Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 543
Filtrar
1.
Food Chem ; 345: 128855, 2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-33340899

RESUMO

This study attempts to investigate natural angiotensin-I converting enzyme (ACE) inhibitors. Soybean protein isolated (SPI) hydrolysate (SPIH) was prepared by Alcalase from inexpensive SPI, and their ACE inhibitory peptides were obtained via membrane separation, ethanol precipitation and adsorption chromatography enrichment. Activated carbon was more suitable for peptide enrichment than eight macroporous resins. The peptide fraction yielded under optimal conditions (protein-active carbon mass ratio 2:1; adsorption pH 3.0 and time 2 h; desorption time 2 h) exhibited a 10.4 times higher ACE-inhibitory activity than SPIH. Novel peptides IY, YVVF, LVF, WMY, LVLL and FF (hydrophobicity values 10.51-12.87; activity scores 0.2373-0.999) might be the main contributors to SPIH's ACE inhibition. IY had the lowest IC50 (0.53 ± 0.02 µM). YVVF had the greatest affinity (-9.8 kcal/mol) for 2OC2 (ACE's C-domain receptor) via H-bonds. IY and WMY could be potent ACE inhibitors, and their ACE-inhibitory activities unaltered and increased after in vitro gastrointestinal digestion.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/análise , Simulação por Computador , Digestão , Simulação de Acoplamento Molecular , Peptídeos/análise , Peptidil Dipeptidase A/metabolismo , Proteínas de Soja/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Interações Hidrofóbicas e Hidrofílicas , Peptídeos/metabolismo , Peptídeos/farmacologia , Peptidil Dipeptidase A/química , Conformação Proteica
2.
Pharmacol Res Perspect ; 9(1): e00691, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33378565

RESUMO

Coronaviruses represent global health threat. In this century, they have already caused two epidemics and one serious pandemic. Although, at present, there are no approved drugs and therapies for the treatment and prevention of human coronaviruses, several agents, FDA-approved, and preclinical, have shown in vitro and/or in vivo antiviral activity. An in-depth analysis of the current situation leads to the identification of several potential drugs that could have an impact on the fight against coronaviruses infections. In this review, we discuss the virology of human coronaviruses highlighting the main biological targets and summarize the current state-of-the-art of possible therapeutic options to inhibit coronaviruses infections. We mostly focus on FDA-approved and preclinical drugs targeting viral conserved elements.


Assuntos
/metabolismo , Infecções por Coronavirus/metabolismo , Coronavirus/metabolismo , Dipeptidil Peptidase 4/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , /antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/metabolismo , Antivirais/administração & dosagem , Antivirais/metabolismo , Azóis/administração & dosagem , Azóis/metabolismo , Coronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/metabolismo , Humanos , Naftoquinonas/administração & dosagem , Naftoquinonas/metabolismo , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/metabolismo , Síndrome Respiratória Aguda Grave/tratamento farmacológico
3.
Ecotoxicol Environ Saf ; 209: 111791, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33360211

RESUMO

A recently isolated osmo-tolerant yeast Candida tropicalis A1, which could decolorize various azo dyes under high-salinity conditions, was systematically characterized in the present study. Stimulating dye-decolorization effectiveness and osmo-tolerance of the yeast by static magnetic field (SMF) was investigated and transcriptomic responses of the yeast to SMF was analyzed to propose possible mechanisms. The results demonstrated that the yeast A1 effectively decolorized (≥ 97.50% within 12 h) and detoxified (from high toxicity to low toxicity within 24 h) 70 mg/L Acid Red B (ARB) under the optimized conditions through a series of steps including naphthalene-amidine bond cleavage, reductive or oxidative deamination/desulfurization, open-loop of hydroxy-substituted naphthalene or benzene and TCA cycle. Moreover, dye decolorization performance and osmo-tolerance of the yeast A1 were further improved by 24.6 mT SMF. Genes encoding high-affinity hexose/glucose transporter proteins and NADH-ubiquinone oxidoreductase were up-regulated by 24.6 mT SMF, which might be responsible for the increase of dye decolorization. Significant up-regulation of glycerol-3-phosphate dehydrogenase and cell wall protein RHD3 suggested that osmo-tolerance was enhanced by 24.6 mT SMF through promoting production and intracellular accumulation of glycerol as compatible solute, as well as regulation of cell wall component. In conclusion, 24.6 mT SMF led to the up-regulation of related genes resulting in enhanced dye biodegradation efficiency and osmo-tolerance of the yeast A1.


Assuntos
Compostos Azo/metabolismo , Biodegradação Ambiental , Candida tropicalis/fisiologia , Antagonistas de Receptores de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Compostos Azo/química , Candida tropicalis/metabolismo , Corantes/química , Naftalenossulfonatos , Transcriptoma
4.
Rev. clín. esp. (Ed. impr.) ; 220(8): 507-510, nov. 2020.
Artigo em Espanhol | IBECS | ID: ibc-192189

RESUMO

La eclosión de la pandemia por COVID-19 supone un reto de enormes dimensiones y, dada la gran presencia de diabetes mellitus tipo2 en la población actual, hace que sea un problema de salud en el que centrar nuestros esfuerzos para dar la mejor respuesta a nuestros pacientes, que son más vulnerables al desarrollo de la infección y candidatos a presentar cuadros clínicos más graves. Este documento pretende abordar la relación entre la infección por COVID-19 y la DM2. Para ello analizaremos brevemente qué datos epidemiológicos sustentan esta asociación y, posteriormente, se profundizará en los mecanismos fisiopatológicos que podrían conectar ambas enfermedades


The emergence of the COVID-19 pandemic represents an enormous challenge. Given the considerable presence of type 2 diabetes mellitus in the current population, the pandemic is a health issue that requires an effort to provide better responses to our patients who are more vulnerable to the onset of infection and who are candidates for presenting more severe symptoms. This document attempts to address the relationship between COVID-19 infection and type 2 diabetes mellitus. To this end, we will briefly analyse whether the epidemiological data support this association and, subsequently, go in depth on the pathophysiological mechanisms that might connect the two diseases


Assuntos
Humanos , Infecções por Coronavirus/complicações , Diabetes Mellitus Tipo 2/complicações , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/complicações , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Peptidil Dipeptidase A/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Peptídeos Semelhantes ao Glucagon/agonistas , Insulina/metabolismo , Indicadores de Morbimortalidade , Sistema Renina-Angiotensina/fisiologia
5.
Life Sci ; 257: 118142, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32712300

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently defined as the worst pandemic disease. SARS-CoV-2 infects human cells via the binding of its S protein to the receptor angiotensin-converting enzyme (ACE2). The use of ACEIs/ARBs (RAAS inhibitors) regulates the renin-angiotensin-aldosterone system (RAAS) and may increase ACE2 expression. Considering the large use of ACEIs/ARBs in hypertensive patients, some professional groups are concerned about whether the use of RAAS inhibitors affects the risk of SARS-CoV-2 infection or the risk of severe illness and mortality in COVID-19 patients. In this review, we summarize preclinical and clinical studies to investigate whether the use of ACEIs/ARBs increases ACE2 expression in animals or patients. We also analyzed whether the use of these drugs affects the risk of SARS-CoV-2 infection, severe illness or mortality based on recent studies. Finally, the review suggests that current evidence does not support the concerns.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Betacoronavirus/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Betacoronavirus/imunologia , Betacoronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Humanos , Inflamação/imunologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco
6.
Food Chem ; 331: 127216, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32650230

RESUMO

The effects of ultrasound working modes using multi-mode S-type ultrasound on the preparation of bioactive peptide from rice protein (RP) were studied with the ACE inhibitory activity of protein-hydrolysate after gastrointestinal simulated digestion as the index. The structure characterizations of protein and enzymolysis products were also studied. Results showed that all the ultrasound working modes pretreatment increased the ACE inhibitory activity significantly (p < 0.05) and 20/40 kHz dual-frequency ultrasound showed the most significant impact, which increased by 38.28% and 27.47% compared to control and ultrasound cleaning machine, respectively. After pretreated by 20/40 kHz dual-frequency ultrasound, the soluble and hydrophobic protein contents, free sulfhydryl content and surface hydrophobicity of RP increased. And the peptide content and hydrophobic amino acid content of protein-hydrolysate after gastrointestinal simulated digestion showed higher value (p < 0.05). In conclusion, the multi-mode S-type ultrasound pretreatment is an effective way in preparation of ACE inhibitory peptide from RP.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/metabolismo , Oryza/metabolismo , Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Proteínas de Plantas/metabolismo , Inibidores da Enzima Conversora de Angiotensina/química , Interações Hidrofóbicas e Hidrofílicas , Peptídeos/química , Peptidil Dipeptidase A/química , Proteínas de Plantas/química , Ligação Proteica , Hidrolisados de Proteína/química , Sonicação , Propriedades de Superfície
8.
ChemMedChem ; 15(18): 1682-1690, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32663362

RESUMO

Angiotensin converting enzyme 2 (ACE2) is the human receptor that interacts with the spike protein of coronaviruses, including the one that produced the 2020 coronavirus pandemic (COVID-19). Thus, ACE2 is a potential target for drugs that disrupt the interaction of human cells with SARS-CoV-2 to abolish infection. There is also interest in drugs that inhibit or activate ACE2, that is, for cardiovascular disorders or colitis. Compounds binding at alternative sites could allosterically affect the interaction with the spike protein. Herein, we review biochemical, chemical biology, and structural information on ACE2, including the recent cryoEM structures of full-length ACE2. We conclude that ACE2 is very dynamic and that allosteric drugs could be developed to target ACE2. At the time of the 2020 pandemic, we suggest that available ACE2 inhibitors or activators in advanced development should be tested for their ability to allosterically displace the interaction between ACE2 and the spike protein.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/metabolismo , Betacoronavirus/química , Peptidil Dipeptidase A/metabolismo , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Regulação Alostérica , Inibidores da Enzima Conversora de Angiotensina/química , Domínio Catalítico , Humanos , Peptidil Dipeptidase A/química , Ligação Proteica , Domínios Proteicos , Receptores Virais/antagonistas & inibidores , Receptores Virais/química , Glicoproteína da Espícula de Coronavírus/química
9.
Food Chem ; 329: 127193, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32516711

RESUMO

This study was aimed to produce bioactive peptides from optimally fermented tempe, and map their overall bioactivities. There were three preparative methods utilized for producing tempe-based peptides, such as water-facilitated extraction, alcalase, and papain hydrolysis, and in combination with membrane filtration. Fermenting soybean at 144 h was selected as the optimum time based on protein content and degree of hydrolysis. Through SDS-PAGE analysis, an increased degree of hydrolysis with longer fermentation time was confirmed. The best preparative method for producing bioactive peptides was through papain hydrolysis and followed by 5 kDa membrane filtration. By this, the enhancement was distinct for antioxidant activity, ACE-, α-glucosidase-, and Kunitz trypsin-inhibitory activity. The annotated peptide sequences resulting from Nano LC Ultimate 3000 Series System tandem Q Exactive™ Hybrid Quadrupole-Orbitrap™ Mass Spectrometer were matched with the BIOPEP database. The major bioactivities of tempe peptides obtained were as an ACE inhibitor, antioxidant, and antithrombotic.


Assuntos
Peptídeos/química , Alimentos de Soja/análise , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Antioxidantes/química , Cromatografia Líquida de Alta Pressão , Bases de Dados de Proteínas , Eletroforese em Gel de Poliacrilamida , Fermentação , Filtração , Farinha/análise , Hidrólise , Espectrometria de Massas , Papaína/metabolismo , Peptídeos/metabolismo , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Solubilidade , Soja/metabolismo , Subtilisinas/metabolismo
10.
Int J Food Microbiol ; 330: 108688, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-32497940

RESUMO

The impact of salt and fat intake on human health drives the consumer's attention towards dairy food with reduced salt and fat contents. How changes in salt and fat content modulate dairy LAB population and the associated proteolytic activities have been poorly studied. Here, non-starter LAB populations from 12 Parmigiano Reggiano (PR) cheeses (12-month ripened), clustered in low salt and fat content (LL-PR) and high salt and fat content (HH-PR) groups, were investigated and identified at specie-level with molecular assays. Lactobacillus rhamnosus was dominant in HH-PR samples, whereas Lactobacillus paracasei in LL-PR samples. (GTG)5 rep-PCR analysis discriminated 11 and 12 biotypes for L. rhamnosus and L. paracasei isolates, respectively. Screening for proteolytic activity identified L. rhamnosus strains more proteolytic than L. paracasei, and, within L. rhamnosus species, HH-PR strains were generally more proteolytic than LL-PR strains. Two L. rhamnosus representatives, namely strain 0503 from LL-PR and strain 2006 from HH-PR, were functionally characterized in cow milk fermentation assay. HH-PR strain 2006 overcame LL-PR strain 0503 in acidification performance, leading to a fermented milk with higher angiotensin I-converting enzyme inhibitory and antioxidant activities. L. rhamnosus 2006 was more prone to release VPP, while L. rhamnosus 0503 released higher amount of IPP. This study provides evidences that salt/fat content affects NSLAB cultivable fraction and the associated proteolytic ability resulting in a complex occurrence of bioactive peptides featuring health-promoting properties.


Assuntos
Anti-Hipertensivos/metabolismo , Queijo/microbiologia , Lactobacillus/isolamento & purificação , Peptídeos/metabolismo , Cloreto de Sódio/análise , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Antioxidantes/metabolismo , Queijo/análise , Gorduras/análise , Fermentação , Lactobacillus/classificação , Lactobacillus/metabolismo , Leite/química , Leite/microbiologia
11.
Hipertens. riesgo vasc ; 37(2): 72-77, abr.-jun. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-189194

RESUMO

El sistema renina-angiotensina (SRA) es una cascada hormonal que regula presión arterial, electrólitos y balance hídrico. La angiotensinaII (AII) ejerce sus efectos a través de los receptores AT1 y AT2. El AT1 se encuentra en el sincitiotrofoblasto; el AT2 predomina durante el desarrollo fetal y su estimulación inhibe el crecimiento celular, aumenta la apoptosis, causa vasodilatación y regula el desarrollo del tejido fetal. Existe además un SRA en la placenta, y la generación local de AII es responsable de la activación de los receptores AT1 del trofoblasto. En el embarazo normal, concomitantemente con reducción de los niveles de presión arterial, se produce un aumento del SRA circulante, pero la presión arterial no sube porque existe refractariedad a la AII, cosa que no ocurre en la preeclampsia. Revisamos la función del SRA en el embarazo normal y en la preeclampsia


The renin-angiotensin system (ARS) is a hormonal cascade that regulates blood pressure, electrolytes and water balance. AngiotensinII (AII) exerts its effects through the AT1 and AT2 receptors. AT1 is found in the syncytiotrophoblast, AT2 predominates during foetal development and its stimulation inhibits cell growth, increases apoptosis, causes vasodilation and regulates the development of foetal tissue. There is also an SRA in the placenta. The local generation of AII is responsible for the activation of AT1 receptors in the trophoblast. In normal pregnancy, concomitantly with reduction of blood pressure the circulating RAS increases, but blood pressure does not rise due to AII refractoriness, which does not occur in preeclampsia. We review the role of the SRA in normal pregnancy and preeclampsia


Assuntos
Humanos , Feminino , Gravidez , Sistema Renina-Angiotensina/efeitos dos fármacos , Pré-Eclâmpsia/metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Hemodinâmica/efeitos dos fármacos , Albumina Sérica/efeitos dos fármacos , Índice de Gravidade de Doença , Espaço Extracelular/efeitos dos fármacos , Homeostase/efeitos dos fármacos
12.
J Dairy Sci ; 103(7): 5805-5815, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32448573

RESUMO

Lactic acid bacteria (LAB) are used as starter cultures in the production of fermented dairy products and have the potential to confer bioactivity relevant to cardiovascular health, as they possess extensive proteolytic systems that liberate small bioactive peptides from larger milk proteins. Certain casein-derived peptides released by various LAB strains during fermentation have been shown to reduce hypertension and to modulate the immune system. We investigated the growth and peptide production of 2 LAB strains, Lactobacillus helveticus R0389 and Lactocaseibacillus rhamnosus R0011, their immunomodulatory activities, as well as their abilities to inhibit the angiotensin-converting enzyme (ACE). Peptide fractions collected from the cell-free supernatant of both medium-grown and milk fermentation cultures were assessed for ACE-inhibitory activity and their effects on the production of proinflammatory and regulatory cytokines by human THP-1 monocytes. Cultures were grown in medium, with or without supplementation with 0.1% casein, or in 3.25% milk fermented with each LAB strain. Casein supplementation increased the growth rate of both LAB strains, and significantly increased ACE-inhibitory activity of peptide fractions collected from both L. helveticus R0389 and L. rhamnosus R0011 cultures grown for 12 h. Fermentation peptide fractions of L. rhamnosus R0011 showed comparable ACE-inhibitory activity to known ACE inhibiting peptides Val-Pro-Pro and Ile-Pro-Pro (up to 79% inhibition) with a significant difference between culture peptide fractions and acidified and nonacidified control fractions collected after 6 d of fermentation. Many milk and casein-derived peptides reported in previous studies have been identified as part of a larger bioactive fraction. We synthesized a group of these peptides to individually assess both ACE-inhibitory and immunomodulatory activity. The known ACE inhibitors Val-Pro-Pro and Ile-Pro-Pro showed similar ACE inhibition to previously published results, while also inducing the production of the regulatory cytokine IL-10 by monocytes in the presence and absence of a proinflammatory stimulant. These synthesized peptides could also induce the production of nitric oxide (NO), a potent vasodilator, in human endothelial cell cultures. Investigating the relationships among these bioactive properties could improve the use of probiotic organisms and their secreted products in the food industry.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Proteínas de Bactérias/farmacologia , Lactobacillus helveticus/química , Lactobacillus rhamnosus/química , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Proteínas de Bactérias/metabolismo , Caseínas/análise , Citocinas/metabolismo , Óxido Nítrico/metabolismo , Peptídeos/metabolismo
13.
Sci Rep ; 10(1): 7883, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398731

RESUMO

Antioxidant activity, angiotensin I-converting enzyme (ACE) inhibitory activity, and protein profile of crust (the dried surface of dry-aged beef) were evaluated compared to unaged, wet-, and dry-aged beef. Antioxidant activity was determined using 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-di-(3-ethylbenzthiazoline sulfonate) radical scavenging activities, ferric reducing antioxidant power, and ferrous ion chelating activity. The crust samples showed the greatest (P < 0.05) ACE inhibitory and antioxidant activity resulting from the three different mechanisms of action (radical scavenging, non-radical redox potential activity, and metal chelating) among the treatments. Small molecular weight protein bands and small peptides (<3 kDa) indicating potent bioactivity were evident in the myofibrillar protein profile of crust samples. The lowest (P < 0.05) ACE inhibitory activity was observed in unaged beef. The results indicate that crust could be utilized in various areas as a functional ingredient possessed antioxidant and ACE inhibitory activity instead of being discarded. In addition, dry aging can use for generation of functional ingredient from beef as the regime.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/metabolismo , Antioxidantes/metabolismo , Proteínas Musculares/metabolismo , Peptídeos/metabolismo , Carne Vermelha/análise , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Antioxidantes/farmacologia , Bovinos , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Quelantes de Ferro/metabolismo , Quelantes de Ferro/farmacologia , Masculino , Oxirredução/efeitos dos fármacos , Fatores de Tempo
14.
J Med Chem ; 63(10): 5488-5500, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32337993

RESUMO

Neprilysin (NEP) and angiotensin-converting enzyme (ACE) are two key zinc-dependent metallopeptidases in the natriuretic peptide and kinin systems and renin-angiotensin-aldosterone system, respectively. They play an important role in blood pressure regulation and reducing the risk of heart failure. Vasopeptidase inhibitors omapatrilat and sampatrilat possess dual activity against these enzymes by blocking the ACE-dependent conversion of angiotensin I to the potent vasoconstrictor angiotensin II while simultaneously halting the NEP-dependent degradation of vasodilator atrial natriuretic peptide. Here, we report crystal structures of omapatrilat, sampatrilat, and sampatrilat-ASP (a sampatrilat analogue) in complex with NEP at 1.75, 2.65, and 2.6 Å, respectively. A detailed analysis of these structures and the corresponding structures of ACE with these inhibitors has provided the molecular basis of dual inhibitor recognition involving the catalytic site in both enzymes. This new information will be very useful in the design of safer and more selective vasopeptidase inhibitors of NEP and ACE for effective treatment in hypertension and heart failure.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/metabolismo , Desenho de Fármacos , Mesilatos/metabolismo , Neprilisina/metabolismo , Peptidil Dipeptidase A/metabolismo , Piridinas/metabolismo , Tiazepinas/metabolismo , Tirosina/análogos & derivados , Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Anti-Hipertensivos/metabolismo , Cristalografia por Raios X/métodos , Mesilatos/química , Neprilisina/química , Peptidil Dipeptidase A/química , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Piridinas/química , Tiazepinas/química , Tirosina/química , Tirosina/metabolismo
16.
Sci Rep ; 10(1): 3976, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132600

RESUMO

The synthetic Angiotensin Converting Enzyme (ACE) inhibitors have side effects and hence demands for natural ACE inhibitors have been rising. The aim of this study is to purify and introduce natural ACE inhibitors extracted from Zizyphus jujuba fruits. Proteins from Zizyphus jujuba were lysed by trypsin, papain and their combination. Acquired peptides were purified and evaluated for ACE inhibitory activity. Peptide fractions with inhibitory activity were sequenced using tandem mass spectrometry. To elucidate the mode of peptide binding to ACE, homology modeling, molecular docking and molecular dynamics simulation were performed. Amino acid sequence of F2 and F4 peptides, which were the most active hydrolysates, were determined to be IER and IGK with the IC50 values of 0.060 and 0.072 mg/ml, respectively. Results obtained by computational analysis revealed that similar to the common ACE competitive inhibitors such as captopril, IER tripeptide binds to the enzyme active site, in vicinity of the zinc binding site, and occupies the S1 and S2' subsites. Binding occurs through hydrogen bonding with Gln293, Lys522, His524, Tyr531 and also several hydrophobic interactions. Collectively, these findings indicate that IER tripeptide inhibits the rabbit ACE enzyme through a competitive mechanism of inhibition with IC50 values in the millimolar range.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Frutas/química , Peptídeos/isolamento & purificação , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Ziziphus/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Hidrólise , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptídeos/química , Peptídeos/metabolismo , Peptidil Dipeptidase A/química , Conformação Proteica , Coelhos
17.
Biochem J ; 477(7): 1241-1259, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32195541

RESUMO

Angiotensin-converting enzyme (ACE) is best known for its formation of the vasopressor angiotensin II that controls blood pressure but is also involved in other physiological functions through the hydrolysis of a variety of peptide substrates. The enzyme contains two catalytic domains (nACE and cACE) that have different affinities for ACE substrates and inhibitors. We investigated whether nACE inhibitor backbones contain a unique property which allows them to take advantage of the hinging of nACE. Kinetic analysis showed that mutation of unique nACE residues, in both the S2 pocket and around the prime subsites (S') to their C-domain counterparts, each resulted in a decrease in the affinity of nACE specific inhibitors (SG6, 33RE and ketoACE-13) but it required the combined S2_S' mutant to abrogate nACE-selectivity. However, this was not observed with the non-domain-selective inhibitors enalaprilat and omapatrilat. High-resolution structures were determined for the minimally glycosylated nACE with the combined S2_S' mutations in complex with the ACE inhibitors 33RE (1.8 Å), omapatrilat (1.8 Å) and SG6 (1.7 Å). These confirmed that the affinities of the nACE-selective SG6, 33RE and ketoACE-13 are not only affected by direct interactions with the immediate environment of the binding site, but also by more distal residues. This study provides evidence for a more general mechanism of ACE inhibition involving synergistic effects of not only the S2, S1' and S2' subsites, but also residues involved in the sub-domain interface that effect the unique ways in which the two domains stabilize active site loops to favour inhibitor binding.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Domínio Catalítico , Metaloendopeptidases/química , Metaloendopeptidases/metabolismo , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pressão Sanguínea/fisiologia , Cristalografia por Raios X , Glicosilação , Humanos , Cinética , Ligantes , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Mutação , Peptidil Dipeptidase A/genética , Ligação Proteica , Conformação Proteica em Folha beta/genética , Sistema Renina-Angiotensina/fisiologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-32172172

RESUMO

Purification of small bioactive peptides from complex biological samples is a difficult task due to the interference of concentrated large biomolecules. In this study, a magnetic immobilized metal affinity chromatography matrix modified by poly (ethylene glycol) methyl ether (IMACM@mPEG) was prepared and applied for the rapid purification of angiotensin I-converting enzyme (ACE) inhibitory peptides from casein hydrolysate. The proposed IMACM@mPEG considerably reduced the non-specific adsorption of large proteins and exhibited improved purification efficiency towards ACE inhibitory peptides. A novel peptide with moderate ACE inhibitory activity (IC50 value of 274 ± 5 µM) was identified as LLYQEPVLGPVR. Lineweaver-Burk plot confirmed the non-competitive inhibition pattern of LLYQEPVLGPVR. The purified peptide was digested after simulated gastrointestinal digestion and produced shorter peptides which contributed to enhanced ACE inhibitory activity. These results indicated that the IMACM@mPEG is an effective method for the prepurification of ACE inhibitory peptide and the purified peptide LLYQEPVLGPVR may have potential as nutraceutical ingredient in functional foods for hypertension treatments.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Caseínas/química , Cromatografia de Afinidade/métodos , Éteres/química , Peptídeos/isolamento & purificação , Polietilenoglicóis/química , Adsorção , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Cobre/química , Óxido Ferroso-Férrico/química , Microesferas , Peptídeos/análise , Peptídeos/metabolismo , Hidrolisados de Proteína , Dióxido de Silício/metabolismo , Propriedades de Superfície
19.
Int J Mol Sci ; 21(3)2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013233

RESUMO

Several milk/whey derived peptides possess high in vitro angiotensin I-converting enzyme (ACE) inhibitory activity. However, in some cases, poor correlation between the in vitro ACE inhibitory activity and the in vivo antihypertensive activity has been observed. The aim of this study is to gain insight into the structure-activity relationship of peptide sequences present in whey/milk protein hydrolysates with high ACE inhibitory activity, which could lead to a better understanding and prediction of their in vivo antihypertensive activity. The potential interactions between peptides produced from whey proteins, previously reported as high ACE inhibitors such as IPP, LIVTQ, IIAE, LVYPFP, and human ACE were assessed using a molecular docking approach. The results show that peptides IIAE, LIVTQ, and LVYPFP formed strong H bonds with the amino acids Gln 259, His 331, and Thr 358 in the active site of the human ACE. Interestingly, the same residues were found to form strong hydrogen bonds with the ACE inhibitory drug Sampatrilat. Furthermore, peptides IIAE and LVYPFP interacted with the amino acid residues Gln 259 and His 331, respectively, also in common with other ACE-inhibitory drugs such as Captopril, Lisinopril and Elanapril. Additionally, IIAE interacted with the amino acid residue Asp 140 in common with Lisinopril, and LIVTQ interacted with Ala 332 in common with both Lisinopril and Elanapril. The peptides produced naturally from whey by enzymatic hydrolysis interacted with residues of the human ACE in common with potent ACE-inhibitory drugs which suggests that these natural peptides may be potent ACE inhibitors.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/metabolismo , Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Proteínas do Soro do Leite/metabolismo , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Sítios de Ligação , Captopril/química , Captopril/metabolismo , Domínio Catalítico , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Peptídeos/química , Peptidil Dipeptidase A/química , Coelhos , Alinhamento de Sequência , Relação Estrutura-Atividade , Proteínas do Soro do Leite/química
20.
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 , Ligação 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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...