CN110028549B - Antihypertensive peptide and antihypertensive protein and application thereof - Google Patents

Antihypertensive peptide and antihypertensive protein and application thereof Download PDF

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CN110028549B
CN110028549B CN201910339075.5A CN201910339075A CN110028549B CN 110028549 B CN110028549 B CN 110028549B CN 201910339075 A CN201910339075 A CN 201910339075A CN 110028549 B CN110028549 B CN 110028549B
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converting enzyme
antihypertensive peptide
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谢静莉
陈绪军
朱巧莎
吴俊杰
周淡
魏东芝
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East China University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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Abstract

The invention discloses a blood pressure lowering peptide and a blood pressure lowering protein and application thereof; the amino acid sequence of the antihypertensive peptide is VHW, and the amino acid sequence of the antihypertensive protein contains VHW; the antihypertensive peptide and the antihypertensive protein can inhibit the activity of angiotensin converting enzyme, thereby reducing blood pressure, and can be used for preparing various antihypertensive drugs or health products.

Description

Antihypertensive peptide and antihypertensive protein and application thereof
Technical Field
The invention belongs to the technical field of food or medicine, and relates to antihypertensive peptides, antihypertensive proteins and application thereof.
Background
Angiotensin Converting Enzyme (ACE) is an enzyme that can cause an increase in blood pressure, and has the following two regulatory pathways.
First, angiotensin converting enzyme cleaves two amino acids (His-Leu) at the terminal of angiotensin I (angiotensinin I) to convert angiotensin I to angiotensin ii (angiotensinin ii). Wherein the amino acid sequence of the angiotensin I is Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu, which is DRVYIHPFHL for short. The amino acid sequence of angiotensin II is Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, abbreviated as DRVYIHPF. Angiotensin II is a vasoconstrictor that promotes constriction of blood vessels, thereby increasing blood pressure.
Secondly, angiotensin converting enzyme can cut two amino acids (Phe-Arg) at the terminal of Bradykinin (Bradykinin) to inactivate the Bradykinin. Wherein the amino acid sequence of bradykinin is Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg, and the amino acid sequence of inactivated bradykinin is Arg-Pro-Pro-Gly-Phe-Ser-Pro. Bradykinin has the function of dilating blood vessels, but in its inactivated state, bradykinin loses its ability to dilate blood vessels, thereby increasing blood pressure.
ACE is a metallopeptidase containing a bound Zn 2+ This is the "essential binding site" to which the substrate binds. Zn 2+ The binding site is the site of the active group of the ACE-catalyzed reaction. The combined action of various ACE inhibitors is with Zn of ACE 2+ The binding sites bind and inactivate.
If angiotensin converting enzyme is inactivated, angiotensin converting enzyme cannot convert angiotensin I into angiotensin II, and blood vessels will not contract; at the same time, angiotensin converting enzyme does not inactivate bradykinin and the blood vessel is dilated. The combined action of the two can reduce blood pressure. Therefore, the search for a polypeptide or protein capable of inactivating angiotensin converting enzyme is a technical problem to be solved.
Disclosure of Invention
One of the objects of the present invention is to provide a hypotensive peptide capable of inhibiting angiotensin converting enzyme.
Another object of the present invention is to provide the use of the above-mentioned antihypertensive peptide.
In order to achieve the above purpose, the solution of the invention is as follows:
a antihypertensive peptide whose amino acid sequence is TTW is called a first antihypertensive peptide.
A hypotensive peptide having an amino acid sequence of VHW, referred to as a second hypotensive peptide.
The amino acid sequence of the antihypertensive peptide is shown as SEQ ID NO: 1, referred to as a third antihypertensive peptide.
Any of the above-mentioned antihypertensive peptides can be used as an angiotensin converting enzyme inhibitor.
Any one of the antihypertensive peptides can be used for preparing antihypertensive drugs.
Any one of the antihypertensive peptides can be used for preparing the antihypertensive health care product.
A blood pressure lowering protein comprising TTW, VHW and a sequence as set forth in SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof.
The blood pressure lowering protein can be used as angiotensin converting enzyme inhibitor.
The blood pressure lowering protein can be used for preparing blood pressure lowering medicines.
The blood pressure lowering protein can be used for preparing blood pressure lowering health products.
Due to the adoption of the scheme, the invention has the beneficial effects that:
the antihypertensive peptide is obtained by screening hydrolysate of natural food, has obvious inhibitory activity on angiotensin converting enzyme, can be independently used for preparing antihypertensive drugs or antihypertensive health products, and can also be used in combination with the antihypertensive drugs in the prior art so as to obtain better synergistic antihypertensive effect.
Drawings
FIG. 1 is a schematic diagram showing hydrogen bond formation between a first antihypertensive peptide of the present invention and the active center of angiotensin-converting enzyme.
FIG. 2 is a schematic diagram showing hydrogen bond formation between a second antihypertensive peptide of the present invention and the active center of angiotensin-converting enzyme.
FIG. 3 is a schematic diagram showing hydrogen bond formation between a third antihypertensive peptide of the present invention and the active center of angiotensin-converting enzyme.
FIG. 4 is a graph showing the hypotensive effect of the antihypertensive peptides.
Detailed Description
The invention provides a plurality of antihypertensive peptides and application thereof.
< first antihypertensive peptide >
The invention provides a blood pressure lowering peptide which consists of three amino acids, wherein the amino acid sequence of the blood pressure lowering peptide is Thr-Thr-Trp, which is TTW for short. For the sake of convenience of explanation, the first antihypertensive peptide will be hereinafter collectively referred to. The amino acids in the present invention are all arranged from the N-terminus to the C-segment.
The molecular docking experiment shows that the first T in the first antihypertensive peptide forms 3 hydrogen bonds with Ala354 of the active center of Angiotensin Converting Enzyme (ACE); the second T in the first antihypertensive peptide forms a hydrogen bond with each of His353, Glu384 and His 513; w in the first antihypertensive peptide forms a hydrogen bond with Glu403, so the first antihypertensive peptide and Angiotensin Converting Enzyme (ACE) together form 7 hydrogen bonds. The formation of these 7 hydrogen bonds is shown in FIG. 1. The amino acids in the circle represent the amino acid sequence in ACE, and the middle chain is the configuration formed by the sequence of the antihypertensive peptide in ACE.
These amino acid residues are important amino acid residues in the active center of Angiotensin Converting Enzyme (ACE), and have an important effect on the activity of ACE. When the first antihypertensive peptide forms a hydrogen bond with these amino acid residues of the active center of Angiotensin Converting Enzyme (ACE), the active center of Angiotensin Converting Enzyme (ACE) is no longer able to bind angiotensin, and the Angiotensin Converting Enzyme (ACE) is inactivated, and thus, the first antihypertensive peptide can act as an angiotensin converting enzyme inhibitor.
< use of the first antihypertensive peptide >
1. The first antihypertensive peptide can be used for preparing antihypertensive drugs.
The first antihypertensive peptide of the present invention can be used alone as an antihypertensive drug, and in this case, the first antihypertensive peptide is used in combination with an auxiliary material to prepare a pharmaceutical granule, a capsule, a tablet (e.g., a sugar-coated tablet or a film-coated tablet), a pill, an oral liquid, an injection, or the like.
When the first antihypertensive peptide is used as a pharmaceutical granule, the excipient may be maltodextrin and/or vanillin.
When the first antihypertensive peptide is used as a sugar-coated tablet, the excipient may be starch and/or magnesium stearate.
When the first antihypertensive peptide is prepared into oral liquid for use, the auxiliary materials can be sodium benzoate, aspartame, acesulfame potassium, essence and purified water.
When the first antihypertensive peptide is used as an injection, the excipient may be mannitol, sodium dihydrogen phosphate and/or disodium hydrogen phosphate. The injection can be prepared into 0.9% sodium chloride injection or 5% glucose injection and then is instilled intravenously or injected intramuscularly.
The first antihypertensive peptide can also be used in combination with antihypertensive drugs in the prior art so as to obtain better synergistic antihypertensive effect.
The blood pressure lowering drugs in the prior art include beta-blockers, calcium antagonists, ACE inhibitors, diuretics, and the like.
Wherein the beta blocker is selected from nebivolol, pralol, arotinolol, atenolol, celiprolol, carvedilol, labetalol, bisoprolol.
The calcium antagonist is selected from nifedipine, amlodipine (including levamlodipine), lercanidipine, felodipine, nilvadipine, lacidipine, and nisoldipine.
The ACE inhibitor is selected from the group consisting of alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, ramipril, ramiprilat, perindopril, quinapril, spirapril, temocapril, trandolapril.
The diuretic is selected from hydrochlorothiazide and trichlorothiazide.
2. The first antihypertensive peptide can be used for preparing antihypertensive health products.
The first antihypertensive peptide of the invention can be prepared into the antihypertensive health product by adding auxiliary materials, wherein the auxiliary materials can comprise: any one or more of starch, gelatin, titanium dioxide, whey protein, sucrose, vitamin E, glutathione, arginine, citrulline, dietary fiber, collagen, cephalin, cellulose, glucose, xylose, honey, lecithin, carotine, vitamin B1, vitamin B2, vitamin C, ferrum, calcium, bee pollen, black fungus powder (200 plus 500 meshes), mushroom powder (300 plus 500 meshes), lucid ganoderma powder (300 plus 500 meshes), konjak powder (300 plus 500 meshes), astragalus powder (200 plus 500 meshes), medlar powder (200 plus 500 meshes) and ginseng powder (500 plus 1000 meshes).
< second antihypertensive peptide >
The invention provides a hypotensive peptide which consists of three amino acids, wherein the amino acid sequence of the hypotensive peptide is Val-His-Trp, which is abbreviated as VHW. For the sake of convenience of explanation, the second antihypertensive peptide will be hereinafter collectively referred to.
The molecular docking experiment shows that V in the second antihypertensive peptide and Glu411 of the active center of Angiotensin Converting Enzyme (ACE) form 2 hydrogen bonds; h in the second antihypertensive peptide forms a hydrogen bond with Ala354, His353 and Glu384 respectively; w in the second antihypertensive peptide forms a hydrogen bond with Tyr520, so that the second antihypertensive peptide and Angiotensin Converting Enzyme (ACE) together form 7 hydrogen bonds. The formation of these 7 hydrogen bonds is shown in FIG. 2.
These amino acid residues are also important amino acid residues in the active center of Angiotensin Converting Enzyme (ACE), and have an important effect on the activity of ACE. When the second antihypertensive peptide forms a hydrogen bond with these amino acid residues of the active center of Angiotensin Converting Enzyme (ACE), the active center of Angiotensin Converting Enzyme (ACE) is no longer able to bind angiotensin, and the Angiotensin Converting Enzyme (ACE) is inactivated, and thus, the second antihypertensive peptide can also act as an angiotensin converting enzyme inhibitor.
< use of the second antihypertensive peptide >
1. The second antihypertensive peptide can be used for preparing antihypertensive drugs.
2. The second antihypertensive peptide can be used for preparing antihypertensive health products.
When the second antihypertensive peptide is used for preparing the antihypertensive drug or the antihypertensive health product, the first antihypertensive peptide can be referred to as an auxiliary material which can be used in combination with the second antihypertensive peptide.
< third antihypertensive peptide >
The invention provides a antihypertensive peptide, the amino acid sequence of which is shown as SEQ ID NO: 1 is shown. For the sake of convenience of explanation, the third antihypertensive peptide will be hereinafter collectively referred to. The third antihypertensive peptide consists of four amino acids, and the amino acid sequence of the third antihypertensive peptide is Lys-Ala-Lys-Trp, which is abbreviated as KAKW.
Molecular docking shows that the first K in the third antihypertensive peptide forms two hydrogen bonds with Ala356 of the ACE active center and one hydrogen bond with Glu 411; w in the third antihypertensive peptide forms 2 hydrogen bonds with Gln281 and forms one hydrogen bond with Tyr520 and Asp415 respectively; the second K in the third antihypertensive peptide forms a hydrogen bond with His353, Lys511 respectively, so that the third antihypertensive peptide and Angiotensin Converting Enzyme (ACE) together form 9 hydrogen bonds. The formation of these 9 hydrogen bonds is shown in FIG. 3. These amino acid residues are important amino acid residues in the active center of Angiotensin Converting Enzyme (ACE), and have an important effect on the activity of ACE. When the third antihypertensive peptide forms a hydrogen bond with these amino acid residues of the active center of Angiotensin Converting Enzyme (ACE), the active center of Angiotensin Converting Enzyme (ACE) can no longer bind angiotensin, and thus Angiotensin Converting Enzyme (ACE) is inactivated, and thus, the third antihypertensive peptide can be used as an angiotensin converting enzyme inhibitor.
< use of third antihypertensive peptide >
1. The third antihypertensive peptide can be used for preparing antihypertensive drugs.
2. The third antihypertensive peptide can be used for preparing antihypertensive health products.
When the third antihypertensive peptide is used for preparing the antihypertensive drug or the antihypertensive health product, the first antihypertensive peptide can be referred to as an auxiliary material which can be used in combination with the third antihypertensive peptide.
< blood pressure-lowering protein >
A blood pressure lowering protein characterized by: it contains TTW, VHW and the amino acid sequence as set forth in SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof.
The above polypeptides and proteins can be synthesized by artificial methods, and thus the synthesis methods are not described in detail.
< use of hypotensive protein >
1. The blood pressure lowering protein can be used for preparing blood pressure lowering medicines.
2. The blood pressure lowering protein can be used for preparing blood pressure lowering health products.
When the antihypertensive protein is used for preparing the antihypertensive drug or the antihypertensive health care product, the first antihypertensive peptide can be referred to as an auxiliary material which can be matched with the antihypertensive protein for use.
The blood pressure lowering activity of various blood pressure lowering peptides and the like will be described below with reference to experiments.
< experiment 1: experiment of in vitro inhibition of angiotensin converting enzyme by various antihypertensive peptides >
The various antihypertensive peptides of the present invention are competitive inhibitors having a strong affinity for the active region of angiotensin converting enzyme, have a higher affinity for the active region than angiotensin I or bradykinin, and are not easily released from the binding region once bound, and thus can reduce the activity of the active region of angiotensin converting enzyme, even inactivate it, thereby preventing angiotensin converting enzyme from converting angiotensin I to angiotensin II and preventing angiotensin converting enzyme from inactivating bradykinin, and thus lowering blood pressure. The inhibitory ability of various antihypertensive peptides against angiotensin converting enzyme was verified by experiments as follows.
The determination principle of this experiment is as follows:
hippurylhistidyl leucine (Hip-His-Leu, HHL for short) can serve as a substrate for Angiotensin Converting Enzyme (ACE) and is hydrolyzed to hippuric acid and His-Leu. The inhibitor can inhibit the ability of the angiotensin converting enzyme to catalyze and hydrolyze the equol histidyl leucine, so that the content of the hippuric acid in the product is reduced, and therefore, the inhibition rate of the inhibitor on the angiotensin converting enzyme can be calculated by detecting the content of the hippuric acid in the product.
The assay procedure for this experiment was as follows:
(1) taking a plurality of EP tubes as reaction containers, adding 20 mu L of deionized water into the EP tube of the control group, and adding 20 mu L of samples to be detected with different concentrations into the EP tube of the experimental group;
(2) 80 μ L of 5M equacy histidyl leucine (HHL) was added to each EP tube and water-bathed at 37 ℃ for 5 min;
(3) adding 10mU L of 310mU/mL Angiotensin Converting Enzyme (ACE) into each EP tube, and carrying out water bath at 37 ℃ for 5min to start the reaction;
(4) when the reaction is complete, adding 400 mu L of M HCL into each EP tube to terminate the reaction;
(5) filtering the reaction liquid in each EP tube by using a filter membrane with the diameter of 0.22 mu m, and storing the filtered liquid in a corresponding liquid phase vial;
(6) and carrying out high performance liquid chromatography detection on the liquid in each liquid phase small bottle, wherein the detection conditions are as follows: and (3) chromatographic column: thermo BDSHYPERSIL C18(250 mm. times.3 mm. times.5 μm); column temperature: 30 ℃; flow rate: 0.8 mL/min; detection wavelength: 228 nm; sample introduction amount: 10mu L of the solution; mobile phase A: ultrapure water (0.1% trifluoroacetic acid TFA); mobile phase B: acetonitrile; the elution conditions are shown in Table 1.
TABLE 1 elution conditions for high performance liquid chromatography
Figure BDA0002040145220000061
(7) The method for calculating the inhibition rate of each sample to be tested on the angiotensin converting enzyme comprises the following steps:
x ═ a control-a)/a control
In the formula: X-ACE inhibition (%);
control-peak area of control;
a-peak area of experimental group.
(8) Calculation of IC50 of the test sample:
and (3) drawing by taking the concentration of the sample to be detected as an abscissa and the ACE inhibition rate as an ordinate to obtain an inhibition rate-sample concentration relation curve, and obtaining the concentration of the sample to be detected when the inhibition rate reaches 50% through the curve, namely the IC50 of the sample to be detected.
Wherein the sample to be tested is a sample containing a first antihypertensive peptide, a second antihypertensive peptide, a third antihypertensive peptide or an antihypertensive protein.
The IC50 of the test samples is shown in table 2.
TABLE 2 IC50 for samples tested
Antihypertensive peptides IC 50 (μM)
First antihypertensive peptide (TTW) 0.61
Second antihypertensive peptide (VHW) 0.91
Third antihypertensive peptide (KAKW) 2.02
The detection results show that the three antihypertensive peptides have obvious effect of inhibiting angiotensin converting enzyme in an in-vitro angiotensin converting enzyme inhibiting experiment, and the inhibition effect of the antihypertensive peptides is close to the in-vitro inhibition effect of lisinopril which is a classical medicine for treating hypertension (IC50 is 0.0214 mu M).
< experiment 2: experiment of in vivo inhibition of angiotensin converting enzyme by various antihypertensive peptides >
The experiment mainly verifies the influence of various antihypertensive peptides on the blood pressure of a hypertensive rat, and comprises the following steps:
(1) spontaneous hypertensive rats (SHRs, 10 weeks in size, male, weight 250-320g) were obtained with blood pressure above 180mmHg and purchased from Shanghaisi Leike animal laboratories;
(2) 6 hypertensive rats are raised in a group, and are circularly illuminated at the temperature of 22 +/-2 ℃ for 12 hours to supply food and drinking water;
(3) dissolving different antihypertensive peptides in physiological saline, calculating the amount of the physiological saline according to 3 mu mol/Kg of each hypertensive rat in an experimental group, performing intragastric administration on the physiological saline according to the amount of 1ml/100g of the weight of the rat, and performing intragastric administration on a control group by using the physiological saline with the same dose and feeding the antihypertensive drug lisinopril;
(4) after gavage, the blood pressure of these hypertensive rats was measured at 0h, 1h, 2h, 4h, 6h and 8h, respectively. All results were measured in triplicate.
The results are shown in FIG. 4. As can be seen from fig. 4, the blood pressure of the three antihypertensive peptides is significantly decreased compared to the control group, indicating that the three antihypertensive peptides have an antihypertensive effect in vivo, and the antihypertensive effect of the three antihypertensive peptides is considered to be better than that of lisinopril in the early stage, compared to lisinopril group.
In conclusion, the antihypertensive peptide not only has better in-vitro antihypertensive activity, but also has good in-vivo activity after being digested and absorbed by gastrointestinal tract, and the antihypertensive function of the antihypertensive peptide is not lost.
The present invention will be further described with reference to the following examples.
Example 1: antihypertensive drug tablet
The antihypertensive drug tablet of this example contains 5 wt% of antihypertensive peptide and 95 wt% of auxiliary materials. The antihypertensive peptide is the first antihypertensive peptide, and the auxiliary materials are starch and magnesium stearate.
In fact, the antihypertensive peptide may be any one or more of the second antihypertensive peptide, the third antihypertensive peptide, and the antihypertensive protein. The adjuvant can be any one or more of starch, sucrose and maltodextrin. The content of the antihypertensive peptide may be 1 to 20 wt% and the content of the auxiliary material may be 80 to 99 wt%.
Example 2: health product for reducing blood pressure
The antihypertensive drug tablet of this example contains 15 wt% of antihypertensive peptide and 85 wt% of auxiliary materials. The antihypertensive peptide is the third antihypertensive peptide, and the auxiliary materials are starch, honey, dietary fiber, arginine and glutathione.
Wherein, the antihypertensive peptide can be any one or more of the first antihypertensive peptide, the second antihypertensive peptide and the antihypertensive protein. The content of the antihypertensive peptide may be 1 to 20 wt% and the content of the auxiliary material may be 80 to 99 wt%.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Figure BDA0002040145220000091
Sequence listing
<110> university of east China's college of science
<120> antihypertensive peptides and antihypertensive proteins, and use thereof
<130> 191033
<141> 2019-04-25
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 4
<212> PRT
<213> Natural food (2 Ambystoma latex x Ambystoma jeffersonia)
<400> 1
Lys Ala Lys Trp
1

Claims (4)

1. The application of the antihypertensive peptide in preparing the angiotensin converting enzyme inhibitor is characterized in that the amino acid sequence of the antihypertensive peptide is VHW.
2. The application of the antihypertensive peptide in preparing the antihypertensive drug is characterized in that the amino acid sequence of the antihypertensive peptide is VHW.
3. The application of the antihypertensive peptide in preparing the antihypertensive health-care product is characterized in that the amino acid sequence of the antihypertensive peptide is VHW.
4. The application of the antihypertensive peptide in preparing the antihypertensive food is characterized in that the amino acid sequence of the antihypertensive peptide is VHW.
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