CN101597324A - A kind of decapeptide inhibiting angiogenesis and application thereof - Google Patents
A kind of decapeptide inhibiting angiogenesis and application thereof Download PDFInfo
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- CN101597324A CN101597324A CNA2009100468735A CN200910046873A CN101597324A CN 101597324 A CN101597324 A CN 101597324A CN A2009100468735 A CNA2009100468735 A CN A2009100468735A CN 200910046873 A CN200910046873 A CN 200910046873A CN 101597324 A CN101597324 A CN 101597324A
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Abstract
The present invention relates to a kind of decapeptide inhibiting angiogenesis and application thereof, belong to the biological medicine technology field.Decapeptide inhibiting angiogenesis provided by the invention is people (Homo sapien) source, aminoacid sequence YNWNSFGLRF, molecular weight is 1303.4, called after Kp-10, the present invention also provides above-mentioned anti-angiogenic rebirth decapeptide to suppress application, especially Kp-10 in the medicine at the preparation angiogenesis to suppress related application in the angiogenesis dependence diseases such as cancer and rheumatoid arthritis, psoriasis, diabetic syndrome, vascular tumor in preparation.The result shows at VEGF (vascular endothelial growth factor) inductive serial experiment, Kp-10 forms in experiment, chick chorioallantoic membrane angiogenesis and the experiment of mouse cornea at human umbilical vein's endotheliocyte (HUVEC) proliferation experiment, migration experiment, microtubule all the obvious suppression effect, can be used for preparing the medicine of angiogenesis inhibiting.
Description
Technical field
The present invention relates to a kind of new anti-angiogenic rebirth protein polypeptide Kp-10, and the application of this protein polypeptide, the biological medicine technology field belonged to.
Background technology
Cancer and cardiovascular disorder, diabetes are the three big diseases that threaten human health.Malignant tumour is first reason of present most countries disease death, and simultaneously, along with the change of environment and people's living habit, the cases of cancer number is in rising trend.
The seventies in last century, the Judah Folkman of medical college of Harvard University proposes to suppress growth of tumor and transfer by angiogenesis inhibiting first.Tumour can only be grown the 2-3 cubic millimeter under the supply that does not have nutrient.If there is new vessel to link to each other with tumour, tumour obtains nutritive substance and oxygen, just can be with the geometricprogression ramp; Tumour cell can also be transferred to other organs by neonatal blood vessels simultaneously, and metastases takes place, and causes human body death.Because tumour is of a great variety, and growth of tumour cell is fast, very easily undergos mutation, and therefore easily medicine is produced resistance, and the endotheliocyte of blood vessel is because inheritance stability, and mutation probability is much smaller relatively.Therefore use anti-angiogenic drugs in theory and be difficult for producing resistance, and anti-angiogenic drugs has the anti-tumor activity of wide spectrum.
Except tumour, the angiogenesis imbalance also can cause multiple diseases such as sacroiliitis, diabetic retinopathy and old maculopathy atherosclerosis, endometritis, psoriasis, leiomyoma of uterus, benign prostatauxe.2004, the drugs approved by FDA first routine angiogenesis inhibitors was used for oncotherapy, and found that angiogenesis inhibitors can treat kinds of tumors, and can be used to treat blind grade for other diseases, had multiple angiogenesis preparation now and was carrying out clinical experiment.
Kisspeptin-10 (Kp-10) is a kind of decapeptide that derives from human KISS1 gene translation product, this decapeptide does not have the report of Kp-10 to angiogenesis and tumor growth aspect at present both at home and abroad by exercising biological function with combining of g protein coupled receptor-GPCR54 (G protein-coupled receptor-54).
Summary of the invention
An object of the present invention is to provide a kind of protein polypeptide of anti-angiogenic rebirth, this polypeptide is people (Homosapien) source, and aminoacid sequence YNWNSFGLRF, molecular weight are 1303.4, called after Kp-10, and active fragments, derivative and analogue.
Another object of the present invention provides the polynucleotide passage of this protein polypeptide of coding.
Another object of the present invention provides the application of Kp-10 in the medicine of the preparation treatment disease relevant unusually with angiogenesis.
Decapeptide inhibiting angiogenesis provided by the invention is people (Homo sapien) source, and aminoacid sequence YNWNSFGLRF, molecular weight are 1303.4, called after Kp-10, and the present invention also provides the conservative property of the protein polypeptide of above-mentioned anti-angiogenic rebirth.
Second aspect of the present invention, the polynucleotide passage of coding decapeptide inhibiting angiogenesis is provided, these polynucleotide comprise a Nucleotide, this Nucleotide be selected from following one group of nucleotides sequence and show at least 70% homology: the polynucleotide of the above-mentioned anti-angiogenic rebirth peptide Kp-10 of (1) coding; (2) with polynucleotide (1) complementary polynucleotide;
A third aspect of the present invention, polypeptide of the present invention or its part can be used for preparing the application of the medicine that treats and/or prevents the disease that the angiogenesis aspect causes.
As used herein, " new anti-angiogenic rebirth peptide " Kp-10 is meant and is substantially free of natural relative other albumen, lipid, carbohydrate or other material in the anti-angiogenic rebirth protein polypeptide.
The invention provides a kind of new polypeptide---anti-angiogenic rebirth polypeptide Kp-10.Polypeptide of the present invention can be the product of chemosynthesis, or uses recombinant technology to produce from protokaryon or eucaryon host (for example, bacterium, yeast, higher plant, insect and mammalian cell).The host used according to reorganization scheme, polypeptide of the present invention can be glycosylated, also can be nonglycosylated.
Polypeptide of the present invention can also comprise or not comprise initial methionine residues.
The present invention also comprises fragment, derivative and the analogue of anti-angiogenic rebirth protein polypeptide Kp-10.As used herein, term " fragment ", " derivative " are meant biological function or the active polypeptide that keeps anti-angiogenic rebirth protein polypeptide Kp-10 of the present invention identical basically with " analogue ".Polypeptide fragment of the present invention, derivative and analogue are meant: (I) a kind of like this, wherein one or more amino-acid residues are replaced by conservative or non-conservative amino acid residues (preferably conservative amino acid residues), and the amino acid that replaces can be that the genetic codon coding also can not arranged; Perhaps (II) is a kind of like this, and certain group on wherein one or more amino-acid residues is replaced by other group and comprises substituting group; Or (III) a kind of like this, polypeptide and another kind of compound (such as the compound that prolongs the polypeptide transformation period, for example polyoxyethylene glycol) merge; Perhaps (IV) is a kind of like this, and wherein additional amino acid is integrated into polypeptide and the peptide sequence that forms (as leader sequence or secretion sequence or be used for the sequence or the proteinogen sequence of this polypeptide of purifying).By the elaboration of this paper, such fragment, derivative and analogue are considered within those skilled in the art's ken.
" homology " is meant the distance of organic evolution distance between the species in same ancestors source, and principal reaction is on Nucleotide or amino acid.Usually series arrangement is got up, to obtain the coupling that maximum is limited the quantity of, " homology " itself has the meaning and the available disclosed technique computes of this area understanding.This term " homology " is that the technician is known.The method of measuring homology or paralogy to be being organized in the computer program by rule, optional, be used to measure two between sequence homology or the computer program means of similarity include, but is not limited to the GCG routine package.
Describe by a peptide species, aminoacid sequence YNWNSFGLRF that it had and reference amino acid sequence have 70% " homology " at least and are meant: in the YNWNSFGLRF sequence, the polypeptide that the aminoacid sequence of this polypeptide and reference sequences at least 70% are identical, nearly 25% aminoacid sequence can be deleted or by another aminoacid replacement in the reference sequences, maybe some aminoacid sequences can be inserted in peptide sequences.Wherein the amino acid of Cha Ruing is nearly with reference to 25% of the total amino acid residue of amino acid, these sudden changes of reference sequences can occur in the amino or the carboxyl art end position of reference sequences, or any place between N-terminal, they or be dispersed in separately in the participation of reference sequences, or near one or more, be present in the reference sequences.
The invention reside in Kp-10 suppresses application, especially Kp-10 in the medicine at the preparation angiogenesis and suppresses related application in the angiogenesis dependence diseases such as cancer and rheumatoid arthritis, psoriasis, diabetic syndrome, vascular tumor in preparation.
The Kp-10 of treatment significant quantity and any one auxiliary material of pharmaceutically permission can be made pharmaceutical composition according to the present invention, also can add the anti-angiogenic drugs that other and Kp-10 do not have antagonistic action.Its preparation can be any one formulation pharmaceutically, includes but not limited to tablet, granule, capsule, pill, oral liquid, injection, liposome etc.
For implementing method of the present invention, Kp-10 can or pass through the administration of implanted reservoir by oral, parenteral, inhaling type spraying." parenteral " comprise in subcutaneous, intracutaneous, intravenously, intramuscular, intraarticular, intra-arterial, the synovial membrane chamber, in the breastbone, in the sheath, intralesional and intracranial injection or input technology.
Oral available solid or liquid dose unit carry out administration as formulations such as art agent, powder, tablet, sugar-coat agent, capsule, granule, suspension agent, solution, syrup, drops, sublingual lozenges.
The end agent is The compounds of this invention is worn into suitable fineness and to make.Powder is that The compounds of this invention is worn into suitable fineness, and the pharmaceutical carrier (as carrier, mannitol and so on edibility carbohydrate etc.) with same fineness is mixed and made into then.As required, also can sneak into materials such as correctives, sanitas, dispersion agent, tinting material, spices.
Capsule is to be filled in the capsule shell and to make making pulverous last agent and powder as mentioned above or going into the described granular material of tablet part.Also lubricant and glidant etc. can be mixed in the powdery substance, in capsule, fill then.If add solubility promoter and disintegrating agent etc., as polyoxyethylene glycol, yellow soda ash, the drug effect in the time of can improving the capsule picked-up.
Useful result of the present invention:
The invention discloses protein polypeptide Kp-10 and the application in the preparation anti-angiogenic drugs thereof.The result shows at VEGF (vascular endothelial growth factor) inductive serial experiment, Kp-10 forms in experiment, chick chorioallantoic membrane angiogenesis and the experiment of mouse cornea at human umbilical vein's endotheliocyte (HUVEC) proliferation experiment, migration experiment, microtubule all the obvious suppression effect, may can be used for preparing the medicine of angiogenesis inhibiting.
Description of drawings
All represent that with p＜0.05 there were significant differences among the figure, *, p＜0.05, * *, p＜0.01, * * *, p＜0.001.
Fig. 1: concentration is that the Kp-10 of 1 micromoles per liter suppresses Human umbilical vein endothelial cells (HUVEC) migration (left side is the VEGF control group, and the right is the VEGF+Kp-10 group);
Fig. 2: concentration is that the Kp-10 of 1 micromoles per liter suppresses the migration (left side is the VEGF control group, and the right is the VEGF+Kp-10 group) in Human umbilical vein endothelial cells (HUVEC) the Boyden cell;
Fig. 3: concentration is that the Kp-10 of 1 micromoles per liter suppresses Human umbilical vein endothelial cells (HUVEC) microtubule formation (left side is not for adding the Kp-10 control group, and the right is for adding the Kp-10 group);
Fig. 4: 10 microgram Kp-10 suppress chick chorioallantoic membrane new vessel new life (left side is a physiology saline control group, and the right is for adding the Kp-10 group, and the arrow indication is a new vessel);
Fig. 5: 1 microgram Kp-10 suppresses VEGF inductive corneal vascularization, and the arrow indication is the slow-releasing granules position, (left side is the VEGF control group, and the right is the VEGF+Kp-10 group).
Embodiment
Embodiment 1:Kp-10 suppresses Human umbilical vein endothelial cells (HUVEC) propagation
Purpose and principle: the Human umbilical vein endothelial cells proliferation experiment adopts MTS Assay.MTS Assay is a kind of measuring method that uses colorimetry to measure viable cell quantity indirectly.CellTiter
The single solution reagent of AQueous comprises a kind of tetrazole compound (inner salt; MTS) and electron coupling reagent (second sulphur azophenlyene, PES).MTS can be had desaturase effect in the metabolic activity cell to generate the particle that dissolves in tissue culture medium (TCM), and the quantity of viable cell directly is directly proportional in light absorption value that 490nm measures product and culture.
Method: in 96 orifice plates, add Human umbilical vein endothelial cells (HUVEC), set up control group and application of sample group.Control group adds solvent, and the application of sample group adds the Kp-10 polypeptide of different concns, and each concentration is done three multiple holes.After hatching 48-72 hour, add the cell proliferation detection reagent, hatched 4 hours again, detect light absorption value at the 490nm place with microplate reader, same experiment is carried out three times altogether.
Result and evaluation: compare with the experiment contrast group, the Human umbilical vein endothelial cells multiplication capacity is suppressed, and illustrates that KP-10 can suppress the propagation of Human umbilical vein endothelial cells.
Embodiment 2: Kp-10 suppresses the Human umbilical vein endothelial cells migration in the scratch experiment
Purpose and principle: under the effect of vascular endothelial growth factor (VEGF), Human umbilical vein endothelial cells can be to the scored area migration that does not have cell.Whether by the endotheliocyte amount of being moved in the cut district in observation, estimating KP-10 has the ability with the migration of inhibition Human umbilical vein endothelial cells.
Method: add Human umbilical vein endothelial cells in 6 orifice plates, when approximately covering with, use Tip standardized cruciform cut, the cell under drawing with PBS is clean adds the substratum that contains different pharmaceutical concentration and VEGF, in 5%CO
237 ℃ of cell migrations that are cultured to the line both sides are to scribe area in the incubator.
Evaluation of result: under inverted microscope, observe the statistics of taking pictures, result's demonstration is compared with control group, and behind the adding Kp-10 peptide, the migration of Human umbilical vein endothelial cells is suppressed, illustrate that the Kp-10 peptide can suppress the migration of Human umbilical vein endothelial cells, same experiment is carried out three times at least.
Experiment embodiment 3:Kp-10 peptide suppresses the migration of Human umbilical vein endothelial cells Boyden cell
Purpose and principle: Boyden migration experiment is separated into two parts based on the Boyden cell by micropore.Cell places top part, following part contains chemokine, and under the inducing of chemokine, last confluent monolayer cells can pass the bottom that microporous membrane migrates to film, and being attached to the back side of film, the influence of microporous membrane ability can detection of drugs be passed in this experiment to endotheliocyte.
Method: with gelatin with cell bag quilt, in the incubator 37 ℃ hatch after, abandon gelatin.Add the cell culture medium that contains VEGF in outer six orifice plates of cell, insert cell in the cell, after in incubator, hatching four hours, all nutrient solutions are inhaled go, cell is fixing in Paraformaldehyde 96, give a baby a bath on the third day after its birth time with PBS, hematoxylin eosin stain, with washing lotion with the excess dyestuff flush away, the microscopically counting of taking pictures, statistic data.
Result and evaluation: compare with control group, give Kp-10 after, the ability that Human umbilical vein endothelial cells is passed the Boyden cell is suppressed, and illustrates that Kp-10 can suppress the ability that endotheliocyte passes microporous membrane, same experiment is carried out three times at least.
Experiment embodiment 4:Kp-10 suppresses Human umbilical vein endothelial cells and becomes pipe
Purpose and principle: Matrigel is the capacitive basilar membrane extract that extracting obtains from murine sarcoma, be rich in extracellular matrix protein, Human umbilical vein endothelial cells can attach into pipe on Matrigel, can utilize this one-tenth pipe characteristic of Human umbilical vein endothelial cells on Mtrigel to study medicine becomes pipe to endotheliocyte influence.
Method: Matrigel is taped against on 48 orifice plates, places in incubator and treated that it solidified in 30 minutes.Every hole adds endotheliocyte, adds the substratum that contains different concns Kp-10 peptide again, examines under a microscope microtubule after the overnight incubation and form situation in 37 ℃ of 5% incubator.Different sites is selected in every hole, calculates microtubule and forms quantity and carry out statistical analysis, and same experiment is carried out three times at least.
Result and evaluation: after the grow overnight, individual cells extends to form tridimensional network to endotheliocyte in Matrigel.Result's demonstration is compared with control group, gives after the Kp-10, and endotheliocyte becomes the pipe process to be affected, and fails to form complete reticulated structure, illustrates that Kp-10 can suppress the human microvascular endothelial cell (mvec) microtubule and form.
Embodiment 5:Kp-10 suppresses the chick chorioallantoic membrane new vessel and forms
Purpose and principle: the chick embryo allantois membrane modle is to generally acknowledge comparatively ideal angiogenesis class medicaments sifting model both at home and abroad at present, and characteristics are that experimental cost is low, and directly perceived, data are reliable.The carrier that will contain medicine places the avascular area on fertilization chick chorioallantoic membrane surface, can be observed the influence that medicine generates new capillary blood vessel.
Method: the chicken embryo of fertilization is placed incubator hatching 5 days, in Bechtop, use the alcohol wipe surface, open an osculum at chicken ovigerm shell blunt end, the Kp-10 that will contain different amounts is added on the filter paper of sterilization, filter paper is added on the chorioallantoic membrane, seals, put into incubator and continue to hatch with scotch tape.
Result and evaluation: hatch two days later, throw off scotch tape, under stereoscopic microscope, take pictures, with newborn microvessel quantity in certain annular extent around the computed in software filter paper, statistics, result's demonstration and control group are relatively, add after the Kp-10, newborn capillary blood vessel generates comparatively small amt, illustrates that Kp-10 can suppress the angiogenesis of chick chorioallantoic membrane, and every group of chicken embryo quantity is 8-10.
Experiment embodiment 6:Kp-10 suppresses the mouse cornea rebirth blood vessel
Purpose and principle: in order to prove conclusively of the influence of further conclusive evidence Kp-10 peptide to angiogenesis, we have also used, and other body inner model---the mouse cornea model is checked, though operate meticulous, but this model is one of gold standard of present world research angiogenesis, because the mouse cornea is an avascular area territory, the blood vessel that induces on cornea all is a new vessel, its principle is: make a pouch on the mouse cornea, implantation contains the slow-releasing granules of vascular endothelial growth factor (VEGF), can induce the blood vessel of depositing Gong Yuan place, angle to grow to the pouch of the slow-releasing granules that contains vascular endothelial growth factor (VEGF).On slow-releasing granules, add VEGF and Kp-10 peptide simultaneously, observe these inductive blood vessel areas and whether change.
Method: with the C57/BL6 mouse anesthesia, open an osculum on the mouse cornea, implant the particle that contains Kp-10 and VEGF+Kp-10 then, a week, observations are then continued to raise in the experiment back.
Result and evaluation: Kp-10 can suppress by vascular endothelial growth factor slow-releasing granules inductive new vessel, and every group of cornea mouse is 7-8.
Claims (13)
1. a decapeptide inhibiting angiogenesis is characterized in that aminoacid sequence is YNWNSFGLRF, and molecular weight is 1303.4.
2. decapeptide inhibiting angiogenesis according to claim 1, it is characterized in that comprising amino acid sequence homology 70% and more than the variant or derivatives thereof.
3. decapeptide inhibiting angiogenesis according to claim 1, it is characterized in that comprising genome sequence that it is corresponding and homology thereof 70% and more than the variant or derivatives thereof;
4. the described decapeptide inhibiting angiogenesis of claim 1 to 3 treats and/or prevents application in the medicine of angiogenesis disease in preparation.
5. the application of decapeptide inhibiting angiogenesis as claimed in claim 4 is characterized in that being prepared into the pharmaceutical composition that contains this decapeptide inhibiting angiogenesis.
6. the application of decapeptide inhibiting angiogenesis as claimed in claim 4 is characterized in that the angiogenesis disease comprises tumour, sacroiliitis, illness in eye, vascular tumor, psoriatic.
7. the application of decapeptide inhibiting angiogenesis as claimed in claim 6 is characterized in that sacroiliitis is rheumatoid arthritis and inflammatory arthritis.
8. the application of decapeptide inhibiting angiogenesis as claimed in claim 6 is characterized in that illness in eye comprises neovascular keratopathy, retinal diseases, iris disease, glaucoma, choroid, cataract, vitreum illness in eye, optic nerve disease.
9. the application of decapeptide inhibiting angiogenesis as claimed in claim 8 is characterized in that retinal diseases is diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity or retinal arterial obstruction.
10. the application of decapeptide inhibiting angiogenesis as claimed in claim 8 is characterized in that choroidopathy is moist old maculopathy.
11. the application of decapeptide inhibiting angiogenesis as claimed in claim 6 is characterized in that tumour comprises primary and insecondary tumour.
12. the application of decapeptide inhibiting angiogenesis as claimed in claim 6 is characterized in that vascular tumor comprises angiomatosis, hemangioblastoma and optimum blood vessel hyperplasia disease.
13. the application of decapeptide inhibiting angiogenesis as claimed in claim 4, it is characterized in that anti-angiogenic drugs is the medicine that suppresses Kaposi ' s sarcoma pathology tissue blood vessel new life, the medicine that suppresses leukemia, lymphoma, myelomatosis hematologic cancers, and the medicine that suppresses Paget ' s disease.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103992376A (en) * | 2013-02-18 | 2014-08-20 | 上海市第一人民医院 | Novel small peptides inhibiting new vessels and application |
| CN103992377A (en) * | 2013-02-18 | 2014-08-20 | 上海市第一人民医院 | Novel small peptides inhibiting new vessels and application |
| CN105859833A (en) * | 2015-01-23 | 2016-08-17 | 上海市第人民医院 | Polypeptide for inhibition of blood vessel neogenesis or growth and application thereof |
| CN113058026A (en) * | 2021-04-02 | 2021-07-02 | 华东师范大学 | Application of Kisspeptin-234 in promoting hair growth |
-
2009
- 2009-03-02 CN CNA2009100468735A patent/CN101597324A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103992376A (en) * | 2013-02-18 | 2014-08-20 | 上海市第一人民医院 | Novel small peptides inhibiting new vessels and application |
| CN103992377A (en) * | 2013-02-18 | 2014-08-20 | 上海市第一人民医院 | Novel small peptides inhibiting new vessels and application |
| CN103992377B (en) * | 2013-02-18 | 2017-05-17 | 上海市第一人民医院 | Small peptides inhibiting new vessels and application |
| CN103992376B (en) * | 2013-02-18 | 2017-05-17 | 上海市第一人民医院 | Small peptides inhibiting new vessels and application |
| CN105859833A (en) * | 2015-01-23 | 2016-08-17 | 上海市第人民医院 | Polypeptide for inhibition of blood vessel neogenesis or growth and application thereof |
| CN105859833B (en) * | 2015-01-23 | 2019-08-13 | 上海市第一人民医院 | Polypeptide and its application of a kind of angiogenesis inhibiting or growth |
| CN113058026A (en) * | 2021-04-02 | 2021-07-02 | 华东师范大学 | Application of Kisspeptin-234 in promoting hair growth |
| CN113058026B (en) * | 2021-04-02 | 2022-07-05 | 华东师范大学 | Application of Kisspeptin-234 in promoting hair growth |
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Open date: 20091209 |