CN102250253A - Fusogenic peptide containing thrombin fragment - Google Patents
Fusogenic peptide containing thrombin fragment Download PDFInfo
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- CN102250253A CN102250253A CN2010101733730A CN201010173373A CN102250253A CN 102250253 A CN102250253 A CN 102250253A CN 2010101733730 A CN2010101733730 A CN 2010101733730A CN 201010173373 A CN201010173373 A CN 201010173373A CN 102250253 A CN102250253 A CN 102250253A
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Abstract
The invention relates to a novel thrombin fragment fusogenic peptide S-TP508 which is obtained by adding a section of stable peptide on the N end of TP508 (the section of stable peptide mainly comprises glutamine and arginine). The fusogenic peptide S-TP508 added with the stable peptide has prolonged half-life period compared with the TP508, overcomes the defect of easiness of enzymolysis of the TP508 and enhances the stability. The invention also relates to a medical composite containing the S-TP508 and application thereof to preparing drugs for treating skin tissue injury and corneal injury.
Description
One. technical field
The present invention relates to new zymoplasm fragment fusogenic peptide S-TP508.The invention still further relates to the pharmaceutical composition that contains described S-TP508.The invention still further relates to described S-TP508 and be used to prepare the purposes for the treatment of skin histology damage and corneal injury medicine.The invention still further relates to the method for the disease of utilizing described S-TP508 treatment skin histology damage and corneal injury.
Two. background of invention
Zymoplasm is a kind of serine protease that is transformed by thrombogen (Porthormbin), main effect in vivo is that the catalysis fibre proteinogen is transformed into scleroproein, reactions such as induced platelet adhesion, gathering and release, be hematoblastic strong inductor, thereby in blood coagulation, play an important role.Prove that now zymoplasm also can stimulate inoblast, epidermal cell proliferation etc. except its blood coagulation effect, also playing an important role aspect the promotion wound healing.
TP508 (thrombin receptor activating peptide) is a fragment of taking from the 508th～530 amino-acid residue of human thrombin original molecule sequence, but discover high affinity thrombin receptor with specificity activating cells surface, irritation cell division and chemotactic, participate in tissue repair, the function of irritation cell hyperplasia and promotion wound healing.
Because TP508 is the small peptide (seeing that sequence is a 12-34 amino acids sequence among the SEQ ID NO:1) that has only 23 amino acid to form, so the transformation period is short, poor stability.Thereby we have added one section stabilized peptide (seeing that sequence is a 1-11 amino acids sequence among the SEQID NO:1) at the N of TP508 end, and this section stabilized peptide mainly is made up of glutamine and arginine.This fusion rotein that adds stabilized peptide has prolonged the transformation period than TP508, has improved stability.As the medicine that applies to human body, overcome TP508 easily by the weakness of acidolysis, have and improve drug effect, reduce patient's dosage, extend the expiration date, reduce significant social and economic benefit such as cost.
The TP508 molecular weight is very little, and the transformation period is very short.This patent is added to the N end of TP508 by the short peptide sequence that has a stabilization function with a section, has improved the transformation period significantly, and stability also significantly improves.This patent is transformed TP508 and mainly contained following reason: (one) TP508 molecular weight ratio is less, and the transformation period weak point can solve the problem of the fracture of peptide bond acidolysis herein preferably.(2) by to the simulation of the secondary structure of fusogenic peptide and according to the data of literatures report, find to have added that stabilized peptide can not influence the formation of its secondary structure of TP508 and tertiary structure that it is bioactive stable promptly to guarantee to transform back TP508.
Three. summary of the invention
One aspect of the present invention relates to a kind of zymoplasm fragment fusogenic peptide, and it is the S-TP508 shown in the SEQ ID NO:1.
As the fusion rotein among the present invention, be the artificial protein that a class nature does not have, it is characterized by the fusion rotein that stabilized peptide and TP508 form, can use a kind of sequence with SEQ ID NO1 in the sequence table, also can use sequence table SEQ ID
The aminoacid sequence of fusion rotein is modified among the NO1, and as inserting, disappearance is suddenlyd change certain or some amino acid and the sequence that obtains, as long as the basic biological activity that keeps original molecule.In other words, also can use adopt its aminoacid sequence substantially with sequence table SEQ ID NO1 in the identical albumen of fusion rotein aminoacid sequence, promptly use aminoacid sequence to have variant or its functional fragment more than or equal to 90% sequence identity.
Those of ordinary skills know, and described S-TP508 can be by the method for dna recombinant expression or the method preparation of chemosynthesis.In the present invention, described S-TP508 obtains by the recombinant expressed method of genetically engineered.
In one embodiment of the invention, obtain S-TP508 by the following method, comprise the steps:
1) structure of expression vector
According to known S-TP508 aminoacid sequence (SEQ ID NO:1), select for use the full gene of intestinal bacteria preference codon to synthesize target gene sequences, simultaneously add restriction enzyme site, obtain the nucleotide sequence of S-TP508 at N-terminal and C-terminal corresponding to coded aminoacid sequence.To handle well with restriction enzyme as the target gene sequences and the screening plasmid pBSK of above-mentioned preparation respectively again, press certain mol proportion as calculated behind each sample concentration and add the T4 linked system.Through the recon that transforms, screening is successful.
Downcut goal gene with Restriction Enzyme, (this plasmid is the kalamycin resistance selection markers with the plasmid pGM of this institute that handles well with Restriction Enzyme with this gene again, energy great expression GST class fusion rotein is that this institute makes up) connect, obtain recon correctly through screening.
2) expression of target protein and separation and purification
To be transformed into the expressive host bacterium as above-mentioned gained recon, go out the cance high-expression gene engineering bacteria,, obtain the engineering bacteria of target protein high expression level then through fermentation through expression screening.High-pressure homogeneous crusher machine bacterium also centrifugally obtains containing purpose precursor protein supernatant liquor, with sample on the supernatant liquor to the GST affinity column, wash-out purpose precursor protein and cut with the proteolytic enzyme enzyme after, again sample is further purified by anion column, make final purity of protein greater than 98% end product.
Another aspect of the present invention relates to a kind of pharmaceutical composition, and it contains S-TP508 of the present invention, and optional pharmaceutically acceptable carrier.
Know that in the present invention term " pharmaceutically acceptable " means the animal that can be used for that pharmacy field generally acknowledges, more particularly can be used for the people's.Term " carrier " refers to thinner, adjuvant (for example (fully or not exclusively) freund's adjuvant), vehicle or be used to holds or the medium of administering therapeutic agent.
These pharmaceutical carriers can be sterile liquids, such as water and oil, comprise being derived from oil, animal, plant or synthetic oil, such as peanut oil, soybean oil, mineral oil, sesame oil, like that.When intravenously was used medicinal compositions, water was preferred carrier.Salt brine solution and aqueous dextrose and glycerine solution also can be used as liquid carrier, especially for Injectable solution.Suitable pharmaceutical excipient comprises starch, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talcum, sodium-chlor, milk powder, glycerine, propylene, ethylene glycol, water, ethanol, like that.If desired, composition can also comprise the wetting or emulsifying agent such as the hyaluronate sodium of lesser amt, or the pH buffer reagent.These compositions can be taked solution, suspension, milk sap, tablet, pill, capsule powder, slowly-releasing prescription, suchlike form.
In one embodiment of the invention, described pharmaceutical composition is the freeze dried injection form, wherein contains the S-TP508 of 0.01%-0.2%, and 5% N.F,USP MANNITOL, and pharmaceutically acceptable carrier.
Medicinal compositions of the present invention is mixed with to use the path compatible with its purpose.The example of using the path includes but not limited to parenteral, for example (for example sucking) in intravenously, intracutaneous, subcutaneous, oral cavity, the nose, through skin (for example local), through mucous membrane and rectal administration.In a specific embodiments, be mixed with composition in suitable intravenously, subcutaneous, intramuscular, oral cavity, the nose or be locally applied to human medicinal compositions according to old process.Usually, being used for the composition that intravenously uses is the solution of sterile isotonic water-based damping fluid.If desired, composition can also comprise solubilizing agent and local anesthetic such as Ergotamine to alleviate the pain of injection site.
In one embodiment of the invention, described composition is an eye drop, wherein contains the S-TP508 of 50-500 μ g/ml, and the microbiotic that is selected from paraxin or Ofloxacine USP 23, and pharmaceutically acceptable carrier; In another embodiment of the present invention, described composition is an eye drop, wherein contains the S-TP508 of 50-500 μ g/ml, an amount of hyaluronate sodium, and pharmaceutically acceptable carrier; In another embodiment of the present invention, described composition is an eye drop, wherein contains the S-TP508 of 50-500 μ g/ml, an amount of hyaluronate sodium, paraxin or Ofloxacine USP 23, and pharmaceutically acceptable carrier.
If want topical application composition of the present invention, then composition can be mixed with form or well-known other form of those skilled in the art of ointment, emulsifiable paste, skin subsides, lotion, gel, shampoo, sprays, aerosol, solution, emulsion.Consult for example " Lei Mingdunshi pharmaceutical science and pharmaceutical dosage form introduction " (Remington ' s Pharmaceutical Sciences andIntroduction to Pharmaceutical Dosage Forms), the 19th edition, Mack publishing company, Easton, the Pennsylvania, nineteen ninety-five.
For non-sprayable local dose form, usually adopt the viscosity that comprises the carrier compatible or one or more vehicle and have the dynamic viscosity that is preferably greater than water to semisolid or solid form with topical application.Suitable prescription includes but not limited to solution, suspension, milk sap, emulsifiable paste, ointment, pulvis, liniment, ointment, like that, if desired, be aseptic or mixed to change various characteristics, such as for example osmotic pressure with auxiliary reagent (for example sanitas, stablizer, wetting agent buffer reagent or salt).Other suitable local dose form comprises sprayable aerosol formulation, and the activeconstituents of wherein preferably uniting solid phase or liquid phase inert support is packaged in the mixture that contains supercharging volatile matter (for example pressurized gas, such as freonll-11) or squeezes in the bottle.If desired, can also in pharmaceutical composition and dosage form, add moistening agent or wetting agent.The example of these extra compositions is well known in the art.
In another embodiment of the present invention, described pharmaceutical composition is an ointment, wherein contains S-TP508 and pharmaceutically acceptable vehicle such as the Vaseline of 0.01%-0.2%.
If method of the present invention comprises the intranasal administration of composition, then composition can be mixed with the form of aerosol, sprays, mist agent or drops.Particularly, the preventative or therapeutic agent of using according to the present invention can use suitable propelling agent (for example Refrigerant 12, the single fluoromethane of trichlorine, dichloro tetrafluoro ethane, carbonic acid gas or other suitable other) to be delivered easily by supercharging packing or atomizer with the form that aerosol spray presents.In the situation of pressurized aerosol, can determine dose unit by valve is provided, to deliver metered amounts.Employed capsule and cartridge case in sucker or the insufflator (being made of for example gelatin) can be mixed with the powdered mixture that contains compound and suitable powder matrix such as lactose or starch.
In another embodiment of the present invention, described pharmaceutical composition is a spray, wherein contains the S-TP508 of 5-500 μ g/ml, and 0.003% ethyl p-hydroxybenzoate and pharmaceutically acceptable carrier.
If it is Orally administered that method of the present invention comprises, then composition can be mixed with tablet, capsule, cartridge bag, soft capsule, solution, suspension, suchlike form.Can be by conventional means with medicinal vehicle such as the tackiness agent (for example pregelatinization W-Gum, polyvinylpyrrolidone or Vltra tears) of accepting; Filler (for example lactose, Microcrystalline Cellulose or secondary calcium phosphate); Lubricant (for example Magnesium Stearate, talcum or silica); Disintegrant (for example yam starch or Explotab); Or wetting agent (for example sodium laurylsulfate) tablet or capsule.Can be by method peridium patch well-known in the art agent.The liquid preparation that is used for oral administration can be taked but be not limited to the form of solution, syrup or suspension, and perhaps they can exist with the form of drying products, water or the dissolving of other suitable media before using.Can be by conventional means with the medicinal additive of accepting, such as suspension agent (for example sorbitol syrups, derivatived cellulose or hydrogenation edible-fat); Emulsifying agent (for example Yelkin TTS or Sudan Gum-arabic); Non-aqueous media (for example Prunus amygdalus oil, oily ester, ethanol or fractionated vegetable oil); And sanitas (for example methyl or propyl group-right-hydroxybenzoate or Sorbic Acid) prepares these liquid preparations.Preparation can also suitably comprise buffering salt, perfume compound, tinting material and sweeting agent.Can suitably prepare the preparation that is used for oral administration with slow release, controlled release or continue to discharge preventative or therapeutic agent.
Method of the present invention comprises that also preparation is used for the using of composition by injection (for example by injecting or transfusion continuously) parenteral administration.The prescription that is used for injecting can exist with the unit dosage form (for example at ampoule or in multi-dose container) that contains extra sanitas.Composition can be taked such as forms such as the suspension in oiliness or the aqueous medium, solution or milk sap, and can contain preparaton, such as suspension agent, stablizer and/or dispersion agent.Perhaps, activeconstituents can be a powder type, uses suitable media (for example aseptic, apirogen water) dissolving before use.
Can be used for the suitable media of parenteral dosage form of the present invention is provided is well-known to those skilled in the art.In certain embodiments, the medium that is suitable for the parenteral dosage form includes but not limited to water for injection USP; Aqueous medium includes but not limited to sodium chloride injection, RingerShi injection liquid, glucose injection, dextrose ﹠ sodium chloride injection and lactic acid RingerShi injection liquid; Water easily mixes medium and includes but not limited to ethanol, polyoxyethylene glycol and polypropylene glycol; And non-aqueous media includes but not limited to Semen Maydis oil, Oleum Gossypii semen, peanut oil, sesame oil, ethyl oleate, Isopropyl myristate and phenylamino benzoic acid methyl esters.
The structure of example one recombinant fusion protein grain and the acquisition of engineering bacteria
With the SEQ ID NO1 aminoacid sequence that designs is template, surveys according to center method, selects the codon of intestinal bacteria preference, obtains the pairing nucleotide sequence of fusion rotein, re-uses full gene synthesis technology and obtains the above-mentioned purpose gene fragment.The recombinant technology of knowing by those of ordinary skills obtains recombination carrier pBSK-S-TP508, and the gene fragment of inserting carrier is carried out sequencing.After verifying the exactness of its gene order, amplification is preserved, and cuts down target gene fragment from this carrier, inserts in the expression vector recombinant plasmid called after p S-TP508.Use CaCl2 method transformed into escherichia coli BL21 then, be coated on and contain antibiotic screening plate culture medium surface, selecting positive bacteria drops on when being cultured to OD600 for 0.6-0.8 in the liquid nutrient medium and to add IPTG 1.0mM and induce 3-4 hour centrifugal collection thalline, a tangible protein expression band occurs during the 10%SDS-PAGE electrophoresis behind the broken bacterium of 8M urea, expression amount is 40%.Monoclonal antibody immunity trace calibrating through natural type PE, show positive reaction, again recombinant expression vector is imported in the expressive host bacterium, through culture expression, hydrophobic chromatography and ion exchange chromatography obtain target protein S-TP508, the engineering bacteria called after pS-TP508/BL21 that efficiently expresses fusion rotein that is obtained.
The expression of example two target proteins
1) shaking bottle expresses: will be as the genetic engineering bacterium p S-TP508/BL21 of above-mentioned preparation, in the LB substratum, shake a bottle incubated overnight (37 ℃ 200rpm), were seeded in the LB substratum in 1: 30 by volume again, cultivate after 3 hours for 37 ℃, add 0.1mMIPTG and induced 4 hours.Collect thalline through the SDS-PAGE electrophoretic analysis, find fusion rotein (43KD) based on solubility expression, expression amount accounts for 40% of bacterial protein.
2) large scale fermentation is expressed:
A. substratum is formed:
A) seed liquor substratum (LB):
Tryptones: 10 grams per liters, yeast powder: 5 grams per liters, sodium-chlor: 10 grams per liters.
B) go up a jar substratum (15 liters):
Sodium phosphate dibasic: 250 grams, potassium primary phosphate: 110 grams, sodium-chlor: 13. grams, ammonium chloride: 30 grams, Tryptones: 120 grams, sal epsom: 30 grams, glucose: 450 grams, feed supplement (500 grams per liter): glucose.
Fermentation and abduction delivering:
I) seed culture:
Draw from the plate identified and to get bacterial classification, be inoculated among 50 milliliters of (250 milliliters triangular flasks) LB, these 50 milliliters of seed liquor are transferred among 700 milliliters of LB after 36 ℃, 200 rev/mins, 8 hours, 36 ℃, 200 rev/mins, overnight incubation.
Ii) ferment and the abduction delivering process:
During cultured seed liquid added jar, mix up each parameter, 37 ℃, 150 change, dissolved oxygen 100%, begin fermentation; Beginning adds 2 hours with 2.5 fast streams after 65 hours, adds 1000 milliliters of feed supplements approximately, adds 1 gram IPTG and induces (three hours).
Example three target protein purifying
Expression of recombinant proteins is finished by the S-TP508/JMl09 engineering bacteria.The centrifugal collection thalline of fermentation secondary fermentation liquid, bacterium is broken in pressure homogenate, collect Glutathione Sepharose chromatography column on the supernatant, wash fusion rotein with the elutriant that contains reduced glutathion (GSH) after the balance, adding 37 ℃ of enzymes of zymoplasm (5NIHU/mL) cut 2 hours, remove GST albumen by cation-exchange chromatography (SP Sepharose Fast Flow) then, obtain purity greater than 95% reorganization S-TP508.
Example four target protein biological activity assay
Materials and methods: 60 of cleaning level (secondary) adult male SD rats, body weight 250-300g, after also abdominal injection vetanarcol (50mg/kg) are anaesthetized simultaneously as inhalation with isoflurane, preserved skin (is shaved hair with electric shaver-for women in rat back 4cm * 7cm scope, and conventional depilation), cut 2 of circular wounds, diameter 2cm in back chest section with eye scissors.Parallel with backbone, be symmetrical in both sides, reach the subcutis holostrome deeply.Divide two groups and treat fusion rotein treatment group: the left side wound of every rat is used 0.1 μ g fusion rotein; The isotonic saline solution control group: the right side wound of every rat is used 40 μ l isotonic saline solutions in contrast.The single cage of rat was fed after operation finished, in clinical follow record related data,
Experimental result:
(1) postoperative is 3,7,10 days, through the surface of a wound area and the isotonic saline solution control group of fusion rotein treatment group (L group) processing
(R group) compares, and surface of a wound area obviously dwindles, and passing in time, and the wound healing degree is quickened.Show the fusion egg
White promotion wound healing effect is remarkable.
Table one, fusion rotein treatment group and isotonic saline solution control group postoperative wound surface area ratio
*p＜0.05，**p＜0.01
Wound area is organized wound area than reduction rate (%)=1-L group wound area/R, shows and merges fusion rotein treatment group than isotonic saline solution control group healing rate.Wound closure rate (%)=(respectively organizing wound original area-wound area)/respectively organize the wound original area, wound is than make rate (%)=R group wound closure rate/L group wound closure rate
(2) postoperative is seven days, from tissue slice, can see, under the suitable situation of new capillary vessel total quantity in fusion rotein treatment group and the isotonic saline solution control group surface of a wound granulation tissue, the shared percentage of bigger capillary vessel more than the fusion rotein treatment group diameter 600 μ m illustrates that much larger than the isotonic saline solution control group fusion rotein promotes that surface of a wound capillary vessel nucleus formation is remarkable.
New vessel quantity in 7 days surface of a wound granulation tissues of table two, fusion rotein treatment group and isotonic saline solution control group postoperative
*p＜0.05，**p＜0.01
Sequence table
＜110〉the military veterinary institute of Military Medical Science Institute
＜120〉a kind of zymoplasm fragment fusogenic peptide that contains
<160>1
<210>1
<211>34
<212>PRT
<213>SEQ?ID?NO：1
<400>1
Gly?Pro?Arg?Lys?Lys?Arg?Arg?Gln?Arg?Arg?Arg?Ala?Gly?Tyr?Lys
1 5 10 15
Pro?Asp?Glu?Gly?Lys?Arg?Gly?Asp?Ala?Cys?Glu?Gly?Asp?Ser?Gly
20 25 30
Gly?Pro?Phe?Val
34
Claims (4)
1. one kind contains the segmental fusogenic peptide of zymoplasm (S-TP508), and its aminoacid sequence is SEQ ID NO:1:GPRKKRRQRR RAGYKPDEGK RGDACEGDSG GPFV
2. polynucleotide sequence, the described zymoplasm fragment of its coding claim 1 fusogenic peptide.
3. pharmaceutical composition, it contains the described zymoplasm fragment of claim 1 fusogenic peptide, and optional pharmaceutically acceptable carrier.
4. the fusogenic peptide in the claim 1, the method for using gene engineering is expressed.
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| CN2010101733730A CN102250253A (en) | 2010-05-17 | 2010-05-17 | Fusogenic peptide containing thrombin fragment |
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| CN2010101733730A CN102250253A (en) | 2010-05-17 | 2010-05-17 | Fusogenic peptide containing thrombin fragment |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105879010A (en) * | 2015-01-17 | 2016-08-24 | 内蒙古天奇生物科技有限公司 | Polypeptide composition capable of promoting healing of wounds and relieving scars after wounds and preparation method of polypeptide composition |
| CN114177346A (en) * | 2021-12-24 | 2022-03-15 | 中国人民解放军军事科学院军事医学研究院 | Hemostatic composition, hemostatic patch and application thereof |
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| CN1622827A (en) * | 2002-01-16 | 2005-06-01 | 德克萨斯系统大学董事会 | Thrombin derived peptides for promoting cardiac tissue repair |
| CN1622826A (en) * | 2002-01-17 | 2005-06-01 | 德克萨斯系统大学董事会 | Stimulation of bone growth and cartilage formation with thrombing peptide derivatives |
| CN1635899A (en) * | 2000-07-19 | 2005-07-06 | 德克萨斯系统大学董事会 | Stimulation of bone growth with thrombin peptide derivatives |
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2010
- 2010-05-17 CN CN2010101733730A patent/CN102250253A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1635899A (en) * | 2000-07-19 | 2005-07-06 | 德克萨斯系统大学董事会 | Stimulation of bone growth with thrombin peptide derivatives |
| CN1622827A (en) * | 2002-01-16 | 2005-06-01 | 德克萨斯系统大学董事会 | Thrombin derived peptides for promoting cardiac tissue repair |
| CN1622826A (en) * | 2002-01-17 | 2005-06-01 | 德克萨斯系统大学董事会 | Stimulation of bone growth and cartilage formation with thrombing peptide derivatives |
Non-Patent Citations (2)
| Title |
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| 《Molecular Pharmacology》 20041217 Kenji Matsushita等 "A Novel Class of Fusion Polypeptides Inhibits Exocytosis" 第1138页右栏最后一段和第1139页表格1 1-4 第67卷, 第4期 * |
| KENJI MATSUSHITA等: ""A Novel Class of Fusion Polypeptides Inhibits Exocytosis"", 《MOLECULAR PHARMACOLOGY》, vol. 67, no. 4, 17 December 2004 (2004-12-17) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105879010A (en) * | 2015-01-17 | 2016-08-24 | 内蒙古天奇生物科技有限公司 | Polypeptide composition capable of promoting healing of wounds and relieving scars after wounds and preparation method of polypeptide composition |
| CN114177346A (en) * | 2021-12-24 | 2022-03-15 | 中国人民解放军军事科学院军事医学研究院 | Hemostatic composition, hemostatic patch and application thereof |
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Application publication date: 20111123 |