CN103113472A - Fusion peptide with myocardial preservation function as well as preparation method and application thereof - Google Patents
Fusion peptide with myocardial preservation function as well as preparation method and application thereof Download PDFInfo
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- CN103113472A CN103113472A CN201310030621XA CN201310030621A CN103113472A CN 103113472 A CN103113472 A CN 103113472A CN 201310030621X A CN201310030621X A CN 201310030621XA CN 201310030621 A CN201310030621 A CN 201310030621A CN 103113472 A CN103113472 A CN 103113472A
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- fusogenic peptide
- betaglycan
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Abstract
The invention discloses a fusion peptide with a myocardial preservation function as well as a preparation method and application thereof and belongs to the field of bio-pharmaceuticals. The fusion peptide with the myocardial preservation function is characterized by comprising an amino acid sequence shown in SEQ ID NO.1. The biological activity research on the obtained fusion peptide proves that the fusion peptide has the effect of treating or preventing arrhythmia, ventricular fibrillation, myocardial ischemia, myocardial infarction, myocardium cell apoptosis and other heart associated diseases. In addition, the invention also provides a method for preparing the fusion peptide and application of the fusion peptide in preparation of medicines with the myocardial preservation function.
Description
Technical field
The present invention relates to a kind of fusogenic peptide and its preparation method and application, particularly a kind of fusogenic peptide with myocardium protecting action and its preparation method and application.Belong to field of biological pharmacy.
Background technology
Myocardial ischemia-reperfusion injury is the universal phenomenon that higher animal body postischemic reperfusion occurs, to cause in heart failure and ARR major incentive, therefore seek the control ischemical reperfusion injury method of suitable and determined curative effect, be study hotspot, the difficult point of cardiovascular field always.Although experiment showed, that ischemic preconditioning has remarkable effect to the myocardial preservation of Ischemic Heart Disease, because needs carry out before myocardial infarction occurs, its clinical application is greatly limited." endogenous myocardial theory " becomes the Disciplinary Frontiers of current cardiovascular research; many tests confirm; the material that exists many endogenous in heart, has cytoprotective character; thereby make myocardial cell's vital movement be in dynamic balance state, seek controlled endogenous myocardial molecule and in addition externally change structure or drug-inducedly become a kind of New Policy of preventing and treating the heart major disease.Known at present, adenosine, nitrogen protoxide and calcitonin-gene-related peptide (Calcitonin Generelated Peptide, CGRP) etc. be endogenous material, it is short that but their effect is held time too rapidly, and main target organ is nerve and blood vessel, and easily degraded, become the property of medicine poor, be not suitable for giving for a long time the patient and treat.In addition, we just stand on starting line the understanding of endogenous myocardial molecule, and under the situation of not grasping whole myocardial preservation molecule correlation function meanings, current understanding to the endogenous myocardial molecular mechanism is incomplete.
Betaglycan also is called transforming growth factor three receptors (TGF β RIII), is that total length is 851 amino acid protein polysaccharide, is TGF-signal β superfamily member.Confirm at present, transmembrane protein glycan betaglycan is comprised of following three parts: 766 amino acid whose extracellular region territory (soluble ectodomain that grow, s-betaglycan), hydrophobic cross-film zone (transmembrane region, TMD), the kytoplasm zone (cytoplasmic domain, c-betaglycan) that shorter 42 amino acid form is expressed in cell surface as the homodimer of a non-covalent associating.Total length betaglycan is accompanied by the extracellular region territory that the outer proximal end region of born of the same parents discharges solubility after the Partial Protein hydrolysis in cross-film zone becomes s-betaglycan, and s-betaglycan can be detected in cell culture fluid and serum.Someone adopts in the body experiment and shows, also can significantly suppress prostate cancer for inoculated tumour animal injection s-betaglycan, the growth of mammary cancer and carcinoma of endometrium, and any virose side reaction does not appear, but glioma is not had obvious effect.Betaglycan expression deletion in most early-stage cancers shows that betaglycan may suppress the progress of cancer.
And the effect in heart disease to betaglycan, and network signal is transduceed and regulatory mechanism it be unclear that.Find at present the fibrosis that the structure synthetic peptide can obviously suppress the spontaneous hypertensive rat cardiac muscle that changes of a s-betaglycan, this collagen with its inhibition TGF-β 1 mediation is synthetic relevant.In addition, we are by the instantaneous expression total length betaglycan that crosses, can obviously see the apoptosis of the Cardiac Fibroblasts that betaglycan inhibition severe hypoxia causes, its concrete mechanism is relevant with the Bax/Bcl-2 apoptotic signal path that suppresses the mediation of TGF-signal β path.Whether but above-mentioned research is only in cardiac fibroblast, and is that total length or s-betaglycan function are studied, express in the myocardial cell for it, and how its function particularly function of c-betaglycan it be unclear that.Well-known myocardial ischemia-reperfusion injury physiopathology is changed to the unbalance of the myocardial cell's who produces in the myocardial remodelling process apoptosis and important ion channel function, thereby causes the generation of heart failure, irregular pulse major disease.Our early-stage Study has confirmed that betaglycan exists high abundance to express in cardiac muscle, higher 1.7 times than expressing in Cardiac Fibroblasts.In the myocardial ischemia-reperfusion injury process, it is expressed significantly and descends.The dUTP breach end-labelling of TUNEL(TdT mediation in early stage) and the electron microscopic observation result show, it is apoptosis-induced that transient transfection total length betaglycan can significantly suppress anoxia-reoxygenation myocardial cells.Reported betaglycan after cutting away extracellular segment, its endochylema fragment c-betaglycan is stable and has activity.Therefore, we design and synthesize the c-betaglycan fusogenic peptide of transformation, namely adopt c-betaglycan to be connected with transduction peptide, utilize transduction peptide with the fusogenic peptide transfered cell.For relatively whether s-betalgycan and c-betaglycan cause apoptosis of cardiac muscle that provide protection is arranged to hypoxia-reoxygenation respectively; we carry out in vitro tests and will add respectively s-betalgycan and c-betaglycan in cell culture fluid, find both all to have the anti-myocardial apoptosis effect.Comprehensive above the discovery, we construct the fusogenic peptide with efficient myocardium protecting action by synthetic or engineered method, and its biologic activity is studied.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of fusogenic peptide with myocardium protecting action.For this reason, the present invention adopts chemosynthesis or engineered method, builds the fusogenic peptide of the heart related diseases such as a kind of Effective Anti myocardial ischemia, heart disorder, and its biologic activity is studied.
A kind of fusogenic peptide with myocardium protecting action of the present invention is characterized in that having the aminoacid sequence shown in SEQ ID NO.1.
Preferably; a kind of fusogenic peptide with myocardium protecting action of the present invention; as shown in SEQ ID NO.1 (RKKRRQRRRWGTGETAGQQVPTSPPASENSSAAHSIGSTQSTPCSSSSTG); 50 amino acid of its total length; 9 amino acid of N end are take basic aminoacids as main; form transduction peptide (wearing the film peptide), can be with the c-betaglycan transfered cell matter that connects later.Thereafter the W that adds is tryptophane, is convenient to use in production process the ultraviolet detection peptide concentration; G is glycine, flexibly connects with thereafter small molecules Amino acid profiles such as TG, guarantees that c-betaglycan three-dimensional arrangement thereafter can not change because introducing transduction peptide, keeps active.The L-Ala of c-betaglycan C end changes glycine into, and the fusogenic peptide that chemosynthesis and genetically engineered are obtained structurally is consistent.
Further, the invention allows for the nucleotide sequence of the described fusogenic peptide of coding.
Preferably, described nucleotide sequence is as shown in SEQ ID NO.2.
Containing the expression vector of described nucleotide sequence and contain the Host Strains of described expression vector also should be within protection scope of the present invention.
The resulting c-betaglycan fusogenic peptide of the present invention is carried out bioactivity research to be found; fusogenic peptide of the present invention can provide cardioprotection, to irregular pulse, chamber quiver, the heart related diseases such as myocardial ischemia, myocardial infarction and apoptosis of cardiac muscle can play treatment or preventive effect.
Therefore, further, the invention allows for described fusogenic peptide and described nucleotides sequence and be listed in preparation and have application in the myocardium protecting action medicine.
Wherein, described have the myocardium protecting action medicine be for prevention or treatment irregular pulse, chamber quiver, the heart related diseases such as myocardial ischemia, myocardial infarction and apoptosis of cardiac muscle.
Further; the invention allows for a kind of method that obtains to have the fusogenic peptide of myocardium protecting action by genetically engineered; it is characterized in that comprising the following steps: select the synthetic nucleotide sequence that is used for expressing described fusogenic peptide of intestinal bacteria preference password; concrete sequence is as shown in SEQ ID NO.3; make synthetic gene 5' end phosphorylation with polynucleotide kinase; with NdeI and Smal digested plasmid pTYB2; recombinate with target gene; transform e. coli bl21 (DE3) competent cell; expressed fusion protein; extract albumen, purifying, and get final product.
Nucleotide sequence shown in described SEQ ID NO.3 is to increase the TATG sequence at 5 of coding strand (shown in SEQ ID NO.2) ' end, ATG wherein is initiation codon, TA is the strand cohesive end that the NdeI enzyme is cut rear generation, 3 ' hold as c-betaglycan C end second amino acid-Threonine password, be flush end.Make synthetic gene 5 ' end phosphorylation with polynucleotide kinase, with NdeI and Smal digested plasmid pTYB2, recombinate with target gene, transform e. coli bl21 (DE3) competent cell, fusogenic peptide is with the formal representation of fusogenic peptide-intein-this fusion rotein of chitin-binding protein, through Affinity chromatography, and intein cracking in the chitin post, discharge fusogenic peptide, and increase a glycine at the C of fusogenic peptide end.Directly obtain the fusogenic peptide of purifying by a step chromatography.
Description of drawings
Fig. 1 is that c-betaglycan is on the impact of IRI inducing mouse myocardial infarction area and apoptosis;
A:2, the infarct size result is measured in 3,5-triphenyltetrazolium chloride (TTC) dyeing, and column diagram is statistics;
* compare p＜0.05.B:Tunel dyeing cardiac bistiocyte apoptosis measurement result with the IRI model group, picture is that three experiments represent result;
Fig. 2 is that BG induces the apoptosis of cardiac muscle effect to hypoxia-reoxygenation;
A:Tunel dyeing observation of cell apoptosis; B: electron microscopic observation Change of Ultrastructure; C:TUNEL apoptosis quantity statistics figure; N=3* compares p＜0.05 with control group; # compares p＜0.05 with model group.
Embodiment
Also the present invention will be further described in conjunction with the embodiments below by experiment, it should be understood that these embodiment only are used for the purpose of illustration, never limit protection scope of the present invention.
Embodiment 1 obtains the method for c-betaglycan fusogenic peptide
Method 1: adopt gene engineering method to obtain the c-betaglycan fusogenic peptide
Select the synthetic nucleotide sequence that is used for expressing described fusogenic peptide of intestinal bacteria preference password, concrete sequence is as shown in SEQ ID NO.3.It is that TA wherein is the strand cohesive end at 5 of coding strand (shown in SEQ ID NO.2) ' increase four bases of TATG, can be connected with the cohesive end compatibility after the NdeI enzyme is cut, and ATG is the initiation codon of translation.3 ' hold the codon into second amino acid-Threonine of c-betaglycan C end, be flush end, can be connected with the flush end that the Smal enzyme is cut generation.Make synthetic gene 5 ' end phosphorylation with polynucleotide kinase, with NdeI and Smal digested plasmid pTYB2, with the target gene restructuring, transform BL21 (DE3) bacterium.The fusion rotein of expressing is through the chitin column chromatography, and cracking in the chitin post directly obtains the fusogenic peptide of purifying.
The sequence of the fusogenic peptide that expression obtains as shown in SEQ ID NO.1,50 amino acid of total length.
Method 2: adopt the artificial chemistry synthetic method to obtain the c-betaglycan fusogenic peptide:
Composition sequence is as shown in SEQ ID NO.1, and the N end is arginine, and the C end is glycine, and total length is 50 amino acid.
The pharmacological evaluation effect research of embodiment 2c-betaglycan fusogenic peptide
Experiment material
Animal: the Wistar rat, female, buy from animal institute of the attached Second Academy of Harbin Medical University.
Reagent: fusogenic peptide c-betaglycan, synthetic according to embodiment 1 method
1, the impact of c-betaglycan fusogenic peptide on the normal anoxia in mice survival time
Method:
Get 20 of mouse, be divided at random two groups, (1) control group iv10ml/kg physiological saline (2) fusogenic peptide group iv10mg/kg; After 30 minutes, mouse is put into 500ml port grinding bottle (containing the 3g sodica calx), after being coated with Vaseline, lid is done.Observe mouse diing time.The results are shown in Table 1.
The impact of table 1 on the normal anoxia in mice survival time
A represents to compare with control group P＜0.05
2, the impact of c-betaglycan fusogenic peptide on the rat ventricular of Aconitine Induced
Method: 20 of Healthy female Wistar rats, be divided at random 2 groups: (1) model group: iv give isometric(al) physiological saline; (2) fusogenic peptide group: iv10mg/kg fusogenic peptide; With 20% urethane (5mg/kg) intraperitoneal injection of anesthesia, animal is faced upward the position be fixed on the mouse platform, and be connected with BL-420 biological function experimental system after 30 minutes, trace electrocardiogram(ECG.After Rat Ecg is stable, Normal group sublingual vein injecting normal saline, all the other group sublingual vein injection 0.04% napelline 1ml/kg(40 μ g/kg), annotated in 5s, the time of origin of observation room premature beat (VP), and statistics ventricular tachycardia (VT), chamber quiver incidence and the sinus rhythm recovery rate of (VF).The results are shown in Table 2.
The impact of table 2 on the rat ventricular of Aconitine Induced
A represents to compare with model group P＜0.05
Result shows, fusogenic peptide of the present invention can relax the rat ventricular of Aconitine Induced, reduces the quiver incidence of (VF) of ventricular tachycardia (VT), chamber, improves the sinus rhythm recovery rate.
3, the c-betaglycan fusogenic peptide brings out on chloroform the impact of quivering in the mouse chamber
Method: get 20 of mouse, be divided at random 2 groups, (1) model group: iv give isometric(al) physiological saline; (2) fusogenic peptide group: iv10mg/kg fusogenic peptide.After administration in 2～3 minutes, with mouse put into one by one contain 5ml chloroform cotton balls cause the 500ml beaker, often change a mouse and need add the 0.5ml chloroform, allow the mouse Inhalation Exposure To Chloroform until cease breathing.Take out immediately and be connected with BL-420 biological function experimental system, tracing electrocardiogram(ECG.The counting chamber incidence of quivering the results are shown in Table 3.
Table 3. brings out on chloroform the impact of quivering in the mouse chamber
A represents to compare with model group P＜0.05
4, the c-betaglycan fusogenic peptide brings out the provide protection of myocardial ischemia in rats to Pituitrin
Method: 30 of healthy Wistar rats, be divided at random 3 groups, 10 every group: (1) Normal group: iv give isometric(al) physiological saline; (2) model group: iv gives isometric(al) physiological saline, (3) fusogenic peptide group: the iv10mg/kg fusogenic peptide.The experiment proxima luce (prox. luc) carries out rat to Pituitrin susceptibility screening experiment.Method is: intravenous injection Pituitrin 1U/kg under Rat Tongue, observe the electrocardiogram(ECG changing conditions, and choose the Pituitrin Sensitive Rats for experiment (the T ripple is obviously raised, and the ST section is raised over 0.1mV).The Sensitive Rats that screening is obtained is used for model group and fusogenic peptide group, begins experiment after 24h.Each group with 20% urethane (5ml/kg) intraperitoneal injection of anesthesia, is faced upward the position with animal and is fixed on the mouse platform, and be connected with BL-420 biological function experimental system after 1 hour all with the 1ml/100g gavage, traces electrocardiogram(ECG.Normal group sublingual vein injecting normal saline after all the other two groups of sublingual vein injection of pituitrin 1U/kg, is observed electrocardiogram(ECG and is changed respectively at once, after 1min.Change into index with T ripple and ST section, judgement degree of myocardial ischemia and drug effect.Abdominal aortic blood after 60min, centrifugation serum is measured and is respectively organized serum lactic dehydrogenase in mice serum (LDH), superoxide-dismutase (SOD), mda (MDA) content, calculating mean value.The results are shown in Table 4.
The impact of table 4. on rats with myocardial ischemia LDH, MDA, SOD
A represents to compare with control group P＜0.05; B represents with the model group ratio, difference P＜0.05 is arranged; C represents to compare P＜0.05 with the fusogenic peptide group;
5, the impact of c-betaglycan fusogenic peptide on IRI inducing mouse myocardial infarction area and apoptosis
Method: we are to mouse peritoneal injection c-betaglycan fusogenic peptide (5mg/kg), carry out ischemical reperfusion injury (ischemia reperfusion injury after three days, IRI) model, the next day to the c-betaglycan fusogenic peptide, getting the left ventricular ischemia marginarium after 7 days carries out infarct size and measures and TUNEL staining examine apoptosis, find that the c-betaglycan fusogenic peptide can significantly reduce the myocardial infarction area that IRI causes, and ischemic marginarium apoptosis of cardiac muscle, result is as shown in Figure 1.
6, the c-betaglycan fusogenic peptide is induced the apoptosis of cardiac muscle effect to hypoxia-reoxygenation
method: adopt neonatal rat myocardial cell to carry out Hypoxia-reoxygenation model (Hy/RH) anoxic 1 hour, reoxygenation carries out TUNEL dyeing identification of cell apoptosis after 24 hours, occurrence degree finds that model group apoptotic cell quantity reaches 76% as shown in Fig. 2 A and 2C, and total length betaglycan transfection group can suppress the apoptosis of cardiac muscle that hypoxia-reoxygenation is induced fully, simultaneously in order to distinguish fragment c-betaglycan myocardium protecting action in the outer solubility e-betaglycan of born of the same parents and born of the same parents, we hatch both to the myocardial cell respectively in advance, and concentration is 100nM, finding both all can reduce hypoxia-reoxygenation induces apoptosis of cardiac muscle to produce, but c-betaglycan compares its anti-apoptosis effect with e-betaglycan more remarkable.Fig. 2 B is the electron microscopic observation result, as seen the model group nucleus is broken, and have the apoptosis feature of vacuolar degeneration, with the consistent total length betaglycan(BG of TUNEL detected result) transfection group, c-betaglycan(c-BG) group and e-betaglycan(e-BG) group compares with model group and all can alleviate the variation that hypoxia-reoxygenation is induced Myocardial ultrastructure.
The above is only the preferred embodiments of the present invention, is only illustrative for the purpose of the present invention, and nonrestrictive; Those of ordinary skills understand, and can carry out many changes to it in the spirit and scope that claim of the present invention limits, revise, and even equivalence change, but all will fall within the scope of protection of the present invention.
Claims (10)
1. the fusogenic peptide with myocardium protecting action, is characterized in that having the aminoacid sequence shown in SEQ ID NO.1.
2. the encode nucleotide sequence of fusogenic peptide claimed in claim 1.
3. nucleotide sequence as claimed in claim 2, is characterized in that described nucleotide sequence is as shown in SEQ ID NO.2.
4. an expression vector, is characterized in that containing the described nucleotide sequence of claim 2 or 3.
5. a Host Strains, is characterized in that containing expression vector claimed in claim 4.
6. fusogenic peptide claimed in claim 1 has application in the myocardium protecting action medicine in preparation.
7. application as claimed in claim 6 is characterized in that describedly having that the myocardium protecting action medicine is used for quivering in prevention or treatment irregular pulse, chamber, the heart related diseases such as myocardial ischemia, myocardial infarction and apoptosis of cardiac muscle.
8. the described nucleotides sequence of claim 2 or 3 is listed in and prepares the application that has in the myocardium protecting action medicine.
9. application as claimed in claim 8 is characterized in that describedly having that the myocardium protecting action medicine is used for quivering in prevention or treatment irregular pulse, chamber, the heart related diseases such as myocardial ischemia, myocardial infarction and apoptosis of cardiac muscle.
10. synthetic method with fusogenic peptide of myocardium protecting action; it is characterized in that comprising the following steps: select the synthetic nucleotide sequence that is used for expressing described fusogenic peptide of intestinal bacteria preference password; concrete sequence makes synthetic gene 5' end phosphorylation with polynucleotide kinase, with NdeI and Smal digested plasmid pTYB2 as shown in SEQ ID NO.3; recombinate with target gene; transform e. coli bl21 (DE3) competent cell, expressed fusion protein extracts albumen; purifying, and get final product.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106138970A (en) * | 2016-08-26 | 2016-11-23 | 闫福林 | One treats ARR Chinese medicine composition |
Citations (2)
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| CN101665539A (en) * | 2009-09-08 | 2010-03-10 | 暨南大学 | Restructured fusion protein PTD-MAX and expression method and application thereof |
| CN102079790A (en) * | 2010-08-06 | 2011-06-01 | 暨南大学 | Recombination fusion protein PACAP-PTD (Pituitary Adenylate Cyclase Activating Peptide-Protein Transduction Domain) as well as expression method and application thereof |
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| CN101665539A (en) * | 2009-09-08 | 2010-03-10 | 暨南大学 | Restructured fusion protein PTD-MAX and expression method and application thereof |
| CN102079790A (en) * | 2010-08-06 | 2011-06-01 | 暨南大学 | Recombination fusion protein PACAP-PTD (Pituitary Adenylate Cyclase Activating Peptide-Protein Transduction Domain) as well as expression method and application thereof |
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| 《生命的化学》 20051231 吴强 等 "穿膜肽的结构特点和穿膜机制" 第304－306页 第25卷, 第4期 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106138970A (en) * | 2016-08-26 | 2016-11-23 | 闫福林 | One treats ARR Chinese medicine composition |
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