light on the distinguishing features of the functional moieties. Docking of representative active DPP4 inhibitors was also performed to unravel key interacting residues. The results of this study are anticipated to be useful in guiding the rational design of novel and robust DPP4 inhibitors for the treatment of diabetes.

Lactobacilli possess inhibitory activity against dipeptidyl peptidase-4 (DPP-4)

Dipeptidyl peptidase-4 (DPP-4) plays an important role in the enzymatic inactivation of incretin hormones. In this context, drugs that inhibit DPP-4 have been developed and clinically approved as therapies for type 2 diabetes. As the primary substrates of DPP-4 are produced in the intestinal lining, we investigated whether lactobacilli colonizing the gut could inhibit this enzyme. Fifteen Lactobacillus strains (Lb 1–15) from human infant faecal samples were isolated, identified, extracted and screened for inhibitory activity against DPP-4. Activity was compared against Lactobacillus reference strains (Ref 1–7), a Gram-positive control (Ctrl 1) and two Gram-negative controls (Ctrl 2–3). A range of DPP-4 inhibitory activity was observed (10–32 %; p < 0.05–0.001). Strains of L. plantarum (12–25 %) and L. fermentum (14 %) had significant inhibitory activity. However, we noted that Escherichia coli (Ctrl 2) and Salmonella Typhimurium (Ctrl 3) had the greatest inhibitory activity (30–32 %). Contrastingly, some isolates (Lb 12–15) and reference cultures (Ref 1–4), instead of inhibiting DPP-4, actually enhanced it, perhaps indicating the presence of X-prolyl-dipeptidyl-amino-peptidase (PepX). This provides a future rationale for using probiotic bacteria or their components for management of type 2 diabetes via DPP-4 inhibition.