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Nga N. Chung - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological activities of cyclic lanthionine enkephalin analogues : δ-opioid receptor selective ligands
Journal of medicinal chemistry, 2002Co-Authors: Yosup Rew, Shelle Malkmus, Camilla I. Svensson, Tony L. Yaksh, Nga N. Chung, Peter W. Schiller, Joel A. Cassel, Robert N. Dehaven, Joseph P. Taulane, Murray GoodmanAbstract:The synthesis and biological test results of a series of enkephalin analogues incorporating the lanthionine modification are presented. The syntheses of four monosulfide-bridged analogues of enkephalins, Tyr-c[d-AlaL-Gly-Phe-d-AlaL]-OH (1a), Tyr-c[d-ValL-Gly-Phe-d-AlaL]-OH (1b), Tyr-c[d-AlaL-Gly-Phe-AlaL]-OH (1c), and Tyr-c[d-ValL-Gly-Phe-AlaL]-OH (1d), where AlaL and ValL denote the lanthionine amino acid ends linked by a monosulfide bridge to form the lanthionine structure, were successfully carried out via preparation of the linear peptide on solid support and cyclization in solution. In vitro binding assays against μ-, δ-, and κ-opioid receptors and in vitro tests using GPI and MVD assays revealed that the dimethyl lanthionine analogues 1b and 1d, denoted as d-ValL in position 2, show substantial selectivity toward the δ-opioid receptor, while the unsubstituted analogues 1a and 1c, denoted as d-AlaL in position 2, bind to both μ- and δ-opioid receptors. The in vivo thermal escape assay by intrathecal ...
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the tipp opioid peptide family development of antagonists agonists and mixed agonist antagonists
Biopolymers, 1999Co-Authors: Peter W. Schiller, Thi M.-d. Nguyen, Grazyna Weltrowska, Irena Berezowska, Brian C Wilkes, Carole Lemieux, Nga N. ChungAbstract:The discovery of the prototype delta opioid antagonists TIPP (H-Tyr-Tic-Phe-Phe-OH) and TIP (H-Tyr-Tic-Phe-OH) in 1992 was followed by extensive structure-activity relationship studies, leading to the development of analogues that are of interest as pharmacological tools or as potential therapeutic agents. Stable TIPP-derived delta opioid antagonists with subnanomolar delta receptor binding affinity and extraordinary delta receptor selectivity include TIPP[Psi] (H-Tyr-TicPsi[CH(2)NH]Phe-Phe-OH] and TICP[Psi] (H-Tyr-TicPsi[CH(2)NH]Cha-Phe-OH); Cha: cyclohexylalanine), which are widely used in opioid research. Theoretical conformational analyses in conjunction with the pharmacological characterization of conformationally constrained TIPP analogues led to a definitive model of the receptor-bound conformation of H-Tyr-Tic-(Phe-Phe)-OH-related delta opioid antagonists, which is characterized by all-trans peptide bonds. Further structure-activity studies revealed that the delta antagonist vs delta agonist behavior of TIP(P)-derived compounds depended on very subtle structural differences in diverse locations of the molecule and suggested a delta receptor model involving a number of different inactive receptor conformations. A further outcome of these studies was the identification of a new class of potent and very selective dipeptide delta agonists of the general formula H-Tyr-Tic-NH-X (X = arylalkyl), which are of interest for drug development because of their low molecular weight and lipophilic character. Most interestingly, TIPP analogues containing a C-terminal carboxamide group displayed a mixed mu agonist/delta antagonist profile, and thus were expected to be analgesics with a low propensity to produce tolerance and physical dependence. This turned out to be the case with the TIPP-derived mu agonist/delta antagonist DIPP-NH(2)[Psi] (H-Dmt-TicPsi[CH(2)NH]Phe-Phe-NH(2)); Dmt: 2',6'- dimethyltyrosine).
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tipp psi a highly potent and stable pseudopeptide delta opioid receptor antagonist with extraordinary delta selectivity
Journal of Medicinal Chemistry, 1993Co-Authors: Peter W. Schiller, Thi M.-d. Nguyen, Nga N. Chung, Grazyna Weltrowska, Brian C Wilkes, Carole LemieuxAbstract:Pseudopeptide analogues of the delta opioid antagonists H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic-Phe-OH (TIP) containing a reduced peptide bond between the Tic2 and Phe3 residues were synthesized. The two compounds, H-Tyr-Tic psi [CH2NH]Phe-Phe-OH (TIPP [psi]) and H-Tyr-Tic psi-[CH2NH]Phe-OH (TIP [psi]), were tested in mu-, delta-, and kappa-receptor-selective binding assays and in the guinea pig ileum (GPI) and mouse vas deferens (MVD) bioassays. In comparison with their respective parent peptides, both pseudopeptide analogues showed increased delta antagonist potency in the MVD assay, higher delta receptor affinity and further improved delta receptor selectivity. The more potent compound, TIPP [psi], displayed subnanomolar delta receptor affinity and in direct comparisons with other selective delta ligands was shown to have unprecedented delta specificity (Ki mu/Ki delta = 10,500). Furthermore, this compound turned out to be highly stable against enzymatic degradation and, unlike other delta antagonists, showed no mu or kappa antagonist properties. TIPP [psi] is likely to find wide use as a pharmacological tool in opioid research.
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differential stereochemical requirements of mu vs delta opioid receptors for ligand binding and signal transduction development of a class of potent and highly delta selective peptide antagonists
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Peter W. Schiller, Grazyna Weltrowska, Brian C Wilkes, Carole Lemieux, T M D Nguyen, B J Marsden, Nga N. ChungAbstract:Abstract Opioid peptide analogs consisting entirely of aromatic amino acid residues and containing conformationally restricted phenylalanine derivatives in position 2 of the peptide sequence were synthesized and pharmacologically characterized in vitro. Both diastereoisomers of H-Tyr-(D or L)-NMePhe-Phe-Phe-NH2 (NMePhe is N alpha-methylphenylalanine) were mu-receptor-selective, were full agonists in the mu-receptor-representative guinea pig ileum assay, and were partial agonists in the mouse vas deferens assay, with the L-NMePhe2 analog displaying somewhat higher intrinsic activity than the D-NMePhe2 analog. Further conformational restriction at position 2 in the sequence, as achieved through substitution of D- or L-tetrahydro-3-isoquinoline carboxylic acid (Tic), produced a configuration-dependent differential effect on receptor selectivity and intrinsic activity, leading to a potent mu-selective mu agonist (the D-Tic2 analog) with increased intrinsic activity in the mouse vas deferens assay and to a potent delta-selective delta antagonist (the L-Tic2 analog). These results demonstrate that imposition of conformational constraints in a peptide not only may alter receptor selectivity but also may decrease, totally abolish, or even enhance intrinsic activity. The tetrapeptide H-Tyr-Tic-Phe-Phe-NH2 was a moderately potent full agonist in the guinea pig ileum assay and, thus, represents a compound with mixed mu-agonist/delta-antagonist properties. The corresponding peptide with a free C-terminal carboxyl group H-Tyr-Tic-Phe-Phe-OH showed high delta-receptor affinity (Ki delta = 1.2 nM), unprecedented delta selectivity (Ki mu/Ki delta = 1410), high potency as delta antagonist (Ke = 3-8 nM against various delta agonists in the mouse vas deferens assay) and, unlike other delta antagonists, had no mu-antagonist properties. The tripeptides H-Tyr-Tic-Phe-OH and H-Tyr-Tic-Phe-NH2 were also delta antagonists.
Peter W. Schiller - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological activities of cyclic lanthionine enkephalin analogues : δ-opioid receptor selective ligands
Journal of medicinal chemistry, 2002Co-Authors: Yosup Rew, Shelle Malkmus, Camilla I. Svensson, Tony L. Yaksh, Nga N. Chung, Peter W. Schiller, Joel A. Cassel, Robert N. Dehaven, Joseph P. Taulane, Murray GoodmanAbstract:The synthesis and biological test results of a series of enkephalin analogues incorporating the lanthionine modification are presented. The syntheses of four monosulfide-bridged analogues of enkephalins, Tyr-c[d-AlaL-Gly-Phe-d-AlaL]-OH (1a), Tyr-c[d-ValL-Gly-Phe-d-AlaL]-OH (1b), Tyr-c[d-AlaL-Gly-Phe-AlaL]-OH (1c), and Tyr-c[d-ValL-Gly-Phe-AlaL]-OH (1d), where AlaL and ValL denote the lanthionine amino acid ends linked by a monosulfide bridge to form the lanthionine structure, were successfully carried out via preparation of the linear peptide on solid support and cyclization in solution. In vitro binding assays against μ-, δ-, and κ-opioid receptors and in vitro tests using GPI and MVD assays revealed that the dimethyl lanthionine analogues 1b and 1d, denoted as d-ValL in position 2, show substantial selectivity toward the δ-opioid receptor, while the unsubstituted analogues 1a and 1c, denoted as d-AlaL in position 2, bind to both μ- and δ-opioid receptors. The in vivo thermal escape assay by intrathecal ...
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the tipp opioid peptide family development of antagonists agonists and mixed agonist antagonists
Biopolymers, 1999Co-Authors: Peter W. Schiller, Thi M.-d. Nguyen, Grazyna Weltrowska, Irena Berezowska, Brian C Wilkes, Carole Lemieux, Nga N. ChungAbstract:The discovery of the prototype delta opioid antagonists TIPP (H-Tyr-Tic-Phe-Phe-OH) and TIP (H-Tyr-Tic-Phe-OH) in 1992 was followed by extensive structure-activity relationship studies, leading to the development of analogues that are of interest as pharmacological tools or as potential therapeutic agents. Stable TIPP-derived delta opioid antagonists with subnanomolar delta receptor binding affinity and extraordinary delta receptor selectivity include TIPP[Psi] (H-Tyr-TicPsi[CH(2)NH]Phe-Phe-OH] and TICP[Psi] (H-Tyr-TicPsi[CH(2)NH]Cha-Phe-OH); Cha: cyclohexylalanine), which are widely used in opioid research. Theoretical conformational analyses in conjunction with the pharmacological characterization of conformationally constrained TIPP analogues led to a definitive model of the receptor-bound conformation of H-Tyr-Tic-(Phe-Phe)-OH-related delta opioid antagonists, which is characterized by all-trans peptide bonds. Further structure-activity studies revealed that the delta antagonist vs delta agonist behavior of TIP(P)-derived compounds depended on very subtle structural differences in diverse locations of the molecule and suggested a delta receptor model involving a number of different inactive receptor conformations. A further outcome of these studies was the identification of a new class of potent and very selective dipeptide delta agonists of the general formula H-Tyr-Tic-NH-X (X = arylalkyl), which are of interest for drug development because of their low molecular weight and lipophilic character. Most interestingly, TIPP analogues containing a C-terminal carboxamide group displayed a mixed mu agonist/delta antagonist profile, and thus were expected to be analgesics with a low propensity to produce tolerance and physical dependence. This turned out to be the case with the TIPP-derived mu agonist/delta antagonist DIPP-NH(2)[Psi] (H-Dmt-TicPsi[CH(2)NH]Phe-Phe-NH(2)); Dmt: 2',6'- dimethyltyrosine).
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tipp analogs highly selective δ opioid antagonists with subnanomolar potency and first known compounds with mixed μ agonist δ antagonist properties
Regulatory Peptides, 1994Co-Authors: Peter W. Schiller, Grazyna Weltrowska, Carole Lemieux, T D Nguyen, N N Chung, Brian C WilkesAbstract:Analogs of the potent and higly selective δ opioid antagonist H-Tyr-Tic-Phe-Phe-OH (TIPP) (Tic=tetrahydroisoquinoline-3-carboxylic acid) (1) containing Trp, 3-(2'-naphthyl)alanine (2-Nal) or homophenylalanine (Hfe) in place of Phe 3 , or p-nitrophenylalanine [Phe(pNO 2 )] in place of Phe 4 exhibited a 1.5-5-fold increase in δ antagonist potency against 6 agonists in the mouse vas deferens (MVD) assay and 3-5-fold enhanced 6 selectivity. The pseudopeptide H-Tyr-TicΨ[CH2-NH]Phe-Phe-OH (TIPP[Ψ]) showed excellent stability against enzymatic degradation, high δ antagonist potency (K e ∼2.5 nM), no μ antagonist properties and unprecedented δ selectivity (K i μ /K i δ =10 500), being 500 times more selective than the non-ipeptide δ antagonist naltrindole
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tipp psi a highly potent and stable pseudopeptide delta opioid receptor antagonist with extraordinary delta selectivity
Journal of Medicinal Chemistry, 1993Co-Authors: Peter W. Schiller, Thi M.-d. Nguyen, Nga N. Chung, Grazyna Weltrowska, Brian C Wilkes, Carole LemieuxAbstract:Pseudopeptide analogues of the delta opioid antagonists H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic-Phe-OH (TIP) containing a reduced peptide bond between the Tic2 and Phe3 residues were synthesized. The two compounds, H-Tyr-Tic psi [CH2NH]Phe-Phe-OH (TIPP [psi]) and H-Tyr-Tic psi-[CH2NH]Phe-OH (TIP [psi]), were tested in mu-, delta-, and kappa-receptor-selective binding assays and in the guinea pig ileum (GPI) and mouse vas deferens (MVD) bioassays. In comparison with their respective parent peptides, both pseudopeptide analogues showed increased delta antagonist potency in the MVD assay, higher delta receptor affinity and further improved delta receptor selectivity. The more potent compound, TIPP [psi], displayed subnanomolar delta receptor affinity and in direct comparisons with other selective delta ligands was shown to have unprecedented delta specificity (Ki mu/Ki delta = 10,500). Furthermore, this compound turned out to be highly stable against enzymatic degradation and, unlike other delta antagonists, showed no mu or kappa antagonist properties. TIPP [psi] is likely to find wide use as a pharmacological tool in opioid research.
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differential stereochemical requirements of mu vs delta opioid receptors for ligand binding and signal transduction development of a class of potent and highly delta selective peptide antagonists
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Peter W. Schiller, Grazyna Weltrowska, Brian C Wilkes, Carole Lemieux, T M D Nguyen, B J Marsden, Nga N. ChungAbstract:Abstract Opioid peptide analogs consisting entirely of aromatic amino acid residues and containing conformationally restricted phenylalanine derivatives in position 2 of the peptide sequence were synthesized and pharmacologically characterized in vitro. Both diastereoisomers of H-Tyr-(D or L)-NMePhe-Phe-Phe-NH2 (NMePhe is N alpha-methylphenylalanine) were mu-receptor-selective, were full agonists in the mu-receptor-representative guinea pig ileum assay, and were partial agonists in the mouse vas deferens assay, with the L-NMePhe2 analog displaying somewhat higher intrinsic activity than the D-NMePhe2 analog. Further conformational restriction at position 2 in the sequence, as achieved through substitution of D- or L-tetrahydro-3-isoquinoline carboxylic acid (Tic), produced a configuration-dependent differential effect on receptor selectivity and intrinsic activity, leading to a potent mu-selective mu agonist (the D-Tic2 analog) with increased intrinsic activity in the mouse vas deferens assay and to a potent delta-selective delta antagonist (the L-Tic2 analog). These results demonstrate that imposition of conformational constraints in a peptide not only may alter receptor selectivity but also may decrease, totally abolish, or even enhance intrinsic activity. The tetrapeptide H-Tyr-Tic-Phe-Phe-NH2 was a moderately potent full agonist in the guinea pig ileum assay and, thus, represents a compound with mixed mu-agonist/delta-antagonist properties. The corresponding peptide with a free C-terminal carboxyl group H-Tyr-Tic-Phe-Phe-OH showed high delta-receptor affinity (Ki delta = 1.2 nM), unprecedented delta selectivity (Ki mu/Ki delta = 1410), high potency as delta antagonist (Ke = 3-8 nM against various delta agonists in the mouse vas deferens assay) and, unlike other delta antagonists, had no mu-antagonist properties. The tripeptides H-Tyr-Tic-Phe-OH and H-Tyr-Tic-Phe-NH2 were also delta antagonists.
Kunio Suetsuna - One of the best experts on this subject based on the ideXlab platform.
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antihypertensive effects of undaria pinnatifida wakame peptide on blood pressure in spontaneously hypertensive rats
Journal of Nutritional Biochemistry, 2004Co-Authors: Kunio Suetsuna, Maekawa Keisei, Jiun Rong ChenAbstract:We examined the angiotensin I-converting enzyme (ACE) inhibitory activity and antihypertensive effect of the hot water extract of wakame, Undaria pinnatifida. Ten dipeptides were isolated from the extract by several steps of chromatography, and their amino acid sequences were Tyr-His, Lys-Trp, Lys-Tyr, Lys-Phe, Phe-Tyr, Val-Trp, Val-Phe, Ile-Tyr, Ile-Trp, and Val-Tyr. Both single administration and repeated oral administration of synthetic Tyr-His, Lys-Tyr, Phe-Tyr, and Ile-Tyr significantly decreased blood pressure in spontaneously hypertensive rats.
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isolation and characterization of angiotensin i converting enzyme inhibitor dipeptides derived from allium sativum l garlic
Journal of Nutritional Biochemistry, 1998Co-Authors: Kunio SuetsunaAbstract:Abstract A concentrate of an aqueous extract of Allium sativum L. (garlic) was fractionated using ion exchange and gel filtration to isolate fractions with angiotensin I-converting enzyme (ACE) inhibitory activity. Fractions with high ACE inhibitory activity were combined and further chromatographed on a reverse-phase column to yield seven dipeptides with ACE inhibitory properties. These dipeptides were identified by sequence analysis and fast atom bombardment mass spectrometry as Ser-Tyr, Gly-Tyr, Phe-Tyr, Asn-Tyr, Ser-Phe, Gly-Phe, and Asn-Phe, with IC 50 (the amount of peptide needed to inhibit ACE activity) values of 66.3, 72.1, 3.74, 32.6, 130.2, 277.9, and 46.3 μM, respectively. Each dipeptide was synthesized and its antihypertensive activity was determined after oral administration in spontaneously hypertensive rats. The blood pressure lowering activity of the dipeptides was lower than that of captopril. However, the presence of these dipeptides in garlic suggests that these compounds may, at least in part, be responsible for the observed antihypertensive effect of garlic (or garlic extracts) in animals and humans. Further, long-term use of dietary garlic may have a protective effect against rise in blood pressure.
Takahisa Nakano - One of the best experts on this subject based on the ideXlab platform.
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angiotensin i converting enzyme inhibitory peptides derived from wakame undaria pinnatifida and their antihypertensive effect in spontaneously hypertensive rats
Journal of Agricultural and Food Chemistry, 2002Co-Authors: Minoru Sato, Takao Hosokawa, Toshiyasu Yamaguchi, Toshiki Nakano, Koji Muramoto, Takashi Kahara, Katsura Funayama, And Akio Kobayashi, Takahisa NakanoAbstract:Seven kinds of angiotensin I-converting enzyme (ACE) inhibitory peptides were isolated from the hydrolysates of wakame (Undaria pinnatifida) by Protease S “Amano” (from Bacillus stearothermophilus) by using three-step high-performance liquid chromatography (HPLC) on a reverse-phase column. These peptides were identified by amino acid composition analysis, sequence analysis, and liquid chromatography−mass spectrometry (LC−MS), as Val-Tyr (IC50 = 35.2 μM), Ile-Tyr (6.1 μM), Ala-Trp (18.8 μM), Phe-Tyr (42.3 μM), Val-Trp (3.3 μM), Ile-Trp (1.5 μM), and Leu-Trp (23.6 μM). These peptides have resistance against gastrointestinal proteases in vitro. Each peptide was determined to have an antihypertensive effect after a single oral administration in spontaneously hypertensive rats (SHR). Among them, the blood pressure significantly decreased by Val-Tyr, Ile-Tyr, Phe-Tyr, and Ile-Trp in a dose of 1 mg/kg of body weight (BW). The present study showed that antihypertensive effect in the hydrolysates of wakame by Prot...
Bin Wang - One of the best experts on this subject based on the ideXlab platform.
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Purification, Identification, Activity Evaluation, and Stability of Antioxidant Peptides from Alcalase Hydrolysate of Antarctic Krill (Euphausia superba) Proteins
'MDPI AG', 2021Co-Authors: Shuang-yi Zhang, Guo-xu Zhao, Shi-kun Suo, Yu-mei Wang, Chang-feng Chi, Bin WangAbstract:For utilizing the largest source of marine proteins, Antarctic krill (Euphausia superba) proteins were defatted and hydrolyzed separately using pepsin, alcalase, papain, trypsin, and netrase, and alcalase hydrolysate (EPAH) showed the highest DPPH radical (DPPH·) and hydroxyl radical (HO·) scavenging activity among five hydrolysates. Using ultrafiltration and chromatography methods, fifteen antioxidant peptides were purified from EPAH and identified as Asn-Gln-Met (NQM), Trp-Phe-Pro-Met (WFPM), Gln-Asn-Pro-Thr (QNPT), Tyr-Met-Asn-Phe (YMNF), Ser-Gly-Pro-Ala (SGPA), Ser-Leu-Pro-Tyr (SLPY), Gln-Tyr-Pro-Pro-Met-Gln-Tyr (QYPPMQY), Glu-Tyr-Glu-Ala (EYEA), Asn-Trp-Asp-Asp-Met-Arg-Ile-Val-Ala-Val (NWDDMRIVAV), Trp-Asp-Asp-Met-Glu-Arg-Leu-Val-Met-Ile (WDDMERLVMI), Asn-Trp-Asp-Asp-Met-Glu-Pro-Ser-Phe (NWD-DMEPSF), Asn-Gly-Pro-Asp-Pro-Arg-Pro-Ser-Gln-Gln (NGPDPRPSQQ), Ala-Phe-Leu-Trp-Asn (AFLWA), Asn-Val-Pro-Asp-Met (NVPDM), and Thr-Phe-Pro-Ile-Tyr-Asp-Tyr-Pro-Gln (TFPIYDPQ), respectively, using a protein sequencer and ESI/MS. Among fifteen antioxidant peptides, SLPY, QYPPMQY and EYEA showed the highest scavenging activities on DPPH· (EC50 values of 1.18 ± 0.036, 1.547 ± 0.150, and 1.372 ± 0.274 mg/mL, respectively), HO· (EC50 values of 0.826 ± 0.027, 1.022 ± 0.058, and 0.946 ± 0.011 mg/mL, respectively), and superoxide anion radical (EC50 values of 0.789 ± 0.079, 0.913 ± 0.007, and 0.793 ± 0.056 mg/mL, respectively). Moreover, SLPY, QYPPMQY and EYEA showed strong reducing power, protective capability against H2O2-damaged plasmid DNA, and lipid peroxidation inhibition ability. Furthermore, SLPY, QYPPMQY, and EYEA had high stability under temperatures lower than 80 °C, pH values ranged from 6–8, and simulated GI digestion for 180 min. The results showed that fifteen antioxidant peptides from alcalase hydrolysate of Antarctic krill proteins, especially SLPY, QYPPMQY and EYEA, might serve as effective antioxidant agents applied in food and health products
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eight antihypertensive peptides from the protein hydrolysate of antarctic krill euphausia superba isolation identification and activity evaluation on human umbilical vein endothelial cells huvecs
Food Research International, 2019Co-Authors: Yuqin Zhao, Lun Zhang, Bin WangAbstract:Abstract In this report, eight antihypertensive peptides were isolated from protein hydrolysate of Antarctic krill (Euphausia superba) using ultrafiltration and chromatography consecutively, and their sequences were identified as Trp-Phe, Tyr-Arg-Lys-Glu-Arg, Tyr-Arg-Lys, Val-Asp, Tyr-Lys-Asp, Phe-Gln-Lys, Phe-Ala-Ser, and Phe-Arg-Lys-Glu. The IC50 values of Trp-Phe (0.32 ± 0.05 mg/mL) and Phe-Ala-Ser (0.15 ± 0.02 mg/mL) on ACE inhibitory activity were significantly (p ≤ .05) lower than those of the other six peptides. Furthermore, Trp-Phe, Tyr-Arg-Lys, Phe-Gln-Lys, and Phe-Ala-Ser did not only increase the nitric oxide (NO) concentration and decreased the content of endothelin-1 (ET-1) in the medium of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner after 24 h, but also significantly reversed the decreased production of NO in the presence of 0.5 μM norepinephrine and the effect of NE on ET-1 production. These results indicate that the isolated antihypertensive peptides can correct the endothelial cell dysfunction induced by norepinephrine.