CN105709211A - Preparation and application of analgesic active peptide SYPU-AGP3 and SYPU-AGP4 - Google Patents
Preparation and application of analgesic active peptide SYPU-AGP3 and SYPU-AGP4 Download PDFInfo
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Abstract
The invention relates to the technical field of biological medicine, and mainly relates to preparation and application of analgesic active peptide SYPG-AGP3 and SYPU-AGP4, in particular to a preparation method of obtaining analgesic active peptide SYPG-AGP3 and SYPU-AGP4 by the utilization of a genetic engineering technology and application of analgesic active peptide SYPG-AGP3 and SYPU-AGP4 in preparation of analgesic medicine.The analgesic active peptide SYPG-AGP3 and SYPU-AGP4 and a pharmaceutically acceptable carrier are mixed to prepare a clinically acceptable injection, or an oral preparation, or a percutaneous absorption preparation, or a mucosa absorption preparation or others used for all kinds of pains.The analgesic active peptide SYPG-AGP3 and SYPU-AGP4 have good analgesic activity, the obtaining method is conventional and simple, and the yield is high.
Description
Technical field:
The present invention relates to biomedicine technical field, relate to antalgic active peptide SYPU-AGP3 and SYPU-AGP4 and it obtains
Obtain method and application, specifically, the present invention relates to antalgic active peptide SYPU-AGP3 and SYPU-AGP4, with and preparation method thereof
With as analgesic application in field of medicaments.
Background technology:
(the Molecular characterization of a possible progenitor sodium such as Zhu Shunyi
Channel toxin from the Old World scorpion Mesobuthus martensii, Shun Yi Zhu,
2006) peptide species from Scorpio was described in 2006, possibly as ancestors' scorpion venom of modulators of ion channels
Polypeptide Mesotoxin.In this document, experimental data does not proves that Mesotoxin is α-toxin, the most real
Test data and prove that its function is to block sodium-ion channel, the most more do not have experimental data explanation Mesotoxin to have analgesia biology
Activity.
(the Molecular dissection of venom from Chinese scorpion such as Zeng Xianchun
Mesobuthus martensii:Identification and characterization of four novel
Disulfide-bridged venom peptides, Xian Chun Zeng, 2006) described from East Asia pincers in 2006
The one peptide species BmKBTx of scorpion, thus it is speculated that this polypeptide may be modulators of ion channels, can produce mammal or insecticide
Toxicity.In this document, experimental data does not proves that BmKBTx is β-toxin, does not the most also have experimental data to prove its merit
Can be to block sodium-ion channel, the most more not have experimental data explanation BmKBTx to have analgesia biological activity.
The aminoacid of Mesotoxin and BmKBTx and disulfide bond composition show the most special with known long Streptomycin
Property (both comprises only three pairs of disulfide bond, and the long Streptomycin of most of scorpion venom contains four pairs of disulfide bond).
Many Buthotoxin polypeptide correlational studyes not mentioned analgesic activities, not directly related with analgesic activities about toxicity yet
Report.According to the literature: some toxin and the closely-related site of toxicity (Lqh α IT, Important for Receptor
Site Recognition, Noam Zilberberg, 1997), to similar toxin-scorpion arialgesic antitumoral peptide (BmK
AGAP) analgesic activities (such as the 8th) uncorrelated.
According to the literature, scorpion venom long-chain alpha-toxin (or claiming alpha-neurotoxin) is divided into α-mammal (god to root
Warp) toxin, class α (neural) toxin and α-insecticide (neural) toxin.As its name suggests, suckling is moved by α-mammal (neural) toxin
Thing is sensitive, and the toxin of relatively low-dose just can make mammal (such as mice) dead；In like manner, α-insecticide (neural) toxin on insects
Sensitivity, the toxin of relatively low-dose just can make insect death；And class α (neural) toxin is the most toxic to mammal and insecticide.
The article that many delivers is had to inquire into α-mammal (neural) toxin to the molecular mechanism of mammalian toxicity and work both at home and abroad
Use specific molecular mechanism, but do not think that Anti mammals Neurotoxins from Scorpion Buthus martensii Karsch can be as the routine of analgesics
Technological means.The conotoxin having listed use the most both at home and abroad only has ziconotide based on N-type calcium as analgesics
The new type analgesic of ion channel.Another patent of invention scorpion analgesia of one of inventor herein Zhang Jinghai application is anti-swollen
Tumor Val-Arg-Gly peptide and preparation method, obtained State Intellectual Property Office of the People's Republic of China mandate (license number:
ZL01128235.5), this patent of invention also obtain PCT, the U.S. (US 7,592,309B2) and European Union (EP 1443053B1)
Mandate.Foregoing invention patent, is isolated and purified from scorpion and the bioactive peptide of analytic structure, belongs to scorpion long-chain poison in terms of structural analysis
Element α family neurotoxin.To sum up, researcher or those skilled in the art can not be from structure prediction or think many from scorpion venom
In peptide, the polypeptide of purification is respectively provided with analgesic activities, and is only studied by Making Innovation Experiments and Research experiment data validation mesh
Whether mark polypeptide has analgesic activities.
Summary of the invention:
It is an object of the invention to provide Making Innovation Experiments research and Research experiment data validation Mesotoxin (SYPU-thereof
And BmKBTx (SYPU-AGP4) has analgesic activities and it is prepared AGP3).
The present invention utilizes biotechnology, it is thus achieved that Mesotoxin and BmKBTx；Studied by vivo bioactivity and test
As a result, find first and confirm that polypeptide Mesotoxin and BmKBTx has analgesic activities, therefore by its named antalgic active peptide
SYPU-AGP3 and SYPU-AGP4；Antalgic active peptide SYPU-AGP3 (Mesotoxin) and the acquisition of SYPU-AGP4 (BmKBTx)
Method is simple, can be mixed with medically acceptable dosage form with respective carrier.The present invention is to utilize biotechnology or change
Learn synthetic technology, it is thus achieved that antalgic active peptide SYPU-AGP3 and SYPU-AGP4.
Specifically, the present invention is achieved through the following technical solutions, and it includes: utilizes technique for gene engineering to obtain analgesia
Bioactive peptide SYPU-AGP3 and SYPU-AGP4, by analgesic activities in the laboratory animal body of acquisition expression product, permissible to obtain
Develop antalgic active peptide-antalgic active peptide SYPU-AGP3 and SYPU-AGP4 of analgesic drug further.Of the present invention
Preparation method is conventional, simple, yield is high, not only has important directive significance and practical value, also establishes for industrialized production
Basis.
It is a further object to provide the preparation method of antalgic active peptide SYPU-AGP3 and SYPU-AGP4, its bag
Include: utilize technique for gene engineering to carry out expressing or being obtained by chemosynthesis.Technique for gene engineering method includes:
(1) the coding DNA of antalgic active peptide SYPU-AGP3 and SYPU-AGP4 is recombinated to expression vector；
(2) convert suitable host cell (protokaryon or eukaryotic cell) with step recombinant expression carrier (1)；
(3) under the conditions of applicable abduction delivering, the incubation step host cell being converted (2)；
(4) the expression product obtained by results also purification.
The present invention provides the expression product isolation and purification method of above-mentioned antalgic active peptide SYPU-AGP3 and SYPU-AGP4.Can
Use the methods such as salt precipitation, ultrafiltration, ion-exchange chromatography, hydrophobic interaction chromatography and gel filtration, from the lysate of cell
And in culture fluid separate and purification needed for expression product.In the separation and purge process of expression product, dodecane can be used
Base sodium sulfonate-polyacrylamide gel electrophoresis (SDS-PAGE), enzyme linked immunosorbent assay (ELISA) or detected by Western blot
(WESTERN) existence of expression product and corresponding molecular size are detected.
The present invention carries out the internal analgesia biologic activity of above-mentioned antalgic active peptide SYPU-AGP3 and SYPU-AGP4 first
Experiment.
Present invention also offers above-mentioned antalgic active peptide SYPU-AGP3 and the SYPU-AGP4 application in field of biological pharmacy,
Specifically ease pain biological activity.
It is also another object of the present invention to provide containing protein as defined above and one or more are pharmaceutically acceptable
Carrier or the pharmaceutical composition of excipient.Can prepare according to basic principle known to art of pharmaceutical industry and method and be suitable to gastrointestinal
Outside road, the pharmaceutical composition of administration (such as sees Remington ' s Pharmaceutical Science, 15th., Mack
Publishing Company,1980).Can be by various route of administration, particularly intravenous, intramuscular, intraarticular, abdominal cavity
In, intranasal, Intradermal, the parenteral routes such as subcutaneous come into operation the pharmaceutical composition of the present invention.
It is a further object to provide the protein as defined above application in producing analgesic.Can use
The protein of the present invention or the pharmaceutical composition containing this protein are as therapeutic agent, for treating the various of particular type human body
Pain related disorders.The treatment effective dose of the pharmaceutical composition of the present invention typically should according to the character of disease, the order of severity and
Sensitive adaptability to medicine, and the factors such as route of administration determines according to principle of individuation by clinician.
In the present invention, term " host cell " includes prokaryotic cell and eukaryotic cell, conventional prokaryotic host cell
Example includes escherichia coli, bacillus subtilis etc..Conventional eukaryotic host cell includes yeast cells, insect cell and mammal
Cell etc..
Detailed description of the invention:
The following examples can make those skilled in the art the present invention is more fully understood rather than limits by any way
The present invention processed gives special approval to the scope of claim.
Embodiment 1:
Antalgic active peptide SYPU-AGP3 and the acquisition of SYPU-AGP4 gene
The present embodiment describes for expressing acquisition antalgic active peptide SYPU-AGP3 of the present invention and the base of SYPU-AGP4 gene
This method.
Sequence (Genbank serial number: DQ872676) according to SYPU-AGP3, (underscore is design forward primer 3F
Nde I restriction enzyme site)；Downstream primer 3R (underscore is EcoR I restriction enzyme site), is specifically shown in following table.Scorpion is built with this laboratory
Tail cDNA is template, and primer 3F and 3R carries out PCR and expand SYPU-AGP3 gene, and condition is: 94 DEG C of 5min；94 DEG C of 30s, 55 DEG C
45s, 72 DEG C of 45s, 30 circulations；72℃5min.
Sequence (Genbank serial number: AF151798) according to SYPU-AGP4, (underscore is design forward primer 4F
Nde I restriction enzyme site)；Downstream primer 4R (underscore is EcoR I restriction enzyme site), is specifically shown in following table.With scorpion tail cDNA as mould
Plate, primer 4F and 4R carries out PCR and expands SYPU-AGP4 gene, and condition is: 94 DEG C of 5min；94 DEG C of 30s, 50 DEG C of 45s, 72 DEG C
45s, 30 circulations；72℃5min.
According to antalgic active peptide SYPU-AGP3 (ID:1) and the aminoacid sequence of SYPU-AGP4 (ID:2) and gene sequence thereof
Row, utilize conventional gene engineering, use RT-PCR method amplify from the scorpion cDNA that laboratory builds SYPU-AGP3 with
The gene of SYPU-AGP4, the aminoacid sequence of antalgic active peptide SYPU-AGP3 and SYPU-AGP4 is respectively as follows:
VKDRFLIINGSYELCVYAENLGEDCENLCKQQKATDGFCRQPHCFCTDMPDDYATR PDTVDPIM (ID:
1)；
DDDPGNYPTNAYGNKYYCTILGENEYCRKICKLHGVTYGYCYNSRCWCEKLEDKDV TI (ID:2).
Embodiment 2:
The acquisition of antalgic active peptide SYPU-AGP3 and SYPU-AGP4
1. antalgic active peptide SYPU-AGP3 and the structure of SYPU-AGP4 gene
The present embodiment enumerates description for expressing antalgic active peptide SYPU-AGP3 of the present invention and the structure of SYPU-AGP4 gene
Build strategy.
N-terminal according to antalgic active peptide SYPU-AGP3 and SYPU-AGP4 (structure is as follows) and C-terminal aminoacid sequence,
Separately design corresponding oligonucleotide primers, simultaneously at 5 ' ends of above-mentioned two oligonucleotide primers, respectively plus respective restriction
Property Cobra venom endonuclease hydrolytic sites sequence, in order to the enforcement of gene recombinaton；The antalgic active peptide SYPU-obtained with embodiment 1
AGP3 and SYPU-AGP4 gene is that template carries out PCR amplification, and agarose gel electrophoresis detection product also carries out the solidifying of nucleic acid fragment
Glue reclaims；After the above-mentioned restriction endonuclease double digestion mentioned with as carry out the plasmid of double digestion at T4DNA
Carry out restructuring under the effect of ligase to connect, thermal transition competent escherichia coli cell DH 5 α, through bacterium colony PCR and restricted
The screening of Cobra venom endonuclease digestion verification submits to biotechnology service company to carry out determined dna sequence after obtaining positive transformant.Knot
Fruit shows, successfully builds antalgic active peptide SYPU-AGP3 and SYPU-AGP4 by the method for said gene engineering and expresses restructuring load
Body.
2. the acquisition of antalgic active peptide SYPU-AGP3 and SYPU-AGP4
Utilize technique for gene engineering, by the gene recombinaton of antalgic active peptide SYPU-AGP3 and SYPU-AGP4 to escherichia coli
In expression plasmid, extract plasmid and check order.
The architectural feature of this recombinant expression plasmid coding expression product is: MHHHHHHMVKDRFLIINGSYELCVYAENLG
EDCENLCKQQKATDGFCRQPHCFCTDMPDDYATRPDTVDPIM；MHHHHHHMDDDPGNYPTNAYGNKYYCTILGENEY
CRKICKLHGVTYGYCYNSRCWCEKLEDKDVTI。
By positive recombiant plasmid thermal transition e. coli bl21 (λ DE3), then from this LB solid plate (containing corresponding screening
Antibiotic) it is seeded to 3ml LB (containing corresponding antibiotic) after upper picking list bacterium colony, in 37 DEG C, 200r/min shaken overnight is cultivated.
According to 1% inoculum concentration, overnight culture is seeded in the triangular flask of the 400ml fresh LB containing corresponding antibiotic, in 37
DEG C, 200r/min shaken cultivation to OD600 is 0.6-0.8, add the inducer isopropyl-β of final concentration of 0.166mmol/L-
D-thiogalactoside (IPTG), cultivates 4h.Terminate fermentation, 3000g, 4 DEG C of centrifugal 20min, collect thalline.Slow with 40ml cracking
Rush liquid (0.1M PBS, 0.5M NaCl) resuspended thalline, carry out ultrasonication, in 12 after ultrasonic end, 000g, 4 DEG C be centrifuged
20min, obtains supernatant, and gained precipitation repeats to crush once according to above-mentioned steps, merges twice supernatant, be directly splined on 0.1M
PBS (pH 8.0,0.5M NaCl) the metal ion-chelant chromatographic column that pre-balance is good, buffers through the pH of two different phases
After liquid respectively fully 5 bed volumes of washing, 0.1M PBS (pH 3.0,0.5M NaCl) is used to carry out eluting and gather in the crops this and wash
De-liquid.Products therefrom verifies its purity through 15%SDS-PAGE.Illustrated by column chromatography chromatogram figure and SDS-PAGE collection of illustrative plates, restructuring
Protein obtains high efficient expression, reaches electrophoresis purity.The expression product of above-mentioned acquisition, utilizes chemical method to rupture at M peptide chain, from
And obtaining antalgic active peptide SYPU-AGP3, architectural feature is: VKDRFLIINGSYELCVYAENLGEDCENLCKQQKATDGFCR
QPHCFCTDMPDDYATRPDTVDPIM；Obtaining antalgic active peptide SYPU-AGP4, architectural feature is: DDDPGNYPTNAYGNKYY
CTILGENEYCRKICKLHGVTYGYCYNSRCWCEKLEDKDVTI。
Embodiment 3:
Internal analgesic activities mice acetic acid writhing test
By analgesic model in Mice Body, the present embodiment determines that antalgic active peptide SYPU-AGP3's and SYPU-AGP4 is internal
Biological activity-analgesic activities.In addition it is also intended to verify the analgesic activities of antalgic active peptide SYPU-AGP3 and SYPU-AGP4.Albumen
Concentration uses Lowry method to be measured.
Mice acetic acid writhing test analgesic model: glacial acetic acid is injected Kunming mouse intraperitoneal as chemical irritant, continues
And cause deep, large area and more lasting pain stimulation, cause mice produce " writhing " reaction (abdominal part indent, trunk with
Back leg extension, hips up).
18-22g Kunming mouse, male and female half and half, random packet, often group 8, tail vein injection sample, press after 20min
0.2ml/20g lumbar injection 0.6% (v/v) acetic acid causes Encelialgia, records the writhing number of times in mice 10min after 5min.Raw
Reason saline is blank, calculates the writhing response suppression ratio of administration group according to the following equation.
Analgesia biological activity test result shows:
1. normal saline blank group laboratory animal writhing number of times (Mean ± SEM) is 44.7 ± 2.27.
2. the laboratory animal writhing response suppression ratio that antalgic active peptide SYPU-AGP3 (dosage, 0.5mg/kg) organizes is
62.9%, relative to normal saline, SYPU-AGP3 has the biological activity that significantly eases pain.
3. the laboratory animal writhing response suppression ratio that antalgic active peptide SYPU-AGP4 (dosage, 0.5mg/kg) organizes is
43.5%, relative to normal saline, SYPU-AGP4 has the biological activity that significantly eases pain.
Claims (8)
1. antalgic active peptide SYPU-AGP3 and SYPU-AGP4 application in preparing analgesic, it is characterised in that described
The aminoacid sequence of SYPU-AGP3 polypeptide as shown in ID:1, the aminoacid sequence such as ID:2 institute of described SYPU-AGP4 polypeptide
Show.
Application the most according to claim 1, it is characterised in that the N-end of described antalgic active peptide SYPU-AGP3
These six cysteine residues of 15, the 25th, the 29th, the 39th, the 44th and the 46th are its analgesic activities conservative half
Guang amino acid residue.
Application the most according to claim 1, it is characterised in that the N-end of antalgic active peptide SYPU-AGP4 the 18th,
These six cysteine residues of 27, the 31st, the 41st, the 46th and the 48th are that its analgesic activities guards half Guang aminoacid
Residue.
4. according to the application described in claim 1-3 any one, it is characterised in that described antalgic active peptide SYPU-AGP3
The most acceptable injection, oral formulations, transdermal can be mixed with pharmaceutically acceptable carrier with SYPU-AGP4
Absorbable preparation, mucous absorption preparation.
5. the preparation method of antalgic active peptide SYPU-AGP3 and SYPU-AGP4, utilizes technique for gene engineering to carry out expressing acquisition,
It is characterized in that, expression host cell is prokaryotic cell or eukaryotic cell.
6. preparation method as claimed in claim 5, it is characterised in that
(1) the coding DNA of antalgic active peptide SYPU-AGP3 and SYPU-AGP4 is recombinated to expression vector；
(2) convert suitable host cell with step recombinant expression carrier (1)；
(3) under the conditions of applicable abduction delivering, the incubation step host cell being converted (2)；
(4) the expression product obtained by results also purification.
7. preparation method as claimed in claim 5, it is characterised in that described prokaryotic cell is escherichia coli or bacillus subtilis, described
Eukaryotic cell be yeast cells, insect cell or mammalian cell.
8. the preparation method of antalgic active peptide SYPU-AGP3 and SYPU-AGP4, utilizes chemical synthesising technology to obtain, and its feature exists
In, described chemosynthesis is synthetic or synthesizer synthesis.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109106942A (en) * | 2018-09-18 | 2019-01-01 | 北京大学深圳研究生院 | Application of polypeptide capable of passing blood brain barrier in preparation of medicine |
| CN109748961A (en) * | 2017-11-01 | 2019-05-14 | 沈阳药科大学 | The preparation and application of antalgic active peptide DKK mutant and its derivative |
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| CN101591668A (en) * | 2009-07-01 | 2009-12-02 | 江苏省中医药研究院 | The production method of Buthus martensii Karsch toxin AGAP |
| CN103304630A (en) * | 2012-03-07 | 2013-09-18 | 中国科学院大连化学物理研究所 | GPCR active polypeptide in scorpion venom of Buthus martensii Karsch, and extracting separation and application thereof |
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| WO2000024772A2 (en) * | 1998-10-23 | 2000-05-04 | E.I. Du Pont De Nemours And Company | Scorpion toxins |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109748961A (en) * | 2017-11-01 | 2019-05-14 | 沈阳药科大学 | The preparation and application of antalgic active peptide DKK mutant and its derivative |
| CN109748961B (en) * | 2017-11-01 | 2022-02-15 | 沈阳药科大学 | Preparation and application of analgesic active peptide DKK mutant and derivative thereof |
| CN109106942A (en) * | 2018-09-18 | 2019-01-01 | 北京大学深圳研究生院 | Application of polypeptide capable of passing blood brain barrier in preparation of medicine |
| WO2020056988A1 (en) * | 2018-09-18 | 2020-03-26 | 深圳瑞健生物科技有限公司 | Use of polypeptide capable of passing through blood-brain barrier in the preparation of drug |
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