CN112694429A - Polypeptide and application thereof in preparing ACE inhibitor or blood pressure lowering product - Google Patents
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Abstract
The invention discloses a polypeptide and application thereof in preparing ACE inhibitors or blood pressure lowering products. The amino acid sequence of the polypeptide is Sar-bAla-Pro; the structure is shown as the general formula (I)
The polypeptide is artificially synthesized by rare amino acids Sar and bAla and conventional amino acid Pro, has a single-chain linear structure, is white powder, is slightly soluble in water, has the molecular weight of 257.14Da, has the tPSA value of 98.74, shows better hydrophobicity, can resist further hydrolysis of protease in vivo, has better ACE (angiotensin converting enzyme) inhibition activity, and has good potential and application value as a lead compound of an effective component of a cardiovascular medicament and functional food for treating hypertension and the like.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to a polypeptide and application thereof in preparing ACE inhibitors or blood pressure lowering products.
Background
The Chinese cardiovascular disease report 2019 indicates that the prevalence rate of cardiovascular diseases in China is in a continuously rising stage. Hypertension is a main risk factor of cardiovascular diseases, is well known and is a promoting factor for the continuous increase of the prevalence rate of cardiovascular diseases in China. The national hypertension survey in 2015 shows that the hypertension disease rate in China is 27.9%, and the number of the national hypertension patients is estimated to be 2.45 hundred million. In 2017, 254 million people in China die of high systolic pressure, and if all hypertension patients are treated and blood pressure is controlled, 80.3 ten thousand cardiovascular disease events are reduced/year (document 1: China cardiovascular health and disease report writing group, China circulation journal 2020, 35 (9): 833-854.)
Among the mechanisms of blood pressure regulation, the Renin-Angiotensin System (RAS) plays an important role. Angiotensinogen generates angiotensin I (Ang I) under the action of renin, the Ang I then forms angiotensin II (Ang II) under the action of angiotensin-converting enzyme (ACE), and the Ang II acts with angiotensin receptor I (AT1) on the surface of vascular endothelium to promote systemic arteriolar contraction and increase blood pressure. Therefore, ACE becomes a target of antihypertensive drugs. Clinical first-line hypotensive pril drugs are Angiotensin Converting Enzyme Inhibitors (ACEIs) and play an important role in treating cardiovascular diseases such as hypertension, myocardial hypertrophy and heart failure. However, they also have certain side effects, such as dry cough, rash, angioedema, and kidney injury.
ACEI drugs are peptides and modified amino acids, and some natural peptide fragments obtained by proteolysis also have ACE inhibitory effect, and play an important role in lowering blood pressure (document 2: Miralles B, Amigo L, Recio I.Critical review and periodic on-chemical antihypertensive peptides, J.agricultural. food chem.,2018,66(36):9384-9390.), without generating the side effect of common pril drugs. Therefore, the development of novel peptide-like compounds with less chemical modification is a demand for the development of safe and side-effect-free ACE inhibitors and antihypertensive drugs.
The polypeptide is a substance between amino acid and protein, and the structural fragment of the protein is formed by combining one or more amino acids according to a certain arrangement sequence through peptide bonds, can play the role of active groups of the protein, and is an important substance for human metabolism and regulation activities. The function of each amino acid series in the polypeptide can be further understood by researching the relation between the structure and the function of the polypeptide. When the polypeptide is designed, the short peptide is selected as much as possible, so that the physiological activity of the polypeptide is improved, and adverse reactions are reduced.
The use of proline in ACE inhibitors and for lowering blood pressure is common and a number of prior art uses for this amino acid. For example, CN201010563755.4 discloses the use of four polypeptides in the preparation of ACE inhibitors and blood pressure lowering drugs, wherein the amino acid sequence of ATVLNYLP is Ala-Thr-Val-Leu-Asn-Tyr-Leu-Pro, the molecular weight is 890.0Da, the polypeptide has ACE inhibitory activity, and the IC thereof5016.97. mu.M; the amino acid sequence of ACEPGVDYVY is Ala-Cys-Glu-Pro-Gly-Val-Asp-Tyr-Val-Tyr, the molecular weight is 1115.2Da, the ACE inhibitory activity is achieved, and the IC is5027.35. mu.M; VTSIDWVR amino acid sequence Val-Thr-Ser-Ile-Asp-Trp-Val-Arg, molecular weight 1088.61Da, ACE inhibitory activity, IC thereof50Is 165 mu M; the amino acid sequence Ser-Ser-Glu-Ala-Asn-Leu-Tyr-Arg of SSEANLYR has molecular weight of 939.45Da, and has ACE inhibitory activity and IC50224 μ M;
CN201510622913.1 discloses a polypeptide compound QEPVLGPVRGPFPIIV for inhibiting the activity of angiotensin converting enzyme and reducing blood pressure, the amino acid sequence of which is Gln-Glu-Pro-Val-Leu-Gly-Pro-Val-Arg-Gly-Pro-Phe-Pro-Ile-Ile-Val, molecular weight 1717Da, ACE inhibitory activity, IC thereof50Only 160.48 μ M. From the prior art, most of the active polypeptide structures using proline as antihypertensive peptide are complex, and are not suitable for industrial application.
Disclosure of Invention
Aiming at the defects of the prior art, the invention discloses a polypeptide and application thereof in preparing ACE inhibitors or blood pressure lowering products, wherein the polypeptide has a simple structure, has good ACE inhibition activity and is suitable for being applied to medicines for treating diseases such as hypertension.
A polypeptide, the amino acid sequence of which is Sar-bAla-Pro; the structure is shown as the general formula (I)
The preparation method of the polypeptide comprises the following steps:
step 1, carrying out coupling reaction on proline dichloro resin and Fmoc-beta-alanine under the action of a coupling agent and an organic solvent, washing with 20% of piperidine/dimethylformamide in volume ratio, removing the terminal Fmoc, carrying out deprotection with piperidine/dimethylformamide in volume ratio of 20% after deprotection is finished, and obtaining an intermediate product after pumping;
and 2, coupling the intermediate product and Fmoc-sarcosine under the action of a coupling agent and an organic solvent, washing with 20% by volume of piperidine/dimethylformamide, deprotecting with piperidine, washing with 20% by volume of piperidine/dimethylformamide after deprotection, draining, and purifying to obtain the polypeptide with the sequence of Sar-bAla-Pro.
The application of the polypeptide in preparing ACE inhibitor or blood pressure lowering product.
An ACE inhibitor contains the above polypeptide, or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
The polypeptide adopts an artificial synthesis method, is in a single-chain linear structure, is white powder, and is slightly soluble in waterMolecular weight is 257.14Da, tPSA value is 98.74, and the product shows better hydrophobicity, has better ACE inhibitory activity and IC50It was 12.47 ± 0.21 μmol/L (mean ± standard deviation, sample size n ═ 3).
The polypeptide Sar-bAla-Pro possesses the characteristics required for ACE inhibitors:
the main activity of ACE inhibitors is mainly determined by the C-terminal amino acid, and the hydrophobicity of the amino acid at the C-terminal position has an important effect on the ACE inhibitory activity, wherein Pro, Trp, Tyr and Phe have higher activity inhibition efficiency at the C-terminal, and Pro is particularly best for binding ACE. Meanwhile, Pro at the end of C can resist digestion of protease, so that the integrity and functional stability of the small peptide structure in the digestive tract are ensured. The molecule with the N end containing hydrophobic amino acid residue has stronger ACE inhibitory activity. The C terminal of the polypeptide compound Sar-bAla-Pro is Pro, and the N terminal contains isomer beta alanine of hydrophobic amino acid alanine and methylated derivative sarcosine of hydrophobic amino acid glycine, which have better hydrophobicity, meet the characteristic requirements of ACE inhibitors and have better ACE inhibitory activity.
2. Within the structural pockets of ACE, there are three major active site pockets, S1(Ala354, Glu384 and Tyr523 residues), S2(Gln281, His353, Lys511, His513 and Tyr520 residues) and S1' (Glu162 residues), respectively. The polypeptide compound Sar-bAla-Pro can form 2 hydrogen bonds with Glu384 in the S1 pocket of ACE, and form 4 hydrogen bonds with His353, Gln281, Lys511 and Tyr520 in the S2 pocket respectively, the binding energy is-7.2 kcal/mol, and the polypeptide compound has better ACE binding capacity (see figure 1).
A pharmaceutical composition for lowering blood pressure comprises the above polypeptide, or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
The design principle is as follows:
the invention starts from quantitative structure-activity relationship (QSAR), utilizes food-borne rare Sarcosine (Sarcosine, Sar) and beta-Alanine (beta-Alanine, bAla) as the basis, combines the structure-activity characteristic of the C terminal Pro of antihypertensive active peptide resistant to peptidase hydrolysis, designs and forms polypeptide compound Sar-bAla-Pro, analyzes and designs the chemical characteristics of the compound and ACE through AutoDock Vina software (v1.1.2), further prepares through artificial synthesis, performs in vitro ACE inhibition analysis and animal experiments, determines the ACE inhibition activity of the application compound, and has good application prospect as the cardiovascular drugs such as hypertension and the like and the active ingredients of health care products.
Has the advantages that:
compared with the prior art, the polypeptide and the application thereof in preparing ACE inhibitors or antihypertensive drugs are composed of rare amino acids Sar, bAla and conventional amino acid Pro according to a specific sequence, have stronger cell membrane permeability and do not have the sequence in natural proteins. The polypeptide can resist the further hydrolysis of protease in vivo, has good ACE (angiotensin converting enzyme) inhibition activity, and has good potential and application value as a lead compound of an effective component of a cardiovascular disease medicament and functional food for treating hypertension and the like.
Drawings
FIG. 1 is a schematic diagram showing the effect of a polypeptide compound Sar-bAla-Pro on hydrogen bonding with an ACE active site;
FIG. 2 is a schematic diagram showing the comparison of docking conformations of the polypeptide compound Sar-bAla-Pro and the ligand compound captopril with tACE, wherein 1 is the polypeptide compound Sar-bAla-Pro and 2 is the ligand compound captopril;
FIG. 3 is a schematic diagram showing the comparison of docking conformations of the polypeptide compound Sar-bAla-Pro and tACE, wherein 1 is the polypeptide compound Sar-bAla-Pro;
fig. 4 is a graph showing the results of analysis of the effect of the polypeptide compound Sar-bsaa-Pro on blood pressure in congenital hypertensive male rats (n-6).
Detailed description of the preferred embodiments
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the following examples. In the following examples, "%" means mass% unless otherwise specified.
Example 1 molecular docking analysis of the binding of the polypeptide Compound Sar-bAla-Pro to ACE
Firstly, the structure of a polypeptide compound Sar-bAla-Pro is generated by chemdraw software
Subsequently, molecular docking simulations were performed using AutoDock Vina software (v1.1.2) to predict binding affinity and conformation of compounds to ACE. The ACE is set to be rigid throughout the simulation. The scores used a weighted sum of steric and hydrophobic interactions, and hydrogen bonds. When running molecular docking, the exhaustive parameters were set to 32, with coordinates set to X:40.69, Y:32.80, and Z: 47.29. The best binding mode for each compound to ACE was selected based on the predicted binding affinity.
The molecular docking result shows that the binding energy of the polypeptide compound Sar-bAla-Pro and ACE in a protonated state is-7.2 kcal/mol, and the polypeptide compound Sar-bAla-Pro shows good binding affinity; the surface area of the topologically polar molecule (tPSA) is 98.74, and the topologically polar molecule shows good hydrophobicity and is easier to penetrate through a lipid membrane layer.
The molecular docking results show that the amino group and carbonyl group of sarcosyl in the polypeptide compound Sar-b-Ala-Pro can form 2 hydrogen bonds with Glu384 in the pocket S1 of the ACE activity pocket, and the bond distances are respectively
And
the sarcosyl ketone group of the polypeptide compound Sar-bAla-Pro forms 1 hydrogen bond with His353 in the pocket of S2 at the respective bond distances of
The hydroxyl group of proline in the polypeptide compound Sar-bAla-Pro and Gln281, Lys511 and Tyr520 in the pocket of S2 respectively form 3 hydrogen bonds, and the bond distances are respectively
And
(see FIG. 1). Shows that the polypeptide compound Sar-bAla-Pro can interact with the active site of ACE to inhibit the activity of ACE.
EXAMPLE 2 Synthesis of polypeptide Compound Sar-bAla-Pro
The polypeptide compound Sar-bAla-Pro of the invention is artificially synthesized by the following specific operations:
firstly, connecting Fmoc-beta-alanine to proline dichloro resin, simultaneously adding TBTU (O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate and DIEA (N, N-diisopropylethylamine) for coupling, wherein the coupling time is 60 minutes, washing 3 times by using piperidine/dimethylformamide with the volume ratio of 20% to remove the terminal Fmoc, then carrying out deprotection by using piperidine, washing 6 times by using piperidine/dimethylformamide with the volume ratio of 20% after the deprotection is finished, and obtaining an intermediate product after pumping to dry;
adding Fmoc-sarcosine, TBTU and DIEA into the intermediate product for coupling, wherein the coupling time is 60 minutes, washing the intermediate product by 20 percent of piperidine/dimethylformamide for 3 times, carrying out deprotection by piperidine, washing the intermediate product by 20 percent of piperidine/dimethylformamide for 6 times after the deprotection is finished, draining the intermediate product, and finally purifying the intermediate product by semi-preparative reverse phase high performance liquid chromatography (a reverse phase column: VYDAC-C18 column (4.6X 250mm,5 mu m), wherein a mobile phase comprises a solution A (0.1 percent (v/v) trifluoroacetic acid dissolved in analytical pure acetonitrile), a solution B (0.1 percent (v/v) trifluoroacetic acid dissolved in pure water), an elution gradient is as follows, the elution gradient is 0-25 min: 5-30 percent A, 95-70 percent B, 26-55 min:100 percent A, the flow rate of 0 percent B: 1.0 ml/min, separating and collecting elution peaks, freeze-drying for later use.
And (3) structure determination: c11H19N3O4 MW257.14, the specific structural formula is shown in the general formula (I)
EXAMPLE 3 detection of ACE inhibitory Activity of polypeptide Compound Sar-bAla-Pro
hippuryl-L-histidyl-L-leucine (HHL) is rapidly decomposed under the catalysis of ACE enzyme to generate Hippuric Acid (HA) and dipeptide histidyl-leucine (HL), after the ACE enzyme inhibitor is added, the activity of the ACE enzyme is inhibited, the generation amount of the HA and the HL is reduced, in the embodiment, the ACE is extracted through rabbit lungs, the enzyme activity is 3.19mU/mL, the color is developed through DAB, the HA generation amount is measured by adopting a spectrophotometer method, and the ACE enzyme activity is analyzed. The hippuric acid in the reactant is extracted by ethyl acetate, then the hippuric acid reacts with pyridine solution (DAB color developing agent) containing p-dimethylaminobenzaldehyde in acetic anhydride to generate an orange compound, the OD value of the compound is directly measured by 459nm colorimetry, and the inhibition rate of the ACE enzyme inhibitor on the ACE enzyme is evaluated according to the following formula. At a concentration (IC) of 50% of the tripeptide synthesized required for inhibition of ACE enzyme activity50) The ACE inhibitory activity of the synthetic tripeptides is defined.
ACE inhibitory activity (%) - (OD)control-ODsample)/(ODcontrol-ODblank)]×100％
Specific reaction systems and conditions are shown in table 1.
TABLE 1 ACE inhibitory Activity detection reaction System and conditions for Sar-bAla-Pro
The ACE inhibitory activity of the polypeptide compound Sar-bAla-Pro is shown in Table 2
TABLE 2 ACE inhibitory Activity of Sar-bAla-Pro
From Table 2, the ACE inhibitory activity IC of the polypeptide compound Sar-bAla-Pro was found50It was 12.47 ± 0.21 μmol/L (mean ± standard deviation, n ═ 3).
The polypeptide compound Sar-bAla-Pro has good ACE inhibitory activity, and has good potential and application value as a lead compound of effective components of medicaments and functional foods for treating cardiovascular diseases such as hypertension and the like.
Example 4 congenital hypertensive male rats (SHR) in vivo hypotensive test.
12 male SHR (spontaneous hypertension rats) rats with similar body weight, same mouse age (week age) and similar initial blood pressure were selected and randomly divided into a normal saline control group and an active tripeptide sample group (Sar-bAla-Pro) with 6 rats per group. Under the waking state of SHR male rats, the rats are firstly placed in a rat bag, the temperature is kept constant, and the Systolic Blood Pressure (SBP) of the rats is measured by adopting a method of using a Softron BP-98A type rat intelligent noninvasive blood pressure meter to measure the tail artery blood pressure by sleeving the tail. Blood pressure of the rats was measured daily starting one week before the experiment and the experimental record was taken after the rats were stably acclimated. Measuring the blood pressure of each group of rats before gastric lavage, performing gastric lavage on a sample (active tripeptide, Sar-bAla-Pro) at a dose of 1.0mg/kg body weight, performing gastric lavage on a control group with equal volume of physiological Saline (Saline), continuously performing gastric lavage for 8 days, fixing SHR rats, exposing tails, preheating in a container for 30min, keeping the temperature at 37 ℃, and measuring the blood pressure of the tail arteries by using a noninvasive sphygmomanometer. Blood pressure values (SBP) of rats in each group are recorded every day after gastric lavage, specifically, the blood pressure value measurement of each day is concentrated at about 10 am, each rat is measured three times, the average value is taken as the blood pressure value of each day of a single rat, the average value and the standard deviation of the blood pressure value of each day of 6 rats in the same group are calculated and are used as data in the graph to represent, and the result is shown in figure 4.
FIG. 4 is a diagram showing the test results of the analysis experiment of the effect of the polypeptide compound Sar-bAla-Pro on blood pressure of congenital hypertensive male rats, and the measured data are analyzed by SPSS software and analyzed by repeated measures of variance. According to the experimental result, compared with the normal saline control group, the blood pressure value of the SHR rat is remarkably reduced (P is less than 0.05) after the stomach is perfused by the polypeptide Sar-bAla-Pro sample with the weight dose of 1.0mg/kg, and the blood pressure of the SHR rat can be basically stabilized at about 167mmHg after the stomach is perfused for 3 days. The active peptide of the invention has better effect of reducing blood pressure.
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.
Claims (5)
1. The polypeptide is characterized in that the amino acid sequence of the polypeptide is Sar-bAla-Pro, and the structure is shown in a general formula (I)
2. The method for preparing the polypeptide based on the claim 1, which is characterized by comprising the following steps:
step 1, carrying out coupling reaction on proline dichloro resin and Fmoc-beta-alanine under the action of a coupling agent and an organic solvent, washing with 20% of piperidine/dimethylformamide in volume ratio, removing the terminal Fmoc, carrying out deprotection with piperidine/dimethylformamide in volume ratio of 20% after deprotection is finished, and obtaining an intermediate product after pumping;
and 2, coupling the intermediate product and Fmoc-sarcosine under the action of a coupling agent and an organic solvent, washing with 20% by volume of piperidine/dimethylformamide, deprotecting with piperidine, washing with 20% by volume of piperidine/dimethylformamide after deprotection, draining, and purifying to obtain the polypeptide with the sequence of Sar-bAla-Pro.
3. The use of a class of polypeptides of claim 1 in the preparation of an ACE inhibitor or a blood pressure lowering product.
4. An ACE inhibitor comprising the polypeptide of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. A pharmaceutical composition for lowering blood pressure comprising the polypeptide of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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