CN101367866A - Crucial active peptide segment with immunosuppression function in early pregnancy factor - Google Patents
Crucial active peptide segment with immunosuppression function in early pregnancy factor Download PDFInfo
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- CN101367866A CN101367866A CNA2008101415514A CN200810141551A CN101367866A CN 101367866 A CN101367866 A CN 101367866A CN A2008101415514 A CNA2008101415514 A CN A2008101415514A CN 200810141551 A CN200810141551 A CN 200810141551A CN 101367866 A CN101367866 A CN 101367866A
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Abstract
The present invention relates to the field of animal reproduction immunology, in particular to a partial peptide segment of the early pregnancy factor of mammal, the amino acid sequence of which is Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val. The peptide segment is the partially synthesized peptide segment of the early pregnancy factor. The present invention synthesizes the partial peptide segment of the early pregnancy factor (EPF) of mammal for the first time, the result of a rosette inhibition test shows that the peptide segment can suppress the formation of rosette, and a rabbit dermatoplasty test also indicates that the EPF has biological activity in terms of immunosuppression. The EPF partial peptide segment is a key peptide segment for the immunosuppression effect, laying down a foundation for the further research on the early pregnancy factor (EPF) and clinic applications thereof.
Description
One, technical field:
The present invention relates to the animal reproduction field of immunology, particularly relate to the partial peptide section of Mammals early pregnancy factor.
Two, background technology:
Early pregnancy factor (early pregnancy factor is the female mammal after fertilization EPF), found a kind of the earliest can be in serum detected pregnancy-associated plasma protein with immunosuppression and growth regulating effect.1974, Australian scholar Morton detected the EPF activity first in pregnant mouse serum when carrying out rosettes inhibition test (RIT), owing to EPF can detect at mouse after fertilization 4～6h, just with its called after " early pregnancy factor ".This discovery has caused countries in the world experts and scholars' concern, has all detected the EPF activity subsequently in pregnant Mammals maternal serums such as gravid woman, sheep, pig, ox, finds that EPF has very high specificity to pregnant parent population.Mouse after fertilization 4h, rabbit after fertilization 16h, rat, sheep, ox, pig after fertilization 24h, people's after fertilization 48h all can detect the EPF activity in serum; The EPF activity may persist to the preceding 4d of childbirth in mice serum, almost continue the whole pregnancy period in sheep, porcine blood serum, may persist to gestation 6th month the people, in case termination of pregnancy, EPF disappears immediately in the serum.
EPF can suppress the cellular immunization of T cell mediated, suppress the formation of rosettes, prevent that parent to embryo and even fetus immunological rejection taking place, it also is a kind of immunosuppressor of malignant cell excretory, in wound healings such as burn, ulcer and similar rheumatism, the effect characteristics of somatomedin are arranged.
EPF is stronger to the tolerance of temperature and potential of hydrogen, and is very stable when being lower than 56 ℃, easy inactivation when surpassing 72 ℃, EPF is made up of the glycoprotein molecule of 102 amino-acid residues, the EPF aminoacid sequence of people, pig and ox is identical, and molecular weight is 10.93kD, and iso-electric point is about 6.5; Mouse EPF aminoacid sequence and people's homozygosity is 97%, and molecular weight is 10.96kD, and iso-electric point is about 6.8.EPF and heat-shock protein family member cpn10 (cpn10) height homology, but different again on cellular localization and function with cpn10, EPF is the effect of cpn10 in the extracellular performance.Cpn10 combines with the cpn60 specificity in cell, and the correct of auxiliary protein folds, but then shows the activity of EPF in the extracellular.
The biological characteristics of EPF is mainly reflected in and suppresses immunity and growth regulating two aspects.At first, having the immune response that suppresses parent and make sperm, embryo avoid the effect of immunological rejection, also is one of biochemical marker of confirming the earliest at present gestation; Next is the growth that EPF can promote tumour cell, also can promote to burn, the healing of wound such as ulcer.Because EPF can strengthen the formation of anti lymphocyte serum (ALS) suppressor T cell garland, therefore, rosettes inhibition test (RIT) is for detecting the active classical way of EPF.EPF can be used for early stage, the super diagnosis of early gestation of animal in the animal reproduction field, detection, the survive situation of embryo biotechnology after embryo transfer of interrupting in gestation, and there is important value the aspects such as treatment of estimating male reproductivity and breeding Immunological diseases.
Three, summary of the invention:
The technical problem to be solved in the present invention: a kind of partial synthesis peptide section of Mammals early pregnancy factor is provided, and this peptide section has the biologic activity of EPF in immunosuppression.
Technical scheme of the present invention is:
The present invention is the EPF/Hsp10 according to the people
(H-Met-Ala-Gly-Gln-Ala-Phe-Arg-Lys-Phe-Leu-Pro-Leu-Phe-As p-Arg-Val-Leu-Val-Glu-Arg-Ser-Ala-Ala-Glu-Thr-Val-Thr-Ly s-Gly-Gly-Ile-Met-Leu-Pro-Glu-Lys-Ser-Gln-Gly-Lys-Val-Le u-Gln-Ala-Thr-Val-Val-Ala-Val-Gly-Ser-Gly-Ser-Lys-Gly-Ly s-Gly-Gly-Glu-Ile-Gln-Pro-Val-Ser-Val-Lys-Val-Gly-Asp-Ly s-Val-Leu-Leu-Pro-Glu-Tyr-Gly-Gly-Thr-Lys-Val-Val-Leu-As p-Asp-Lys-Asp-Tyr-Phe-Leu-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gl y-Lys-Tyr-Val-Asp-OH), adopt polypeptide synthetic method, the peptide section of salvage different lengths, again each peptide section is carried out immunosuppressive activity and detects, find:
H-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-OH has the formation that suppresses rosettes with the peptide section that contains this section peptide, in immunosuppression, has the biologic activity of EPF.
Mammiferous aminoacid sequence with crucial active peptide segment of immunosuppressive action of the present invention is Phe Arg Asp Gly Asp Ile Leu Gly Lys Tyr Val.
The partial synthesis polypeptide that this peptide section is an early pregnancy factor.
The encode nucleotide sequence of described active peptide segment.
Positive beneficial effect of the present invention:
(1) the present invention has synthesized the partial peptide section of Mammals early pregnancy factor EPF first, detect by the rosettes inhibition test, found that this peptide section can suppress the formation of rosettes, detect, show that also EPF has biologic activity in immunosuppression by the rabbit dermatoplasty.
(2) EPF partial peptide section of the present invention is the crucial peptide section of immunosuppressive action, for further research early pregnancy factor EPF and clinical application thereof are laid a good foundation.
Four, embodiment:
Embodiment one: adopt the synthetic EPF/Hsp10 of Peptide synthesizer
The peptide section of (H-Met-Ala-Gly-Gln-Ala-Phe-Arg-Lys-Phe-Leu-Pro-Leu-Phe-As p-Arg-Val-Leu-Val-Glu-Arg-Ser-Ala-Ala-Glu-Thr-Val-Thr-Ly s-Gly-Gly-Ile-Met-Leu-Pro-Glu-Lys-Ser-Gln-Gly-Lys-Val-Le u-Gln-Ala-Thr-Val-Val-Ala-Val-Gly-Ser-Gly-Ser-Lys-Gly-Ly s-Gly-Gly-Glu-Ile-Gln-Pro-Val-Ser-Val-Lys-Val-Gly-Asp-Ly s-Val-Leu-Leu-Pro-Glu-Tyr-Gly-Gly-Thr-Lys-Val-Val-Leu-As p-Asp-Lys-Asp-Tyr-Phe-Leu-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gl y-Lys-Tyr-Val-Asp-OH) is as follows:
H-Cys-Met-Ala-Gly-Gln-Ala-Phe-Arg-Lys-Phe-Leu-Pro-Leu-Phe-Asp-Arg-Val-Leu-Val-Glu-Arg-OH
H-Cys-Val-Leu-Val-Glu-Arg-Ser-Ala-Ala-Glu-Thr-Val-Thr-Lys-Gly-Gly-Ile-Met-Leu-Pro-Glu-OH
H-Cys-Ile-Met-Leu-Pro-Glu-Lys-Ser-Gln-Gly-Lys-Val-Leu-Gln-Ala-Thr-Val-Val-Ala-Val-Gly-OH
H-Cys-Val-Val-Ala-Val-Gly-Ser-Gly-Ser-Lys-Gly-Lys-Gly-Gly-Glu-Ile-Gln-Pro-Val-Ser-Val-OH
H-Cys-Gln-Pro-Val-Ser-Val-Lys-Val-Gly-Asp-Lys-Val-Leu-Leu-Pro-Glu-Tyr-Gly-Gly-Thr-Lys-OH
H-Cys-Tyr-Gly-Gly-Thr-Lys-Val-Val-Leu-Asp-Asp-Lys-Asp-Tyr-Phe-Leu-Phe-Arg-Asp-Gly-Asp-OH
H-Cys-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH
H-Asp-Lys-Asp-Tyr-Phe-Leu-Phe-Arg-Asp-Ser-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH
H-Lys-Asp-Tyr-Phe-Leu-Phe-Arg-Asp-Ser-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH
H-Asp-Tyr-Phe-Leu-Phe-Arg-Asp-Ser-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH
H-Phe-Leu-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH
H-Leu-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH
H-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH
H-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH
H-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH
H-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-OH
H-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-OH。
According to the aminoacid sequence of EPF, use the synthetic difficulty characteristic of peptide programanalysis, design polypeptide synthesis program adopts Peptide synthesizer to carry out the synthetic automatically and manual synthetic method synthetic peptide sequence that combines.Idiographic flow is as follows:
Design synthetic peptide sequence → peptide programanalysis → design synthesis program → by the calculating of the substitution value of resin and take by weighing Fmoc-AA-Wang-resin or Rink resin → DMF swelling resin →
*Add 20%piperidine/DMF and take off the Fmoc protection, stirring 6min →
*Add next bit amino acid and HBTU and carry out acylation reaction, N
2Stirring reaction 30min →
*With the performance of Kaiser method or TNBS method test reaction →
*DMF washes 5 times, each 1min → repeat to have
*Step, on resin, connect next bit amino acid, up to this peptide sequence is synthetic finishes → according to the difference of component peptide chain amino acid, choose suitable reagent and precipitate TFA polypeptide → Sephadex G-25 desalting and purifying → LC-MS and HPLC Analysis and Identification and purified polypeptide with being connected of TFA method cracking peptide chain and resin → cold diethyl ether.
When synthesizing polypeptide, can add a halfcystine at the N-terminal of peptide sequence.
With aminoacid sequence FRDGDILGKY is example, and synthetic 5 required reagent of μ mol polypeptide and operating process are as follows:
Main agents: N, N-dimethyl formamide (DMF); Deprotecting regent I:20%Piperidine/DMF; Deprotection agent II: methylene dichloride (DCM); Condensation, activating reagent: 2-(1H-benzotriazole)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) is dissolved in NMM (nitrogen methylmorpholine)/DMF; Cutting reagent: 94% trifluoroacetic acid (TFA); 20 kinds of Fmoc protection amino acid (concentration of every seed amino acid is 25 μ mol/L); Fmoc-Ala-OH; Fmoc-Cys (Trt)-OH; Fmoc-Asp (OtBu)-OH; Fmoc-Glu (OtBu)-OH; Fmoc-Phe-OH; Fmoc-Gly-OH; Fmoc-His (Trt)-OH; Fmoc-Ile-OH; Fmoc-Lys (Boc)-OH; Fmoc-Leu-OH; Fmoc-Met-OH; Fmoc-Asn (tBu)-OH; Fmoc-Pro-OH; Fmoc-Gln (Trt)-OH; Fmoc-Arg (Pbf)-OH; Fmoc-Ser (tBu)-OH; Fmoc-Thr (tBu)-OH; Fmoc-Val-OH; Fmoc-Trp (Boc)-OH; Fmoc-Tyr (tBu)-OH.
Main resin: Fmoc-Leu-Wang-Resin; The Symphony Peptide synthesizer is produced by U.S. ProteinTechnology company.
Amino acid coupling step during polypeptide is synthetic:, take by weighing 10mgFmoc-Leu-Wang-Resin and put into reaction flask according to purpose peptide chain output; (1) adds 1.25ml DMF, mix 10min, use N
2Blow DMF off, repeat 3 times; (2) add 1.25ml 20%piperidine/DMF, mix 5min, use N
2Blow liquid off, add 1.25ml 20%piperidine/DMF, mix 15min; (3) repeating step (1); (4) Fmoc-Met-OH of adding 1.25ml25 μ M; Add 1.25ml 0.4NMM/DMF, hybrid reaction 45min uses N
2Blow liquid off; (5) repeating step (1); (6) repeating step (1)～(5) add Fmoc-Met-OH, Fmoc-Gln (Trt)-OH successively, finish each amino acid whose coupling in the peptide sequence; (7) use N
2Dry up resin.
Synthetic peptide cutting basic step is as follows: (1) adds 1.25ml DMF, mixes 10min, uses N
2Blow DMF off, repeat more than 3 times; (2) add 1.25ml 20%piperidine/DMF, mix 5min, use N
2Blow liquid off, add 1.25ml 20%piperidine/DMF, mix 15min; (3) repeating step (1); (4) wash more than three times with DCM; (5) add the 94%TFA hybrid reaction more than 2 hours; (6) collect cleaved products.
Polypeptide synthesis product is slightly carried: anhydrous diethyl ether slowly joined in the product of collection, and ice bath 10min, 300rpm 10min stays precipitation, abandons supernatant, repeat 3 times, throw out Freeze Drying Equipment drying ,-20 ℃ of preservations are standby.The sample that takes a morsel is used for HPLC and GC-MS detects.
Embodiment two: adopt the LC-MS instrument to carry out the evaluation and the purity check of section of synthesized peptide
Purifying and evaluation polypeptide Waters Quattro Micro LC-MS instrument (LC-MS).
Elution system is: 1. A liquid: 50mL/L acetonitrile/H
2O solution; 2. B liquid: 950mL/L acetonitrile/H
2O solution.Hand sampling, each 1mL, flow velocity 4mL/min; Linear gradient: in the 45min, B liquid is raised to 500mL/L from 50mL/L, is raised to 950mL/L from 500mL/L in the 5min then, and B liquid is done last wash-out.Uv-absorbing is detected at the 220nm place, press the peak and collect component, be used for mass spectrometric detection, the mass spectrum inspection polypeptide adopts electron spray ionisation to resolve mass spectrum and identifies polypeptide, and data analysis software is Masslynx4.0, method is carried out in strict accordance with operational manual, detect the molecular mass of synthetic polypeptide, molecular mass is detected correct component collect freeze-drying, become the pure product that need, standby.
Embodiment three: the rosettes inhibition test detects the immunosuppressive activity of synthetics
1. the preparation of human lymphocyte: vein is gathered human blood, 0.1% heparin sodium anti-freezing, add equal-volume D-Hanks balanced salt solution, mixing, be superimposed on gently in the 10ml centrifuge tube that fills the equivalent lymphocyte separation medium by every pipe 2～3ml, 2000rpm 20min, after the centrifugal end, draw parting liquid and position, blood plasma boundary greyish white layer, with the D-Hanks liquid of 5 times of volumes with the centrifugal 10～15min of 1000rpm, wash 2 times, get 1 cell suspension, expect that with platform orchid refuses to dye method microscopy counting cells, calculate the cell motility rate, motility rate should adjust to 4 * 10 with the D-Hanks liquid that contains 20% calf serum with cell more than 95%
6Individual/mL.
2. the preparation of sheep red blood cell (SRBC) suspension (SRBC): take a blood sample from the sheep jugular vein with ordinary method, 0.1% heparin sodium anti-freezing, separating red corpuscle is washed 3 times with D-Hanks liquid, and being made into final concentration is 1 * 10
8The red cell suspension of individual/mL is for using the same day.
3. calf serum: remove in the calf serum the heterophil antibody of sheep red blood cell (SRBC),, add the long-pending sheep red blood cell (SRBC) of half piezometric through 56 ℃ of 30min heat inactivations, after the mixing, 37 ℃ of water-bath 20min.After the water-bath, 2000rpm10min draws supernatant liquor.
4. rosettes inhibition test: get 500 μ L lymphocyte suspensions (4 * 10
6Individual/as mL) to mix with 100 μ L testing samples, hatch 30min for 37 ℃.Get 9 parts of Incubating Solutions respectively, every part 50 μ L adds D-Hanks liquid 100 μ L and ALG serial dilutions (1:2 respectively in 9 parts of Incubating Solutions
2* 10
3, 2
4* 10
3..., 2
16* 10
3) 100 μ L, hatch 60min for 37 ℃; Adding D-Hanks liquid cleans 2 times; Add 1% sheep red blood cell (SRBC) suspension, 50 μ L and the D-Hanks liquid 50 μ L that contain 20% calf serum again, fully mixing 800rpm 5min discards most of supernatant liquor, re-suspended cell; Add fixedly 10min of 1～2 0.8% glutaraldehyde again, smear, the garland number in per 200 lymphocytes is write down in the compound dye liquor dyeing of Ji Mu Sa-Rui Shi.The high dilution of ALS calculated when the RIT value was lower than negative control group 75% by the garland number, promptly with inverse * 10 of the highly diluted multiple of ALS
-3After the expression of taking the logarithm, its calculation formula is:
RIT=log
2(10
-3The highly diluted multiple of/ALS).
5. adopt the rosettes inhibition test to detect to each peptide section, the activated peptide section of result is:
H-Cys-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH，
H-Asp-Lys-Asp-Tyr-Phe-Leu-Phe-Arg-Asp-Ser-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH，
H-Lys-Asp-Tyr-Phe-Leu-Phe-Arg-Asp-Ser-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH，
H-Asp-Tyr-Phe-Leu-Phe-Arg-Asp-Ser-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH，
H-Phe-Leu-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH，
H-Leu-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH，
H-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-Asp-OH，
H-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-OH。
The immunosuppressive activity of above-mentioned each peptide section is identical.
Embodiment four: the immunosuppressive activity of rabbit dermatoplasty detection of peptides section
1. laboratory animal: 20 of rabbit of the same race, carry out mutual dermatoplasty between 2, as the receptor site, opposite side is as the donor site in its buttocks one side for every rabbit.Each transplants a place.
2. make wound: rabbit is put in Baoding on the multifunctional operating table, its left and right buttocks is shaved hair respectively, cleaned.With the sterilization of 0.1% bromogeramine, 3% PROCAINE HCL, PHARMA GRADE injection liquid is done local fan-shaped infiltration anesthesia in buttocks, operation cuts a flap that comprises the skin holostrome, and area is 1cm * 3cm, thoroughly hemostasis.
3. the surface of a wound is handled: after the surface of a wound is fully stopped blooding, be dissolved in physiological saline with penicillin and clean the surface of a wound, remove blood stains, transudate and fragment of tissue.Be overlying on the surface of a wound with Yunnan white powder, cover gauze outward, fix with adhesive tape.By the 12nd day, granulation face secretory product reduced, and granulation has covered the whole surface of a wound, the densification of granulation particle, solid, no oedema, and pinkiness, glossy.At this moment, the excision chela tissue that granulates.Clean the granulation face with the physiological saline that contains penicillin, remove pus, edge of wound and wound are enclosed and are used 75% alcohol disinfecting, and then with the gauze flap coverage that is soaked with physiological saline, the protection granulation tissue prepares to carry out dermatoplasty.
4. dermatoplasty: get the flap of allogeneic rabbit opposite side buttocks holostrome, clean, transplant, sew up and fixing wrapping in the surface of a wound of another rabbit with physiological saline.
5. transplanting aftertreatment: 20 rabbit are divided into 2 groups, and 10 as test group, and 10 are contrast.Observe the healing state of transplantation site every day.
Test group is 4 days after transplanting, 8 days, 12 days, 16 days and 20 days intravenous injection peptide sections (H-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-OH presses the 1mg/ml dilution with PBS) respectively, every each intravenous injection 500 μ L.Control group is injected with PBS equivalent.
6. skin-grafting survives the standard judgement: skin graft and granulation face merge fully, and the granulation face is aging; The skin graft pigment is gradually to diffusion all around; Quilt hair ramp on the skin graft; Immunological rejection is not found more than January in the skin-grafting back, thinks that transplanted skin survives.
7. result:
Test group (10): transplant unsuccessful for 3; Transplant successfully for 7, healing time is 21～27 days, average 25 days.
Control group (10): do not transplant successfully for 3; 4 after transplanting the 9th～14 days, skin-grafting is ostracised, plant bed concave surface contour smoothing, skin-grafting does not have hair; 2 appearance repulsions in the 18th day after transplanting, skin-grafting comes off, 1 success, healing time is 26 days.
Experiment conclusion: by above-mentioned experiment as can be seen, have 7 to transplant successfully in 10 rabbit of test group, show that H-Phe-Arg-Asp-Gly-Asp-Ile-Leu-Gly-Lys-Tyr-Val-OH is the active crucial peptide section of EPF immunosuppressive action.
Sequence table
＜110〉Henan Province Animal Immunology Key Laboratory
＜120〉has the crucial active peptide segment of immunosuppressive action in the early pregnancy factor
＜130〉polypeptide synthetic method
<160>1
<170>PatentIn?version3.4
<210>1
<211>11
<212>PRT
＜213〉artificial sequence
<400>1
Claims (4)
1. have the crucial active peptide segment of immunosuppressive action in the Mammals, it is characterized in that: the aminoacid sequence of this peptide section is Phe Arg Asp Gly Asp Ile Leu Gly Lys Tyr Val.
2. active peptide segment according to claim 1 is characterized in that: the partial peptide section that described peptide section is an early pregnancy factor.
3. active peptide segment according to claim 1 is characterized in that: described peptide section is synthetic polypeptide.
4. the nucleotide sequence of coding claim 1 described active peptide segment.
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| EP2485753A1 (en) * | 2009-10-09 | 2012-08-15 | CBIO Limited | Chaperonin 10 variants |
| AU2010305328A8 (en) * | 2009-10-09 | 2012-09-13 | Cbio Limited | Chaperonin 10 variants |
| CN102711793A (en) * | 2009-10-09 | 2012-10-03 | 悉生物有限公司 | Chaperonin 10 variants |
| EP2485753A4 (en) * | 2009-10-09 | 2013-12-11 | Cbio Ltd | Chaperonin 10 variants |
| AU2010305328B2 (en) * | 2009-10-09 | 2016-02-18 | Cbio Limited | Chaperonin 10 variants |
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