CN105968187A - Angiogenesis agonist polypeptide and application - Google Patents
Angiogenesis agonist polypeptide and application Download PDFInfo
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- CN105968187A CN105968187A CN201610407048.3A CN201610407048A CN105968187A CN 105968187 A CN105968187 A CN 105968187A CN 201610407048 A CN201610407048 A CN 201610407048A CN 105968187 A CN105968187 A CN 105968187A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
The invention relates to the field of medicine, in particular to angiogenesis agonist polypeptide, namely, polypeptide capable of treating ischemic diseases. The angiogenesis agonist polypeptide is characterized in that the sequence of the polypeptide is a brand-new sequence, and the angiogenesis agonist polypeptide has the function of promoting angiogenesis. The angiogenesis agonist polypeptide is used for cerebral arterial thrombosis. The angiogenesis agonist polypeptide has the advantages that the angiogenesis agonist polypeptide is novel micro-molecule polypeptide screened out of cytomembrane surface receptor sequence protein which has the sequence of GPR124 and has angiogenesis activity, the polypeptide sequence can combine specificity and integrin, adhesion and transfer of cells in the angiogenesis process are adjusted, and therefore the function of treating the ischemic disease is achieved. Potential new medicine development value is achieved.
Description
Technical field:
The present invention relates to drug world, be particularly used for treating the angiogenesis agonist polypeptide medicine of cardiovascular and cerebrovascular disease.
Background technology:
Angiogenesis (Angiogenesis) refers to develop from existing blood capillary or blood capillary posterior vein and form new blood vessel,
Specifically include that activation phase blood vessel basement membrane degradation；The activation of vascular endothelial cell, breed, migrate；Rebuild and form new blood vessel
And vasoganglion, it is the complex process of a different kinds of molecules relating to various kinds of cell.Vascularization is to promote angiogenesis factor and suppression
The complex process of factor coordinative role, the two is in poised state under normal circumstances, and once this balances to break and will activate blood vascular system
System, makes angiogenesis excessively or suppression vascular system makes vascular deterioration.Angiogenesis is from the process first depositing blood vessel and producing neovascularity,
Angiogenesis can occur after wound healing, endometrical cycle change, tumor, myocardial infarction and diabetes.
Apoplexy (Stroke) is central nervous system (CNS) relevant vascular diseases, has high incidence, high disability rate
Feature.Apoplexy is divided into cerebral infarction (ischemic stroke) and hemorrhagic apoplexy.Cerebral infarction, is also called
Cerebral infarction, is most common person in cerebrovascular, accounts for 75%, and case fatality rate average 10%～15%, disability rate is high.At present,
The method intervening cerebral infarction clinically is the most limited.The treated effect using anticoagulant in acute stage time window is 5%；
Neuroprotective class medicine just suffers from failure in the research and development phase for the treatment of apoplexy.
Research finds, angiogenesis becomes to improve, by number of ways, the brain injury that cerebral infarction causes.First, newly
Angiogenic is conducive to new Doppler flow mapping to be formed, and improves the tissue perfusion around ischemic region, promotes that oxygen and nutrient enter tissue；Its
Secondary, somatomedin, such as fibrocellular somatomedin (FGF2), neurotrophic factor derived from brain (BDNF), vascular endothelial growth
The factor (VEGF), granulocyte colony-stimulating factor (G-CSF) and other neurotrophic factors etc., can promote in brain injury region
The existence of chrotoplast, colloid and Neuronal Survival, suppress neuronal apoptosis；Again, it is impaired that newborn blood vessel participates in excision
Tissue；Finally, the microenvironment of angiogenesis promoting can be that offer " the little border of blood vessel " is reinvented and migrated to neural stem cell.Therefore,
Promote that angiogenesis can effectively treat cerebral infarction, be the important channel of cerebral infarction early treatment.
G-G-protein linked receptor 124 (G-protein coupled receptor 124, GPR124) is the novel of discovery in 2003
Cell membrane surface receptors.Initially, GPR124 be determined as tumor vascular endothelium label (Tumor endothelial marker,
TEM), TEM5 therefore it is also called.GPR124 is because having the gpcr protein of longer extracellular space and 7 trans-membrane region
Hydrolysis territory GPS (GPCR proteolytic site), is confirmed to be and sticks class G-G-protein linked receptor.
Finding in body research in recent years, GPR124, in regulation CNS angiogenesis, plays vital effect.First
First, GPR124 is specific expressed at CNS endotheliocyte and pericyte (Pericyte), and such feature explanation GPR124 has
CNS blood vessel-specific；Again, GPR124 is germinateed and by the way of cell migration by regulation angiogenesis, promotes specific C NS
Vascularization, illustrates that GPR124 not only has the effect of angiogenesis, and to angiogenesis later stage, the shape to ripe blood vessel
Become also to have effect；Secondly, GPR12 promotes the foundation of blood brain barrier.Therefore, GPR124 is that specificity mediation CNS blood vessel is raw
The novel endothelial cell receptor become, can become the novel targets for the treatment of CNS relevant vascular diseases.
Research find, GPR124 can generate with vasoactive: the protease on extracellular matrix (ECM), as thrombin,
MMP2 (MMP2), GELB (MMP9) can make soluble T EM5 (sTEM5) from
Splitting away off on GPR124, specific binding with integrin alpha v beta 3, regulation cell adheres in angiogenesis and migrates；
Endothelial cell differentiation forms tubule, and sTEM5 splits away off specific binding with integrin alpha v beta 3 from GPR124, in promoting
Chrotoplast, to the migration of pericyte and adhesion, forms specific C NS blood vessel, sets up BBB.While it is true, present stage does not has
It is directly used in treatment ischemic diseases, including the research of apoplexy about sTEM5.And, GPR124 splits away off
Soluble T EM5 (sTEM5) molecular weight is relatively big, and short term contact can induce allergic immune reaction, and Long Term Contact then can cause anti-
Body neutralizing effect, thus drug resistance occurs.Therefore, inventor wishes to find has sTEM5 function, and molecular weight is little
Polypeptide, promotes angiogenesis.Finally, this little molecule is used for developing into the medicine of cerebral infarction.
Summary of the invention:
The present invention seeks to, for a kind of angiogenesis agonist polypeptide of design, to there is promotion angiogenesis function, may be used for controlling
Treat cerebral infarction.Molecular weight is little, high specificity.
The technical scheme is that a kind of angiogenesis agonist polypeptide of offer, sequence is RGDFRWPR, and its sequence is brand-new
Sequence.There is promotion angiogenesis function, treat for cerebral infarction.Described polypeptide, uses chemical synthesis to prepare.
The principle of the present invention is the difference in functionality district that inventor analyzes GPR124 cell membrane surface receptors；According to difference in functionality district,
Intercept out a plurality of peptide sequence from GPR124 sequence albumen, and modified；Going out through Preliminary screening can be with functional integration element
The peptide sequence that receptor-specific combines；Then carry out the test of angiogenesis, and determine that there is the novel little of angiogenic activity
Molecular polypeptide；Finally, use and test at body animal disease model, verify that polypeptide of the present invention promotes angiogenesis and treatment ischemic
The medical value of disease.
Beneficial outcomes:
The beneficial effects of the present invention is, sequence RGDFRWPR of the present invention is angiogenesis agonist polypeptide, be from
The new small molecule polypeptide with angiogenic activity filtered out in GPR124 cell membrane surface receptors sequence albumen.Inventor
Know that through great many of experiments the angiogenesis agonist polypeptide of the present invention can be combined with integrin by specificity, there is regulation cell and exist
Angiogenesis adhere to and migrates, thus playing treatment ischemic diseases, including the effect of cerebral infarction.Have latent
New drug development value.
Accompanying drawing explanation
Fig. 1 angiogenesis agonist polypeptide mass spectroscopy result.
The high performance liquid chromatography chromatogram of Fig. 2 angiogenesis agonist polypeptide.
Fig. 3 angiogenesis agonist polypeptide molecular docking simulation drawing.(A) molecular docking figure, is wherein angiogenesis in white box
Agonist polypeptide；(B) molecular docking active sites point diagram, marks what acceptor molecule was combined with angiogenesis agonist polypeptide
Amino acid residue: 1.Arg arginine；2.Gly glycine；3.Asp aspartic acid；4.Phe phenylalanine；5.Trp color
Propylhomoserin；6.Pro proline.
Detailed description of the invention
Embodiment 1
The chemical synthesis process of polypeptide
Polypeptide uses solid-state chemical reaction method method synthesis (by the synthesis of Karebay Biochem company), uses high performance liquid chromatograph pure
Change, obtain polypeptide.Using mass spectroscopy such as Fig. 1, its aminoacid sequence is SEQ ID NO:1.Measure by RP-HPLC method
Purity, result shows, the polypeptide degree that embodiment 1 obtains is 97.95%, meets design requirement.Chromatogram such as Fig. 2.
Embodiment 2
The result that polypeptide docks with acceptor molecule
Use the molecular docking function module of molecular docking software, evaluate the degree that polypeptide docks with acceptor molecule.Method: (1)
Receptor prepares: from Brookheaven albumin crystal structural database (http://www.rcsb.org/pdb/), retrieve respective egg
No. PDB of polymeric immunoglobulin receptor；(2) part prepares: analyze the difference in functionality district of GPR124 cell membrane surface receptors；According to difference
Functional areas, intercept out the aminoacid sequence of SEQ ID NO:1, as ligand structure from GPR124 sequence albumen；(3)
Molecular docking: C-score option is chosen, runs docking, carries out function marking.
Evaluating marking result to show, the total-score value that the polypeptide of embodiment 1 is combined with specific receptor is 11.2391.Meet
The specific binding requirement of software regulation is more than 4.Therefore, the embodiment specificity of Toplink more than 1 and multi-targeted receptor have specific binding.
Docking simulation figure is as shown in Figure 3.
Embodiment 3
Scratch experiment is used to evaluate the polypeptide impact on migration of vascular endothelial cells.First with marker pen at 24 orifice plates behind, use
Ruler compares, and uniform must draw horizontal line, per every about 0.5cm together, crosses via.Every hole is through 3 lines；Logarithm will be become raw
Long HUVEC cell, with 2.0 × 105Individual/hole adds in 24 well culture plates, cultivates 24h.Second day with 10 μ l rifle head ratios
Ruler, be perpendicular to horizontal line cut behind, with the cross point of cut and horizontal line behind for Orientation observation site；Experimental port, sun
Property drug control hole is separately added into Experimental agents angiogenesis agonist polypeptide and the positive control polypeptide sTEM5 of variable concentrations；Empty
White group adds the solvent of same volume, and every hole sets five multiple holes；Put into 37 DEG C, 5%CO2Incubator, cultivates.By 0,12,
24 hours, take pictures；Measure 0,12,24 scratch width.With different time points, record cut at fixed position, three, every hole
The change of width, is cell migration distance.According to formula computation migration rate (migration rate, MR): mobility=reality
Test scratch width-experiment scratch width of n-th hour of the 0th hour, migrate the promotion rate %=(mobility-sky of experimental group
The mobility of white group) × 100%/blank mobility organized.
The effect that human vascular endothelial is migrated by table 1 embodiment 1 polypeptide
* p ＜ 0.05, * * p ＜ 0.01 is compared with blank group
Result is as shown in table 1, and angiogenesis agonist polypeptide can promote that human vascular endothelial migrates, with the 12h of 10 μ g/ml
Migration promotion rate the highest, be 125.55%.
Embodiment 4
The effect that human vascular endothelial is bred by angiogenesis agonist polypeptide.Use MTT colorimetric evaluation polypeptide people's blood vessel
The effect of endothelial cell proliferation.By the HUVEC cell of logarithmic growth, with 8.0 × 104Individual/hole adds in 96 well culture plates,
Cultivating 24h, experimental port, positive drug control hole are separately added into Experimental agents angiogenesis agonist polypeptide and the sun of variable concentrations
Property comparison polypeptide sTEM5；Blank group adds the solvent of same volume.Every hole sets five multiple holes, and after cultivating 48h, every hole adds
MTT, after effect 4h, adds DMSO, hatches 10min, measures absorbance A value, by public affairs at microplate reader 570nm
Formula growth of tumour cell suppression ratio=(1-experimental group light absorption value/matched group light absorption value) × 100%.Result shows, angiogenesis swashs
Dynamic agent polypeptide does not has cel l proliferation to HUVEC cell, does not i.e. have cytotoxicity.
Embodiment 5
The impact that vascular endothelial cell tubular structure is formed by angiogenesis agonist polypeptide.Vascular endothelial cell tubule is used to be formed
The impact that vascular endothelial cell tubular structure is formed by test evaluation polypeptide.10mg/ml Matrigel matrigel is added 96 holes
In plate, every hole 40 μ l, is polymerized 1h in 37 DEG C of incubators.Again by the HUVEC cell of logarithmic growth, with 4000/100
μ l/ hole adds in culture plate, and meanwhile, experimental port, positive drug control hole are separately added into the Experimental agents of culture medium, variable concentrations
Angiogenesis agonist polypeptide and positive control medicine polypeptide sTEM5；Blank group adds the solvent of same volume.Every hole sets three
Multiple hole, at 37 DEG C, serum-free medium is cultivated.Each group of pipe is examined under a microscope respectively at medicine effect 6h, 9h, 12h
The formational situation of shape structure, takes pictures, records the quantity that tubule is formed.
Table 2 embodiment 1 polypeptide forms the impact of test to tubule
* p ＜ 0.05, * * p ＜ 0.01 is compared with blank group
Result is as shown in table 2: angiogenesis agonist polypeptide can promote that human vascular endothelial tubule is formed, with 5 μ g/ml's
The quantity that the tubule of 12h is formed is most, 6,9, the tubule quantity of formation of 12h be respectively 318.0 ± 13.0,190.0 ± 4.0
(p ＜ 0.05), 152.3 ± 1.5 (p ＜ 0.01).
Embodiment 6
The impact on rat artery ring angiogenesis of the angiogenesis agonist polypeptide.Take the SD male rat 4 of 6-8W, disconnected neck
Vertebra is put to death, and takes tremulous pulse, puts into and cleans containing in high anti-PBS liquid, cuts with ophthalmologic operation and tweezers remove vascular outer fiber and fat group
Knit；Cut the arterial ring of 0.5～1mm length, clean several times with the PBS liquid anti-containing height；The 96 porocyte culture plates in pre-cooling
In, (10mg/ml Matrigel is put into the 5mg/ml Matrigel matrigel 60 μ l that the addition of every hole is melted in advance by 12h in advance
4 DEG C of refrigerators melt, before using, dilute 2 times by culture medium), thoracic aortic ring is placed in parallel in glue embedding, 2, every hole is moved
Circulus venosus；37 DEG C of polymerization 15min, make gelling solid；The DMEM culture fluid (containing 10%FBS, VEGF 5ng/ml) that every hole adds
The medicinal liquid 100 μ l of preparation, respectively experimental port, positive drug control hole are separately added into the Experimental agents of culture medium, variable concentrations
Angiogenesis agonist polypeptide and positive control medicine polypeptide sTEM5；Blank group adds the solvent of same volume, and each concentration is extremely
Few 3 multiple holes, change fresh culture dosing every other day；Endotheliocyte near arterial ring is observed under inverted microscopes on the 5th, 7th
With the generation situation of new vessels, record the blood capillary spline structure number of each arterial ring one circle.The result that test obtains calculates mean
± SD, and carry out adding up T inspection, * P ＜ 0.05 is significant difference, and * * P ＜ 0.01 is pole significant difference.
The impact on rat artery ring angiogenesis of table 3 embodiment 1 polypeptide
* p ＜ 0.05, * * p ＜ 0.01 is compared with blank group
Result is as shown in table 3: embodiment 1 polypeptide can promote rat artery ring angiogenesis, dosage at 1-10 μ g/ml time
In dose dependent, when 10 μ g/ml, effect is the strongest, compared with blank group, has significant difference (p ＜ 0.05).
Embodiment 7
The impact on rat cerebral infarction model of the angiogenesis agonist polypeptide.Take the SD male rat of 8-12W, set up rat brain
Cerebral infarction models, observes the impact on rat cerebral infarction model of the angiogenesis agonist polypeptide.Rat anesthesia, takes and escribes on the right side of cervical region
Mouthful, external carotid artery (ECA) and internal carotid artery (ICA) on the right side of separation, separate ECA trunk, ligature at its far-end 1.5cm, cut
Disconnected.It is not switched on carotid sheath, does not separate and tie wings arteria palatina (PPA).The ligature of lifting ECA stump, uses miniature blood vessel
It is clipped in CCA and separates at ECA, ECA is pressed from both sides temporarily and closes, between vascular clamp and ECA stump, ligature seam zygonema, no
Urgent.Use 0.2-0.3mm nylon wire silica gel line support catheter embolus, by inlet wire near ECA stump, tighten stitching thread, pine
Open vascular clamp, promote nylon wire to enter people ICA, enter people away from ICA and ECA crotch.About during 1.8-1.9cm, there is stop sense,
Show that bolt line has passed past middle cerebral artery (MCA), arrive the initial part of anterior cerebral artery (ACA).The record thromboembolism time started,
Stitching thread on ECA is tightened.2h after thromboembolism, extracts nylon wire.With Neurological deficits for evaluating brain function defect journey
Degree index, be described as: 0 point-impassivity functional impairment symptom, rat carried tail unsettled time two forelimbs stretch earthward；1 point-light
Micro-neurologic impairment, rat carried tail unsettled time focus offside forelimb be flexing, raise, take on interior receipts, elbow joint stretches；2
Point-the focal neurologic impairment of moderate, oriented paralysis side rotates sign；The focal neurologic impairment of 3 points-severe, oriented disease
Stove offside is fallen sign；4 points-decline without spontaneous activity and human-subject test.1-3 level is modelling success.Model will after setting up
60 rat model machines are divided into 6 groups, treatment group and matched group.Each group all gives skin in the same day (first day) nylon wire when extracting
Hemostasis relative medicine, subsequently, 2 times/d, 10d altogether；Treatment group subcutaneous injection embodiment 1 polypeptide, dosage is respectively 20,10,
5,2.5mg/Kg, matched group urokinase, dosage is 5000U/Kg.14d observation Neurological deficits after modeling, meanwhile,
Take cerebral tissue, section, 2%TTC dye, hatch, fix after, take pictures and use Image ProPlus6.0 image analysis system
Calculate brain sheet infarct size and brain sheet area, calculate cerebral infarct size percentage ratio, cerebral infarct size percentage ratio=(brain sheet according to formula
Infarct size/brain sheet area) × 100%.
The impact on rat cerebral infarction model of table 4 embodiment 1 polypeptide
* p ＜ 0.05, * * p ＜ 0.01 is compared with model group
Embodiment 1 polypeptide is to rat cerebral infarction model result as shown in Table 4: it is big that embodiment 1 polypeptide can improve cerebral infarction model
The Neurological deficits of Mus, is dose dependent when dosage is at 2.5-20mg/Kg, compared with model group, has statistics
Difference.It addition, embodiment 1 polypeptide can reduce rat cerebral infarction area, compared with model group, there is significant difference.
Conclusion: embodiment 1 polypeptide is obvious to rat cerebral infarction model cerebral infarction model curative effect, can be as clinical rat cerebral infarction mould
The effective candidate therapeutics of type cerebral infarction.
Claims (5)
1. an angiogenesis agonist polypeptide, it is characterised in that the sequence of described polypeptide is SEQ ID NO:1.
2. according to the polypeptide described in claims 1, it is characterised in that have the function promoting angiogenesis.
3. according to the polypeptide described in claims 1, it is characterised in that for treating the effect of ischemic diseases.
4. according to the polypeptide described in claims 3, it is characterised in that described ischemic diseases is cerebral infarction.
5. according to the arbitrary described polypeptide of claims 1-4, it is characterised in that the method that recombinant expressed body or chemosynthesis can be used
Preparation.
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| CN106349344A (en) * | 2016-08-30 | 2017-01-25 | 苏州普罗达生物科技有限公司 | L-arginine accelerant polypeptide and application thereof |
| CN106647355A (en) * | 2016-11-09 | 2017-05-10 | 中国民用航空飞行学院 | Data processing method and system for flight situation environment evaluation |
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