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1.
J Agric Food Chem ; 68(2): 541-548, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31860295

RESUMO

Besides their nutritional value, whey protein (WP) peptides are food components retaining important pharmacological properties for controlling hypertension. We herein report how the use of complementary experimental and theoretical investigations allowed the identification of novel angiotensin converting enzyme inhibitory (ACEI) peptides obtained from a WP hydrolysate and addressed the rational design of even shorter sequences based on molecular pruning. Thus, after bromelain digestion followed by a 5 kDa cutoff ultrafiltration, WP hydrolysate with ACEI activity was fractioned by RP-HPLC; 2 out of 23 collected fractions retained ACEI activity and were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In the face of 128 identified peptides, molecular docking was carried out to prioritize peptides and to rationally guide the design of novel shorter and bioactive sequences. Therefore, 11 peptides, consisting of 3-6 amino acids and with molecular weights in the range from 399 to 674 Da, were rationally designed and then purchased to determine the IC50 value. This approach allowed the identification of two novel peptides: MHI and IAEK with IC50 ACEI values equal to 11.59 and 25.08 µM, respectively. Interestingly, we also confirmed the well-known ACEI IPAVF with an IC50 equal to 9.09 µM. In light of these results, this integrated approach could pave the way for high-throughput screening and identification of new peptides in dairy products. In addition, the herein proposed ACEI peptides could be exploited for novel applications both for food production and pharmaceuticals.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Peptídeos/química , Proteínas do Soro do Leite/química , Animais , Bovinos , Desenho de Drogas , Humanos , Cinética , Simulação de Acoplamento Molecular , Peso Molecular , Peptidil Dipeptidase A/química , Hidrolisados de Proteína/química
2.
J Agric Food Chem ; 68(3): 759-768, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31841328

RESUMO

In this study, we investigated the antihypertensive effects in vitro and in vivo of novel angiotensin-converting enzyme inhibitory (ACEI) peptides purified and identified from bovine bone gelatin hydrolysate (BGH). Thirteen ACEI peptides were identified from BGH, and among which, RGL-(Hyp)-GL and RGM-(Hyp)-GF exhibited high ACE inhibition with IC50 values of 1.44 and 10.23 µM. Molecular docking predicted that RGM-(Hyp)-GF and ACE residues of Glu384, His513, and Lys511 formed hydrogen-bonding interactions at distances of 2.57, 2.99, and 2.42 + 3.0 Å. RGL-(Hyp)-GL formed hydrogen bonds with Lys511 and Tyr523 and generated hydrogen-bonding interactions with His387 and Glu411 in the zinc(II) complexation motif at distances of 2.74 and 3.03 + 1.93 Å. The maximal decrements in systolic blood pressure in spontaneously hypertensive rats induced by one-time gavage of RGL-(Hyp)-GL and RGM-(Hyp)-GF at 30 mg/kg were 31.3 and 38.6 mmHg. RGL-(Hyp)-GL had higher enzyme degradation resistance than that of RGM-(Hyp)-GF in vitro incubation in rat plasma, and they were sequentially degraded into pentapeptides and tetrapeptides within 2 h. Our results indicate that BGH can serve as a nutritional candidate to control blood pressure.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Osso e Ossos/química , Gelatina/química , Peptídeos/química , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/isolamento & purificação , Pressão Sanguínea/efeitos dos fármacos , Bovinos , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Simulação de Acoplamento Molecular , Peptídeos/administração & dosagem , Peptídeos/isolamento & purificação , Peptidil Dipeptidase A/química , Hidrolisados de Proteína/química , Ratos , Ratos Endogâmicos SHR
3.
Food Chem ; 303: 125400, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470275

RESUMO

Siraitia grosvenorii fruit (SGF) has been used as a natural sweetener and traditional medicine in China for more than two centuries. This study evaluated the effect of SGF extract supplementation (0.5%, 1%, and 2%) on the chemical, microbial and sensory properties of probiotic yogurt. The antioxidant, angiotensin-converting-enzyme inhibitory (ACE-I) and antibacterial bioactivities were determined. SGF extract supplementation improved some of the chemical and physicochemical characteristics. Probiotic yogurt with the fruit extract had significantly more Lactobacillus casei and Lactobacillus bulgaricus, whereas there was no significant effect on the number of Streptococcus thermophiles. The bioactivities were significantly increased by SGF extract supplementation. Probiotic yogurt with 2% SGF extract showed the highest antioxidant, ACE-I, and antibacterial activities, whereas the one with 1% SGF extract conferred the highest sensory attributes score. Overall, SGF extract offers a promising option as a dietary supplement to produce novel dairy products that have high nutritional and bioactivity values.


Assuntos
Cucurbitaceae/química , Aditivos Alimentares/análise , Extratos Vegetais/análise , Probióticos/análise , Iogurte/microbiologia , Inibidores da Enzima Conversora de Angiotensina/análise , Antioxidantes/análise , China , Frutas/efeitos dos fármacos , Humanos , Lactobacillus casei/genética , Lactobacillus casei/crescimento & desenvolvimento , Lactobacillus casei/isolamento & purificação , Lactobacillus delbrueckii/genética , Lactobacillus delbrueckii/crescimento & desenvolvimento , Lactobacillus delbrueckii/isolamento & purificação , Peptidil Dipeptidase A/química , Paladar , Iogurte/análise
4.
J Sci Food Agric ; 100(1): 315-324, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31525262

RESUMO

BACKGROUND: In order to utilize tilapia skin gelatin hydrolysate protein, which is normally discarded as industrial waste in the process of fish manufacture, we study the in vivo and in vitro angiotensin-I-converting enzyme (ACE) inhibitory activity of the peptide Leu-Ser-Gly-Tyr-Gly-Pro (LSGYGP). The aim was to provide a pharmacological basis of the development of minimal side effects of ACE inhibitors by comparative analysis with captopril in molecular docking. RESULTS: This peptide from protein-rich wastes showed excellent ACE inhibitory activity (IC50  = 2.577 µmol L-1 ) and exhibited a mixed noncompetitive inhibitory pattern with Lineweaver-Burk plots. Furthermore, LSGYGP and captopril groups both showed significant decreases in blood pressure after 6 h and maintained good digestive stability over 4 h. Molecular bond interactions differentiate competitive captopril upon hydrogen bond interactions and Zn(II) interaction. The C-terminal Pro generates three interactions (hydrogen bonds, hydrophilic interactions and Van der Waals interactions) in the peptide and effectively interacts with the S1 and S2 pockets of ACE. CONCLUSION: LSGYGP, with an IC50 value of 2.577 µmol L-1 , has an antihypertensive effect in spontaneously hypertensive rats. Through comparison with captopril, this study revealed that LSGYGP may be a potential food-derived ACE inhibitory peptide and could act as a functional food ingredient to prevent hypertension. © 2019 Society of Chemical Industry.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Captopril/química , Hipertensão/tratamento farmacológico , Peptídeos/química , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Captopril/administração & dosagem , Ciclídeos , Digestão , Proteínas de Peixes/química , Trato Gastrointestinal/metabolismo , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Cinética , Masculino , Simulação de Acoplamento Molecular , Peptídeos/metabolismo , Peptídeos/farmacologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/química , Hidrolisados de Proteína/metabolismo , Ratos , Ratos Endogâmicos SHR
5.
J Sci Food Agric ; 99(15): 6822-6832, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31385307

RESUMO

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitory peptides were found to alleviate acute hepatitis significantly. In this study, we purified and identified ACE inhibitory peptide from cashew to evaluate its protective role on alcohol-induced acute hepatitis in mice. RESULTS: The ACE inhibitory peptides were purified by using consecutive chromatographic techniques. One of these peptides (FETISFK) exhibited the highest ACE inhibition rate (91.04 ± 0.31%). In vivo, the results showed that ACE inhibitory peptide decreased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) caused by alcohol exposure. Moreover, it could increase the activities of superoxide dismutase (SOD) and glutathione (GSH), and decrease the level of malondialdehyde (MDA). It was also found to down-regulate markedly the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). It could also decrease the expression of ACE, angiotensin II (AngII) and angiotensin II type 1 receptor (AT1 R). CONCLUSION: These findings support the view that the ACE inhibitory peptide alleviated acute hepatitis by down-regulating the ACE-AngII-AT1 R axis, broadening the research approach to prevent acute hepatitis, and providing experimental data for the development and utilization of cashews. © 2019 Society of Chemical Industry.


Assuntos
Anacardium/química , Inibidores da Enzima Conversora de Angiotensina/química , Hepatite/tratamento farmacológico , Peptídeos/química , Extratos Vegetais/química , Doença Aguda/terapia , Álcoois/efeitos adversos , Angiotensina II/genética , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Hepatite/enzimologia , Hepatite/etiologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Nozes/química , Peptídeos/administração & dosagem , Peptídeos/isolamento & purificação , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
6.
ACS Appl Mater Interfaces ; 11(35): 31700-31708, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31404498

RESUMO

A N-doped hollow copolymer tube (NHCT) was fabricated via template-free one-pot asynchronous polymerization strategy. Discrepancies of monomer polymerization speed and their hydrophilic-hydrophobic interaction resulted in the assembly of a hollow tube having inner diameter and double wall thickness of ∼230 and 40 nm, respectively. The formation and growth mechanism of NHCT analyzed via advanced characterization revealed that the unique growth processes tuned a demarcating surface layer between inner (hydrophilic) and outer (hydrophobic) layers. The screening and recognition ability of NHCT were determined for two specific dipeptides (WW and RR) possessing great discrepancies in hydrophilicity and angiotensin converting enzyme inhibitory (ACE-I) activity. NHCT realized high adsorption capacity (1.57 mmol/g) and selectivity (∼1274) for hydrophilic dipeptide RR (low ACE-I activity) from the mixture of RR/WW. As a result, ACE-I activity for residual solution were enhanced about 4.1 times as compared to original solution from natural silkworm pupae protein hydrolysate. Awarding to these results and its facile and discerning ability, NHCT can be envisioned to be of great value for the separation of small functional peptides from a natural edible source.


Assuntos
Dipeptídeos , Análise de Alimentos , Nitrogênio/química , Peptidil Dipeptidase A/química , Polimerização , Polímeros , Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/química , Dipeptídeos/análise , Dipeptídeos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Polímeros/síntese química , Polímeros/química
7.
Life Sci ; 235: 116796, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470003

RESUMO

AIM: Depressor arm of the renin-angiotensin system (RAS) exerts reno-protective effects in chronic kidney diseases like diabetic nephropathy. However, same is still elusive under AKI and hyperglycaemia comorbidity. Hence, the present study delineates the role of angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in AKI under normal and hyperglycaemia condition. METHODS: Non-diabetic (ND) and Streptozotocin-induced diabetes mellitus (DM) rats were subjected to ischemic renal injury (IRI). Rats underwent IRI were treated with an AT2R agonist, C21 (0.3 mg/kg/day, i.p.) or ACE2 activator, Dize, (5 mg/kg/day, p.o.) either alone or as combination therapy. Renal histopathology and immunohistochemistry, proximal tubular fraction isolation, ELISA, immunoblotting and qRT-PCR were performed for subsequent analysis. KEY FINDINGS: Rats subjected to IRI displayed an increase in plasma ACE, AT1R, AT2R, Ang II, and reduction in ACE2, Ang-(1-7) expressions, with augmented renal inflammation and apoptosis. These changes were more prominent in diabetic rats with IRI. Co-administration of C21 and Dize augmented ACE2, Ang-(1-7), AT2R and MasR expressions, and attenuated tubular injury in both DM and ND rats. CONCLUSION: We demonstrated that pharmacological activation of AT2R and ACE2 protects DM and ND rats from IRI by preventing oxidative stress, inflammation and apoptosis-mediated tubular damage.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/etiologia , Peptidil Dipeptidase A/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Estresse Oxidativo , Peptidil Dipeptidase A/química , Ratos , Ratos Wistar , Receptor Tipo 2 de Angiotensina/química
8.
Amino Acids ; 51(8): 1209-1220, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31321559

RESUMO

Up to now, numerous peptides/hydrolysates derived from casein and whey protein have shown angiotensin-I-converting enzyme (ACE) inhibitory. In this research, quantum topological molecular similarity (QTMS) indices of amino acids were utilized in quantitative sequence-activity modeling (QSAM) to predict the activity of a set of milk-driven peptides with ACE inhibition. Since the derived peptides have not the same number of residues, we overcame this issue by auto cross covariance (ACC) methodology. Then, some QSAMs were built to predict the pIC50 value of ACE peptides derived from Bovine Casein and Whey. The model established an acceptable relationship between the selected variables and the pIC50 of the peptides. To estimate the performance of the developed models, casein and whey proteins from human, goat, bovine and sheep were virtually broken by trypsin and chymotrypsin enzymes and the ACE activity of the resultant virtual peptides were predicted and some new ACE peptides were proposed.


Assuntos
Aminoácidos/análise , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Caseínas/farmacologia , Leite/química , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/química , Proteínas do Soro do Leite/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Caseínas/química , Bovinos , Cabras , Humanos , Hidrólise , Modelos Moleculares , Fragmentos de Peptídeos/química , Ovinos , Proteínas do Soro do Leite/química
9.
ACS Appl Mater Interfaces ; 11(26): 23039-23049, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31252506

RESUMO

Introduction of targeted defects into microporous UiO-66s for manipulating their three-dimensional size and surface properties can endow them with adsorption and separation areas involving angiotensin-converting-enzyme-inhibitory (ACE-inhibitory) peptides. Three hydrophobic amino acids (AAs) (i.e., proline (Pro), phenylalanine (Phe), and tryptophan (Trp)) having different physical/chemical properties were applied to in situ tailor defects in UiO-66 through targeted incoordination of missing linkers or missing nodes. Characterization results revealed a uniform oval shape of the developed defects with lengths ranging from 1.8 to 3.1 nm, which was also highly consistent with our molecular simulation. Among these three defective UiO-66s, Phe and Trp imprinted UiO-66s significantly promoted the adsorption affinity of small ACE-inhibitory peptides (uptake: 1.25 mmol g-1 for DDFF and 1.37 mmol g-1 for DDWW) and ultrahigh selectivity for DDFF (249) or DDWW (279) from inactive KKKK solution based on a lock-and-key mechanism. As a result, the imprinted UiO-66 showed an enrichment capacity for ACE-inhibitory peptides about eight times higher than that of pristine UiO-66. Therefore, the amino acid imprinting strategy endorsed by its facile and discerning ability can be envisioned to be of great value for small functional peptide separation and oriented enrichment in biomedicines.


Assuntos
Adsorção/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/química , Peptídeos/química , Peptidil Dipeptidase A/química , Aminoácidos/química , Humanos , Peptidil Dipeptidase A/genética , Fenilalanina/química , Prolina/química , Propriedades de Superfície
10.
J Agric Food Chem ; 67(24): 6757-6764, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31184153

RESUMO

In the present study we purified and identified peptides from broccoli protein hydrolysates and evaluated their angiotensin-converting enzyme (ACE) inhibitory activity in vitro and hypotensive effect in vivo. Three ACE inhibitory peptides were isolated and identified as IPPAYTK, LVLPGELAK, and TFQGPPHGIQVER, and their inhibitory IC50 values were 23.5, 184.0, and 3.4 µM, respectively. We then investigated the effect of gastrointestinal digestion on ACE inhibitory activity. We detected almost two times the ACE inhibitory activity of the peptide LVLPGELAK following simulated digestion than prior to digestion. LVLPGE and LAK, two novel peptides exhibiting high ACE inhibitory activity, were discovered following digestion and possessed IC50 values of 13.5 and 48.0 µM, respectively. The hypotensive effect of the peptides was assessed after oral administration to spontaneous hypertensive rats (SHRs). We found that LVLPGE and LAK demonstrated a significant hypotensive effect in vivo. Protein from broccoli may thus constitute a potential antihypertensive peptide source.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Brassica/química , Hipertensão/tratamento farmacológico , Peptídeos/administração & dosagem , Proteínas de Plantas/química , Administração Oral , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Pressão Sanguínea/efeitos dos fármacos , Feminino , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Mapeamento de Peptídeos , Peptídeos/isolamento & purificação , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/química , Ratos , Ratos Endogâmicos SHR
11.
J Agric Food Chem ; 67(29): 8149-8159, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31246442

RESUMO

Ganoderma lucidum (G. lucidum) has been widely used in Asia to treat hypertension, but the active substances responsible for its antihypertensive effects remain unclear. Using the well-established angiotensin I-converting enzyme (ACE) as a target, we identified three ACE inhibitory peptides (ACEIPs), Gln-Leu-Val-Pro (QLVP), Gln-Asp-Val-Leu (QDVL), and Gln-Leu-Asp-Leu (QLDL), which account for the antihypertensive activity of G. lucidum. Notably, QLVP worked in a mixed-type manner against ACE with an IC50 value of 127.9 µmol/L. Molecular dynamics simulation suggested that the potent charge energy of QLVP, which interacted with Gln242 and Lys472 of ACE via a hydrogen bond and a salt bridge, potentially contributed to ACE inhibitory activity. Moreover, QLVP markedly activated angiotensin I-mediated phosphorylation of endothelial nitric oxide synthase in human umbilical vein endothelial cells and partly reduced mRNA and protein expression of the vasoconstrictor factor endothelin-1. This is the first report of the antihypertensive activity of small ACEIPs originating from G. lucidum mycelia, paving the way for the possible application of these peptides as potent drug candidates for treating hypertension.


Assuntos
Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Peptídeos/química , Peptídeos/isolamento & purificação , Reishi/química , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Linhagem Celular , Humanos , Cinética , Espectrometria de Massas , Simulação de Dinâmica Molecular , Micélio/química , Mapeamento de Peptídeos , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo
12.
Food Funct ; 10(6): 3421-3429, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31134998

RESUMO

A Porphyra dioica protein extract was enzymatically hydrolysed and then fractionated using semi-preparative reverse-phase high performance chromatography. The hydrolysate and its fractions were tested for their oxygen radical absorbance capacity (ORAC) along with their angiotensin converting enzyme (ACE) and dipeptidyl peptidase IV (DPP-IV) inhibitory activities. The most potent fraction was analysed by liquid chromatography mass spectrometry. Eight peptide sequences were selected for synthesis based on their structure-activity criteria for bioactivity. Asp-Tyr-Tyr-Lys-Arg showed the highest ORAC activity (4.27 ± 0.15 µmol Trolox equivalent per µM). Thr-Tyr-Ile-Ala had the highest ACE inhibitory activity (IC50: 89.7 ± 7.10 µM). Tyr-Leu-Val-Ala was the only peptide showing DPP-IV inhibitory activity (IC50: 439 ± 44 µM). Apart from Asp-Tyr-Tyr-Lys-Arg and Thr-Tyr-Ile-Ala, which displayed increased ORAC activity, the bioactivities of the peptides were either maintained or decreased following in vitro simulated gastrointestinal digestion. The results indicate that P. dioica-derived peptides may have potential applications as health enhancing ingredients.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Antioxidantes/química , Inibidores da Dipeptidil Peptidase IV/química , Peptídeos/química , Porphyra/química , Hidrolisados de Proteína/química , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Antioxidantes/isolamento & purificação , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/isolamento & purificação , Peptídeos/isolamento & purificação , Peptidil Dipeptidase A/química
13.
Med Chem ; 15(6): 574-587, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31084594

RESUMO

BACKGROUND: The Angiotensin-I converting enzyme (ACE) is one of the most important components of the renin-angiotensin-aldosterone system controlling blood pressure and renal functions. Inhibitors of ACE are first line therapeutics used in the treatment of hypertension and related cardiovascular diseases. Somatic ACE consists of two homologous catalytic domains, the C- and N-domains. Recent findings have shown that although both domains are highly homologous in structure, they may have different physiological functions. The C-domain is primarily involved in the control of blood pressure, in contrast to the N-domain that is engaged in the regulation of hematopoietic stem cell proliferation. The currently available ACE inhibitors have some adverse effects that can be attributed to the non-selective inhibition of both domains. In addition, specific Ndomain inhibitors have emerged as potential antifibrotic drugs. Therefore, ACE is still an important drug target for the development of novel domain-selective drugs not only for the cardiovascular system but also for other systems. OBJECTIVE: Detailed structural information about interactions in the protein-ligand complex is crucial for rational drug design. This review highlights the structural information available from crystallographic data which is essential for the development of domain selective inhibitors of ACE. METHODS: Over eighty crystal complexes of ACE are placed into the Protein Database. An overview of X-ray ACE complexes with various inhibitors in C- and N-domains and an analysis of their binding mode have given mechanistic explanation of the structural determinants of selective ligand binding. In addition, ACE domain selective inhibitors with dual modes of action in complexes with ACE are also discussed. CONCLUSION: Selectivity of ACE inhibitors for the N- and C-domain is controlled by subtle differences in the amino-acids forming the active site. Reported studies of crystal complexes of inhibitors in the C- and N-domains revealed that most selective inhibitors interact with non-conserved amino-acids between domains and have distinct interactions with the residues in the S2 and S2' subsites of the ACE catalytic site. Moreover, unusual binding of the second molecule of inhibitors in the binding cavity opens new possibilities of exploiting more distant regions of the catalytic center in structure-based design of novel drugs.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/metabolismo , Peptidil Dipeptidase A/metabolismo , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Domínio Catalítico , Cristalografia por Raios X , Desenho de Drogas , Humanos , Peptidil Dipeptidase A/química , Ligação Proteica , Domínios Proteicos , Especificidade por Substrato
14.
J Agric Food Chem ; 67(25): 7147-7156, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31140270

RESUMO

Egg proteins are recognized as excellent sources of bioactive peptides, such as angiotensin-converting enzyme inhibitory (ACEi) peptides. Oral administration of a thermolysin-digested egg white hydrolysate (T-EWH) caused a significant blood pressure reduction in spontaneously hypertensive rats; a further ACEi assay implied that its ACEi activity was enhanced after in vitro gastrointestinal (GI) digestion. These results indicated that T-EWH contained ACEi peptides resisting GI digestion and/or being further released during GI digestion. Therefore, the objective of this study was to identify these responsible ACEi peptides from T-EWH. The conventionally activity-guided fractionation was applied, coupled with a synchronized GI digestion throughout, during which both peptide yield and ACEi activity before and after the GI digestion were measured. Finally, six ACEi peptides (LAPYK, LKISQ, LKYAT, INKVVR, LFLIKH, and LGHWVY) with good GI resistance were identified with IC50 values <20 µM, especially LKYAT (0.09 µM). The structure-activity relationship of these peptides was discussed. The discovery of GI-resistant ACEi peptides could further support the application of egg white proteins as functional food ingredients.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Proteínas do Ovo/química , Trato Gastrointestinal/metabolismo , Hipertensão/metabolismo , Peptídeos/química , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Galinhas , Digestão , Clara de Ovo/química , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Peptídeos/administração & dosagem , Peptídeos/metabolismo , Peptidil Dipeptidase A/química , Hidrolisados de Proteína/química , Ratos , Ratos Endogâmicos SHR
15.
J Agric Food Chem ; 67(19): 5544-5551, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31007021

RESUMO

The purpose of the study was to investigate the transepithelial transport route of Arg-Leu-Ser-Phe-Asn-Pro (RLSFNP), a milk-derived angiotensin-converting enzyme (ACE) inhibitory peptide, and to encapsulate RLSFNP in a liposome to improve its intestinal bioavailability. The transport route was investigated using transport inhibitors in a human intestinal Caco-2 cell monolayer model. Sodium azide and wortmannin significantly reduced the permeability of RLSFNP ( P < 0.01), indicating that energy-dependent transcytosis is involved in the transport of RLSFNP across Caco-2 cells. The hexapeptide RLSFNP was then embedded in liposomes, and the RLSFNP liposome was characterized. Afterward, the cellular uptake and transepithelial transport ability of the RLSFNP liposome across Caco-2 cell monolayers was observed. The results demonstrated that the RLSFNP liposome was successfully prepared, having a significant sustained release and storage capability. The RLSFNP liposome can be absorbed by Caco-2 cells, with an increased intestinal absorption of RLSFNP compared to RLSFNP alone. The results showed a new way to improve RLSFNP intestinal bioavailability.


Assuntos
Células Epiteliais/metabolismo , Lipossomos/química , Peptídeos/metabolismo , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Transporte Biológico , Células CACO-2 , Composição de Medicamentos , Humanos , Mucosa Intestinal/metabolismo , Lipossomos/metabolismo , Modelos Biológicos , Peptídeos/química , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo
16.
J Food Sci ; 84(5): 1170-1179, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30997940

RESUMO

High blood pressure can lead to cardiovascular diseases. The objective of this work was to obtain protein hydrolysates with antihypertensive potential from chia oil industry meal byproduct. Chia seed protein isolates (CPIs) were obtained from chia seed meal byproduct. CPI was hydrolyzed using different proteases (alcalase, pepsin, trypsin, and α-chymotrypsin) and their biological potential was evaluated using in vitro and in silico approaches. Chia seed pepsin protein hydrolysate showed the highest angiotensin-converting enzyme inhibition potential IC50 of 0.128 mg/mL (P < 0.05) compared to the rest of hydrolysates. Peptide sequence LIVSPLAGRL presented the lowest predicted binding energy and highest inhibition potential (-9.5 kcal/mol) compared to other sequenced peptides and positive controls (captopril and lisinopril). Chia peptides showed potential to block angiotensin-converting enzyme by interacting with its catalytic site. Chia seed oil industry meal byproduct could be used as an inexpensive source of protein and bioactive peptides with antihypertensive potential. PRACTICAL APPLICATION: This research shows an upcycling alternative for chia oil industry byproduct. Chia meal is a rich source of protein and can be used to generate bioactive peptides with antihypertensive potential. Chia protein isolate was obtained from chia meal and hydrolyzed using different enzymes, pepsin showed the highest antihypertensive potential. Chia meal waste could be a low-cost source of protein and protein hydrolysates that could be used as a food ingredient with antihypertensive potential.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Anti-Hipertensivos , Pepsina A , Peptidil Dipeptidase A , Proteínas de Plantas , Salvia/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacologia , Domínio Catalítico , Pepsina A/química , Pepsina A/metabolismo , Pepsina A/farmacologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Proteínas de Plantas/farmacologia , Hidrolisados de Proteína/química , Hidrolisados de Proteína/metabolismo , Hidrolisados de Proteína/farmacologia
17.
PLoS One ; 14(4): e0215609, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30998765

RESUMO

Angiotensin-I converting enzyme (ACE) is a two-domain dipeptidylcarboxypeptidase involved in regulating blood pressure via the kallikrein-kininand renin-angiotensin-aldosterone complex. Therefore, ACE is a key drug target for the treatment of cardiovascular system diseases. At present many works are focus on searching for new inhibitory peptides of ACE to control the blood pressure. In order to exploit the interactions between ACE and its inhibitors, molecular dynamics simulations were used. The results showed that (a) the secondary structures of the three inhibitor-protein complexes did not change significantly; (b) root-mean-square deviation (RMSD), radius of gyration (Rg), and solvent-accessible surface area (SASA) values of Leu-Ile-Val-Thr (LIVT)-ACE complexes were significantly higher than that of other systems; (c) the backbone movement of LIVT was vigorous in Asp300-Val350, compared with that in Tyr-Leu-Val-Pro-His (YLVPH) and Tyr-Leu-Val-Arg(YLVR), as shown by the center-of-mass distance; and (d) the backbone movement of Asp300-Val350 may contribute to the interaction between ACE and its inhibitors. Our theoretical results will be helpful to further the design of specific inhibitors of ACE.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Simulação por Computador , Modelos Moleculares , Peptídeos/química , Peptidil Dipeptidase A/química , Humanos , Domínios Proteicos , Relação Estrutura-Atividade
18.
Mar Drugs ; 17(3)2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893907

RESUMO

Angiotensin I-converting enzyme (ACE) inhibitory peptides derived from seaweed represent a potential source of new antihypertensive. The aim of this study was to isolate and purify ACE inhibitory peptides (ACEIPs) from the protein hydrolysate of the marine macroalga Ulva intestinalis. U. intestinalis protein was hydrolyzed by five different proteases (trypsin, pepsin, papain, α-chymotrypsin, alcalase) to prepare peptides; compared with other hydrolysates, the trypsin hydrolysates exhibited the highest ACE inhibitory activity. The hydrolysis conditions were further optimized by response surface methodology (RSM), and the optimum conditions were as follows: pH 8.4, temperature 28.5 °C, enzyme/protein ratio (E/S) 4.0%, substrate concentration 15 mg/mL, and enzymolysis time 5.0 h. After fractionation and purification by ultrafiltration, gel exclusion chromatography and reverse-phase high-performance liquid chromatography, two novel purified ACE inhibitors with IC50 values of 219.35 µM (0.183 mg/mL) and 236.85 µM (0.179 mg/mL) were obtained. The molecular mass and amino acid sequence of the ACE inhibitory peptides were identified as Phe-Gly-Met-Pro-Leu-Asp-Arg (FGMPLDR; MW 834.41 Da) and Met-Glu-Leu-Val-Leu-Arg (MELVLR; MW 759.43 Da) by ultra-performance liquid chromatography-tandem mass spectrometry. A molecular docking study revealed that the ACE inhibitory activities of the peptides were mainly attributable to the hydrogen bond and Zn(II) interactions between the peptides and ACE. The results of this study provide a theoretical basis for the high-valued application of U. intestinalis and the development of food-derived ACE inhibitory peptides.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Ulva , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/uso terapêutico , Estabilidade de Medicamentos , Ensaios Enzimáticos , Hidrólise , Hipertensão/tratamento farmacológico , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Peptídeo Hidrolases/metabolismo , Peptídeos/química , Peptídeos/isolamento & purificação , Peptídeos/uso terapêutico , Peptidil Dipeptidase A/química , Hidrolisados de Proteína/química , Hidrolisados de Proteína/isolamento & purificação , Hidrolisados de Proteína/metabolismo , Alga Marinha/química
19.
Protein Pept Lett ; 26(7): 494-501, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30919768

RESUMO

BACKGROUND: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. METHODS: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. RESULTS: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 µg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. ß-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. CONCLUSION: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Cicer/química , Inibidores de Glicosídeo Hidrolases/química , Lectinas/química , Peptidil Dipeptidase A/química , Extratos Vegetais/química , alfa-Amilases/antagonistas & inibidores , alfa-Glucosidases/química , Animais , Anti-Hipertensivos/química , Antioxidantes/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/química , Coelhos , Sementes/química , alfa-Amilases/química
20.
J Med Food ; 22(3): 286-293, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30835154

RESUMO

Mojarra of Nile tilapia (Oreochromis niloticus) skeleton was used as protein source for the preparation of protein hydrolysates and peptide fractions with angiotensin-converting enzyme (ACE) inhibitory activity. The flour presented a content of 34.92% protein and a brightness (luminosity, L*) of 82.29. Protein hydrolysates were obtained from the protein-rich flour with the enzymes Flavourzyme® and Alcalase® reaching degree of hydrolysis (%DH) of 52% and 67% at 100 min of reaction, respectively. Both hydrolysates showed low-molecular-weight (MW) peptides estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The hydrolysates obtained with Flavourzyme at 60 min and at 80 min with Alcalase showed greater ACE inhibitory activity with IC50 values of 0.238 and 0.344 mg/mL, respectively. The peptide fraction A (MW >10 kDa) with Flavourzyme and fraction B (MW = 10-5 kDa) with Alcalase obtained by ultrafiltration of hydrolysates with higher DH presented IC50 of 0.728 and 0.354 mg/mL, respectively, whereas peptide fraction C (MW = 5-3 kDa) with both enzymes hydrolysates with greater ACE inhibitory activity showed IC50 values of 0.470 and 0.634 mg/mL. The components obtained in this study could be used as functional ingredients in the design and development of functional foods.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Ciclídeos , Proteínas de Peixes/química , Peptídeos/química , Animais , Biocatálise , Hidrólise , Cinética , Peptidil Dipeptidase A/química , Hidrolisados de Proteína/química , Subtilisinas/química
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