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1.
Nutrients ; 12(3)2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32197331

RESUMO

Arthrospira platensis (spirulina) is a cyanobacterium, which contains mainly two phycobiliproteins (PBP), i.e., C-phycocyanin (C-PC) and allophycocyanin (APC). In this study, PBP were hydrolyzed using trypsin, and the composition of the hydrolysate was characterized by HPLC-ESI-MS/MS. Furthermore, the potential anti-diabetic activity was assessed by using either biochemical or cellular techniques. Findings suggest that PBP peptides inhibit DPP-IV activity in vitro with a dose-response trend and an IC50 value falling in the range between 0.5 and 1.0 mg/mL. A lower inhibition of the DPP-IV activity expressed by Caco-2 cells was observed, which was explained by a secondary metabolic degradation exerted by the same cells.

2.
J Agric Food Chem ; 68(7): 2082-2090, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31984733

RESUMO

IAVPTGVA (Soy1) and LPYP are two soybean peptides, which display a multifunctional behavior, showing in vitro hypocholesterolemic and hypoglycemic activities. A preliminary screening of their structures using BIOPEP suggested that they might be potential angiotensin-converting enzyme (ACE) inhibitors. Therefore, a bottom-up-aided approach was developed in order to clarify the in vitro hypotensive activity. Soy1 and LPYP dropped the intestinal and renal ACE enzyme activity with IC50 values equal to 14.7 ± 0.28 and 5.0 ± 0.28 µM (Caco-2 cells), and 6.0 ± 0.35 and 6.8 ± 0.20 µM (HK-2 cells), respectively. In parallel, a molecular modeling study suggested their capability to act as competitive inhibitors of this enzyme. Finally, in order to increase both their stability and hypotensive properties, a suitable strategy for the harmless control of their release from a nanomaterial was developed through their encapsulation into the RADA16-assembling peptide.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Peptídeos/química , Extratos Vegetais/química , Soja/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Peptidil Dipeptidase A/química , Extratos Vegetais/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
3.
J Agric Food Chem ; 67(43): 11825-11838, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31588750

RESUMO

There is now great interest in food protein hydrolysates and food-derived peptides, because they may provide numerous health benefits. Among other foodstuffs, microalgae appear to be sustainable sources of proteins and bioactive peptides that can be exploited in foods and functional formulations. This review considers protein hydrolysates and individual peptides that may be relevant in cardiovascular disease prevention because they mimic the functions of mediators involved in pathologic processes that represent relevant risk factors for cardiovascular disease development, such as hypercholesterolemia, hypertension, diabetes, inflammation, and oxidative status. Some of these peptides are also multifunctional (i.e., they offer more than one benefit). Moreover, the most efficient techniques for protein extraction and hydrolyzation are commented on, as well as the best methodologies for high-throughput detection and quantification. Finally, current challenges and critical issues are discussed.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Microalgas/química , Peptídeos/administração & dosagem , Animais , Humanos , Peptídeos/química , Peptídeos/isolamento & purificação , Hidrolisados de Proteína/química
4.
J Med Chem ; 62(13): 6163-6174, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31260298

RESUMO

Proprotein convertase subtilisin/kexin 9 (PCSK9) is responsible for the degradation of the hepatic low-density lipoprotein receptor (LDLR), which in turn regulates the circulating low-density lipoprotein cholesterol (LDL-C) level. For this reason, the PCSK9 inhibition, by small molecules or peptides, is a validated therapeutic approach for fighting hypercholesterolemia and cardiovascular diseases. In this field, we have recently reported an imidazole-based peptidomimetic that has shown PCSK9 inhibitory activity in the micromolar range. Here, by applying advanced computational techniques, the binding mechanism of that imidazole peptidomimetic was predicted. Then, among a small set of poly-imidazole analogs, compounds showing the highest theoretical affinity were suitably synthesized, relying on a van Leusen reaction based multicomponent strategy. One compound (named RIm13) displayed a PCSK9 inhibitory activity 10-fold lower than the template compound, and, remarkably, at a concentration of 1 µM, it successfully prevented the LDLR degradation mediated by PCSK9 on HepG2 cells. As well as increasing the LDL uptake at the same concentration, RIm13 represents currently one of the most potent small molecules targeting the PCSK9/LDLR protein-protein interaction.

5.
Nutrients ; 11(7)2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31330826

RESUMO

GQEQSHQDEGVIVR (T9) is a peptide originated by the tryptic digestion of lupin ß-conglutin that is absorbed in human intestinal Caco-2 cells. A previous study has shown that T9 impairs the protein-protein interaction between mutant D374Y Proprotein Convertase Subtilisin/Kexin 9 (PCSK9D374Y) and the low-density lipoprotein receptor (LDLR), thus exerting a hypocholesterolemic effect. Moreover, a bioinformatic study predicting that T9 may potentially act as an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCoAR), has suggested a complementary cholesterol-lowering activity. The present study demonstrates that T9 inhibits in vitro the HMGCoAR functionality with an IC50 value of 99.5 ± 0.56 µM. Through the inhibition of either HMGCoAR or PCSK9D374Y activities, T9 enhances the LDLR protein levels leading to an improved ability of HepG2 cells transfected with the mutant PCSK9D374Y-FLAG plasmid to uptake extracellular LDL with a final cholesterol-lowering effect. In addition, T9 modulates the PCSK9D374Y signaling pathway in transfected HepG2 cells leading to a decrease of PCSK9D374Y and HNF-1α protein levels. All these results indicate that the hypocholesterolemic effects of T9 are due to a dual mechanism of action involving either the modulation of the PCSK9D374Y or LDLR pathways. This may represent an added value from a therapeutic point of view.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos/farmacologia , Pró-Proteína Convertase 9/metabolismo , Sequência de Aminoácidos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Mutação , Peptídeos/química , Pró-Proteína Convertase 9/genética
6.
ACS Med Chem Lett ; 10(4): 425-430, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30996774

RESUMO

The inhibition of the PCSK9/LDLR protein-protein interaction is a promising strategy for developing new hypocholesterolemic agents. Familial hypercholesterolemia is linked to specific PCSK9 mutations: the D374Y is the most potent gain-of-function (GOF) PCSK9 mutation among clinically relevant ones. Recently, a lupin peptide (T9) showed inhibitory effects on this mutant PCSK9 form, being also capable to increase liver uptake of low density lipoprotein cholesterol. In this Letter, aiming to improve the potency of this peptide, the T9 residues mainly responsible for the interaction with PCSK9D374Y (hot spots) were computationally predicted. Then, the "non-hot" residues were suitably substituted by new amino acids capable to theoretically increase the structural complementarity between T9 and PCSK9D374Y. The outcomes of this study were confirmed by in vitro biochemical assays and cellular investigations, showing that a new T9 analog is able to increase the LDLR expression on the liver cell surface by 84% at the concentration of 10 µM.

7.
J Agric Food Chem ; 67(17): 4824-4830, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30969121

RESUMO

This study was aimed at evaluating the cellular mechanism through which peptic (P) and tryptic (T) soybean hydrolysates modulate the targets involved in hypocholesterolemic pathways in HepG2 and antidiabetic pathways in Caco-2 cells. Both hydrolysates (tested in the concentration range of 0.5-2.5 mg/mL) inhibited the 3-hydroxy-3-methylglutaryl-CoA reductase activity in HepG2 cells. In addition, Soybean P increased LDLR protein levels on HepG2 membranes by 51.5 ± 11.6% and 63.0 ± 6.9% (0.5-1.0 mg/mL) whereas Soybean T increased them by 55.2 ± 9.7% and 85.8 ± 21.5% (0.5-1.0 mg/mL) vs the control, with a final improved HepG2 capacity in the uptake of extracellular LDL. Soybean P reduced in vitro the dipeptidyl peptidase-IV activity by 16.3 ± 3.0% and 31.4 ± 0.12% (1.0 and 2.5 mg/mL), whereas Soybean T reduced it by 15.3 ± 11.0% and 11.0 ± 0.30% (1.0 and 2.5 mg/mL) vs the control. Finally, both hydrolysates inhibited dipeptidyl peptidase-IV activity in situ in human intestinal Caco-2 cells. This investigation may help to explain the activities observed in experimental and clinical studies.


Assuntos
Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Peptídeos/química , Extratos Vegetais/química , Soja/química , Células CACO-2 , Células Hep G2 , Humanos
8.
J Agric Food Chem ; 67(13): 3615-3623, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30879293

RESUMO

Soy1 (IAVPTGVA) and Lup1 (LTFPGSAED), two peptides from soybean and lupin protein hydrolysis, have been singled out as dipeptidyl peptidase IV (DPP-IV) activity inhibitors in different model systems. However, their activity is affected by their instability toward intestinal proteases. Here, an innovative strategy based on nanogels was developed in order to increase both their stability and antidiabetic properties through encapsulation into the RADA16 peptide. The nanogel formation was stimulated by a solvent-triggered approach, allowing us to produce stable nanogels ( G' = 1826 Pa, stress-failure ≥50 Pa) with shear-thinning propensity. ThT binding assay, and ATR-FTIR spectroscopy experiments showed that nanogels self-aggregated into stable cross-ß structures providing higher resistance against proteases (ex vivo experiments) and increased bioavailability of Soy1 and Lup1 peptides (in situ experiments on Caco-2 cells). Hence, this simple and harmless nanotechnological approach could be a key-step in making innovative nanomaterials for nutraceuticals delivering.


Assuntos
Inibidores da Dipeptidil Peptidase IV/química , Lupinus/química , Peptídeos/química , Soja/química , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Humanos , Hidrólise , Cinética , Nanoestruturas/química , Espectrometria de Massas em Tandem
9.
Sci Rep ; 9(1): 2343, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787312

RESUMO

The inhibition of the PCSK9/LDLR protein-protein interaction (PPI) is a promising strategy for developing new hypocholesterolemic agents. Recently, new antibodies have been approved for therapy, but the high cost and low patients' compliance stimulate the development of alternatives. Starting from the structural information available for the complex between PCSK9 and TVFTSWEEYLDWV (Pep2-8) peptide inhibitor and using computational methods, in this work we identified two Pep2-8 analogs as potential inhibitors of the PCSK9/LDLR PPI. Their biological characterization confirmed the theoretical outcomes. Remarkably, the treatment of HepG2 cells with these peptides increased the LDLR protein level on the cellular membrane, with activities that were 100 and 50 times better than the one of Pep2-8 tested at a 50 µM concentration. Moreover, they were 50 and 5 times more active than Pep2-8 in improving the functional ability of HepG2 cells to uptake extracellular LDL.

10.
J Agric Food Chem ; 66(40): 10552-10557, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30226051

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in cholesterol homeostasis, because it induces the low-density lipoprotein receptor (LDLR) degradation. This protein may carry some positive or negative mutations: PCSK9D374Y is one of the most dangerous gain-of-function mutations. This paper reports the identification of the first food-derived peptide able to inhibit the protein-protein interaction (PPI) between PCSK9D374Y and LDLR. In fact, T9 (GQEQSHQDEGVIVR), an absorbable peptide deriving from lupin ß-conglutin, is able to impair the PPI between PCSK9D374Y and the LDLR, with an IC50 value equal to 285.6 ± 2.46 µM. The consequence of this inhibition is an increase of the protein level of the LDLR located on hepatic cell membranes up to 74.3 ± 4.4% and the restoration of the functional capability of HepG2 cells to uptake extracellular low-density lipoprotein up to 83.1 ± 1.6%. Finally, the putative binding mode of T9 to the LDLR binding site located on PCSK9D374Y was postulated by in silico tools.


Assuntos
Mutação com Ganho de Função , Peptídeos/química , Pró-Proteína Convertase 9/química , Pró-Proteína Convertase 9/genética , Receptores de LDL/química , Proteínas de Armazenamento de Sementes/química , Sítios de Ligação , Células Hep G2 , Humanos , Modelos Moleculares , Peptídeos/metabolismo , Pró-Proteína Convertase 9/metabolismo , Ligação Proteica , Receptores de LDL/genética , Receptores de LDL/metabolismo
11.
Nutrients ; 10(8)2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30104520

RESUMO

Recent investigations have focused on food-derived peptides as novel natural inhibitors of dipeptidyl peptidase IV (DPP-IV), a new target for diabetes. This study aimed to optimize fast, sensitive, and cost-effective DPP-IV assays in situ on human intestinal Caco-2 cells and ex vivo on human serum. Both assays were applied to investigate the inhibitory activity of soy and lupin peptides. The best conditions for in situ DPP-IV activity in Caco-2 cells were obtained using 2-day cells and 50 µM Gly-Pro-AMC. Sitagliptin, used as reference inhibitor, showed a dose-dependent response with a 50% inhibition concentration (IC50) of 0.6 µM. A lower IC50 (0.2 µM) was obtained for sitagliptin on human serum incubated with the substrate for 24 h. Both assays were applied to assess the activity of Lup1 (LTFPGSAED) and Soy1 (IAVPTGVA) on DPP-IV. Lup1 and Soy1 inhibited DPP-IV in situ, with IC50 values of of 207.5 and 223.2 µM, respectively, and maintained their inhibitory activity ex vivo on circulating DPP-IV with a slightly lower potency. These assays can be used to characterize the DPP-IV inhibitory activity of food-derived molecules more accurately than in vitro biochemical tests. This combined approach also considers their effects on the circulating form of DPP-IV, correlated to metabolic diseases.


Assuntos
Colo/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteínas de Armazenamento de Sementes/farmacologia , Proteínas de Soja/farmacologia , Células CACO-2 , Colo/enzimologia , Colo/patologia , Dipeptidil Peptidase 4/sangue , Humanos , Fosfato de Sitagliptina/farmacologia
12.
Food Chem ; 239: 935-945, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-28873655

RESUMO

An investigation on the proteome of the sweet kernel of apricot, based on equalisation with combinatorial peptide ligand libraries (CPLLs), SDS-PAGE, nLC-ESI-MS/MS, and database search, permitted identifying 175 proteins. Gene ontology analysis indicated that their main molecular functions are in nucleotide binding (20.9%), hydrolase activities (10.6%), kinase activities (7%), and catalytic activity (5.6%). A protein-protein association network analysis using STRING software permitted to build an interactomic map of all detected proteins, characterised by 34 interactions. In order to forecast the potential health benefits deriving from the consumption of these proteins, the two most abundant, i.e. Prunin 1 and 2, were enzymatically digested in silico predicting 10 and 14 peptides, respectively. Searching their sequences in the database BIOPEP, it was possible to suggest a variety of bioactivities, including dipeptidyl peptidase-IV (DPP-IV) and angiotensin converting enzyme I (ACE) inhibition, glucose uptake stimulation and antioxidant properties.


Assuntos
Prunus armeniaca , Biblioteca de Peptídeos , Peptídeos , Proteômica , Espectrometria de Massas em Tandem
13.
Eur J Nutr ; 57(2): 499-511, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27757595

RESUMO

BACKGROUND: Cardiovascular diseases are currently the commonest cause of death worldwide. Different strategies for their primary prevention have been planned, taking into account the main known risk factors, which include an atherogenic lipid profile and visceral fat excess. METHODS: The study was designed as a randomized, parallel, single-center study with a nutritional intervention duration of 12 weeks. Whole soy foods corresponding to 30 g/day soy protein were given in substitution of animal foods containing the same protein amount. RESULTS: Soy nutritional intervention resulted in a reduction in the number of MetS features in 13/26 subjects. Moreover, in the soy group we observed a significant improvement of median percentage changes for body weight (-1.5 %) and BMI (-1.5 %), as well as for atherogenic lipid markers, namely TC (-4.85 %), LDL-C (-5.25 %), non-HDL-C (-7.14 %) and apoB (-14.8 %). Since the majority of the studied variables were strongly correlated, three factors were identified which explained the majority (52 %) of the total variance in the whole data set. Among them, factor 1, which loaded lipid and adipose variables, explained the 22 % of total variance, showing a statistically significant difference between treatment arms (p = 0.002). CONCLUSIONS: The inclusion of whole soy foods (corresponding to 30 g/day protein) in a lipid-lowering diet significantly improved a relevant set of biomarkers associated with cardiovascular risk.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Dieta com Restrição de Gorduras , Dislipidemias/dietoterapia , Alimento Funcional , Síndrome Metabólica/prevenção & controle , Sobrepeso/dietoterapia , Alimentos de Soja , Adiposidade , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Colesterol/sangue , LDL-Colesterol/sangue , Estudos de Coortes , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/fisiopatologia , Feminino , Humanos , Itália/epidemiologia , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia , Pessoa de Meia-Idade , Sobrepeso/sangue , Sobrepeso/complicações , Sobrepeso/fisiopatologia , Fatores de Risco , Circunferência da Cintura , Perda de Peso
14.
Front Chem ; 6: 670, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30733941

RESUMO

Although there is an increasing interest for bioactive food protein hydrolysates as valuable ingredients for functional food and dietary supplement formulations, their potential applications are hampered by their insufficient stability in physiological conditions. In this study, an innovative strategy based on nanomaterials was developed in order to increase the hempseed hydrolysate stability and the anti-diabetic properties, through their encapsulation into ionic self-complementary RADA16 peptide based-hydrogels. Atomic force microscope (AFM) morphological analysis indicated that the new nanomaterials were composed of a nanofibril network, whose increased diameter in respect to native RADA16 suggests the presence of transient non-covalent interactions among the RADA16 supramolecular assemblies and the embedded hempseed peptides. Structural analysis by FT-IR spectroscopy indicated typical ß-sheet signatures. The RADA16-hempseed protein hydrolysate hydrogel was shown to act as a novel dipeptidyl peptidase IV (DPPIV) inhibitor in different biological assays. Finally, this nanoformulation was used as a drug delivery system of the anti-diabetic drug sitagliptin, helping to reduce its dosage and eventually associated side-effects.

15.
J Agric Food Chem ; 65(47): 10174-10184, 2017 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-29096438

RESUMO

The seed of industrial hemp is an underexploited protein source. In view of a possible use in functional foods, a hempseed protein concentrate was hydrolyzed with pepsin, trypsin, pancreatin, or a mixture of these enzymes. A detailed peptidomic analysis using data-dependent acquisition showed that the numbers of peptides identified ranged from 90 belonging to 33 parent proteins in the peptic hydrolysate to 9 belonging to 6 proteins in the pancreatin digest. The peptic and tryptic hydrolysates resulted to be the most efficient inhibitors of 3-hydroxymethyl-coenzyme A reductase activity when tested on the catalytic domain of the enzyme. Using the open access tools PeptideRanker and BIOPEP, a list of potentially bioactive peptides was generated: the alleged activities included the antioxidant property, the glucose uptake stimulating activity, the inhibition of dipeptidyl peptidase-IV and angiotensin-converting enzyme I.


Assuntos
Cannabis/química , Peptídeos/química , Proteínas de Plantas/química , Sementes/química , Inibidores da Enzima Conversora de Angiotensina/química , Antioxidantes/química , Inibidores da Dipeptidil Peptidase IV/química , Hidrólise , Pancreatina/química , Pepsina A/química
16.
J Agric Food Chem ; 65(48): 10482-10488, 2017 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-29112398

RESUMO

A hemp seed protein isolate, prepared from defatted hemp seed meals by alkaline solubilization/acid precipitation, was subjected to extensive chemical hydrolysis under acid conditions (6 M HCl). The resulting hydrolysate was fractionated by semipreparative RP-HPLC, and the purified fractions were tested as inhibitors of angiotensin converting enzyme (ACE). Mono- and bidimensional NMR experiments and LC-MS analyses led to the identification of four potentially bioactive peptides, i.e. GVLY, IEE, LGV, and RVR. They were prepared by solid-phase synthesis, and tested for ACE-inhibitory activity. The IC50 values were GVLY 16 ± 1.5 µM, LGV 145 ± 13 µM, and RVR 526 ± 33 µM, confirming that hemp seed may be a valuable source of hypotensive peptides.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Cannabis/química , Peptídeos/química , Proteínas de Plantas/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Hidrólise , Espectrometria de Massas , Peptídeos/isolamento & purificação , Peptidil Dipeptidase A/química , Hidrolisados de Proteína/química , Sementes/química
17.
J Agric Food Chem ; 65(40): 8829-8838, 2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-28931275

RESUMO

This study had the objective of preparing a hempseed protein hydrolysate and investigating its hypocholesterolemic properties. The hydrolysate was prepared treating a total protein extract with pepsin. Nano HPLC-ESI-MS/MS analysis permitted identifying in total 90 peptides belonging to 33 proteins. In the range 0.1-1.0 mg/mL, it inhibited the catalytic activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) in a dose-dependent manner. HepG2 cells were treated with 0.25, 0.5, and 1.0 mg/mL of the hydrolysate. Immunoblotting detection showed increments in the protein levels of regulatory element binding proteins 2 (SREBP2), low-density lipoprotein receptor (LDLR), and HMGCoAR. However, the parallel activation of the phospho-5'-adenosine monophosphate-activated protein kinase (AMPK) pathway, produced an inactivation of HMGCoAR by phosphorylation. The functional ability of HepG2 cells to uptake extracellular LDL was raised by 50.5 ± 2.7%, 221.5 ± 1.6%, and 109 ± 3.5%, respectively, versus the control at 0.25, 0.5, and 1.0 mg/mL concentrations. Finally, also a raise of the protein level of proprotein convertase subtilisin/kexintype 9 was observed. All of these data suggest that the mechanism of action has some similarity with that of statins.


Assuntos
Anticolesterolemiantes/química , Cannabis/química , Peptídeos/farmacologia , Sementes/química , Aminoácidos/farmacologia , Anticolesterolemiantes/farmacologia , Sobrevivência Celular , Células Hep G2 , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/enzimologia , Hipercolesterolemia/metabolismo , Lipoproteínas LDL/metabolismo , Peptídeos/química , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Espectrometria de Massas em Tandem
18.
J Agric Food Chem ; 64(51): 9601-9606, 2016 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-27983830

RESUMO

Dipeptidyl peptidase IV (DPP-IV) is a new molecular target correlated with the development of type 2 diabetes. Literature describes the identification of some inhibitory peptides from the hydrolysis of different food proteins. This article reports a study on six peptides from soybean and lupin proteins, i.e., Soy 1 (IAVPTGVA), Soy 2 (YVVNPDNDEN), Soy 3 (YVVNPDNNEN), Lup 1 (LTFPGSAED), Lup 2 (LILPKHSDAD), and Lup 3 (GQEQSHQDEGVIVR), which were screened for their capacity to inhibit the activity of DPP-IV, using an in vitro bioassay against human recombinant DPP-IV. Two peptides Soy 1 and Lup 1 resulted to be efficient inhibitors with IC50 values equal to 106 and 228 µM, respectively. A molecular docking analysis predicted the key molecular interactions, stabilizing the active peptides within DPP-IV enzyme. Soy and lupin proteins may be sources of DPP-IV inhibitory peptides potentially useful for the prevention of type 2 diabetes.


Assuntos
Inibidores da Dipeptidil Peptidase IV/química , Lupinus/química , Peptídeos/química , Proteínas de Plantas/química , Soja/química , Sequência de Aminoácidos , Simulação por Computador , Dipeptidil Peptidase 4/química , Humanos , Cinética , Simulação de Acoplamento Molecular , Dados de Sequência Molecular
19.
Org Biomol Chem ; 14(41): 9736-9740, 2016 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-27722650

RESUMO

Herein we report on the multicomponent synthesis of a novel imidazole-based compound, able to act efficiently as a minimalist ß-strand mimic. Biological evaluation proved its ability to impair the LDLR-PCSK9 protein-protein interaction, disclosing it as the first small molecule exerting a PCSK9-mediated hypocholesterolemic effect.


Assuntos
Imidazóis/química , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/metabolismo , Células Hep G2 , Humanos , Modelos Moleculares , Pró-Proteína Convertase 9/química , Ligação Proteica/efeitos dos fármacos , Conformação Proteica , Receptores de LDL/química
20.
Sci Rep ; 6: 29931, 2016 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-27424515

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recently identified as a new useful target for hypercholesterolemia treatment. This work demonstrates that natural peptides, deriving from the hydrolysis of lupin protein and absorbable at intestinal level, are able to inhibit the protein-protein interaction between PCSK9 and the low density lipoprotein receptor (LDLR). In order to sort out the best potential inhibitors among these peptides, a refined in silico model of the PCSK9/LDLR interaction was developed. Docking, molecular dynamics (MD) simulations and peptide binding energy estimations, by MM-GBSA approach, permitted to select the two best candidates among tested peptides that were synthesized and evaluated for their inhibitory activity. The most active was P5 that induced a concentration dependent inhibition of the PCSK9-LDLR binding, with an IC50 value equal to 1.6 ± 0.33 µM. Tested at a 10 µM concentration, this peptide increased by 66 ± 21.4% the ability of HepG2 cells to take up LDL from the extracellular environment.


Assuntos
Lupinus/química , Peptídeos/farmacologia , Proteínas de Plantas/farmacologia , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/metabolismo , Sequência de Aminoácidos , Células CACO-2 , Fluorescência , Humanos , Simulação de Dinâmica Molecular , Peptídeos/química , Proteínas de Plantas/química , Pró-Proteína Convertase 9/química , Ligação Proteica/efeitos dos fármacos , Receptores de LDL/química
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