CN104211778A - Transforming growth factor beta 1 agonist polypeptide and preparing method and application thereof - Google Patents
Transforming growth factor beta 1 agonist polypeptide and preparing method and application thereof Download PDFInfo
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- CN104211778A CN104211778A CN201410509347.9A CN201410509347A CN104211778A CN 104211778 A CN104211778 A CN 104211778A CN 201410509347 A CN201410509347 A CN 201410509347A CN 104211778 A CN104211778 A CN 104211778A
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Abstract
The invention relates to the field of medicine, in particular to polypeptide compounds used for preventing or treating cerebral infarction. Transforming growth factor beta 1 agonist polypeptide 1 is characterized in that the sequence of the transforming growth factor beta 1 agonist polypeptide 1 is HANFCLGPCPY1WSLDTQYS. The transforming growth factor beta 1 agonist polypeptide 1 is prepared by aid of the Fmoc protective solid-phase synthesis technology with Rink amido MBHA resin as the carrier, N,N-DIPCDI as the condensation agent and the trifluoroacetic acid as the cutting reagent. The transforming growth factor beta 1 agonist polypeptide can be in covalent linkage with an adjuvant which is bovine serum albumin, human serum albumin or polyethylene glycol. The invention further relates to the application of the transforming growth factor beta 1 agonist polypeptide in cerebral infarction treatment. The transforming growth factor beta 1 agonist polypeptide can be used to prevent or treat cerebral infarction through various administration methods including subcutaneous injection or intramuscular injection, intravenous injection or intravenous drip, or oral administration such as pills, capsules and nasal sprays. The transforming growth factor beta 1 agonist polypeptide can target to promote expression of the transforming growth factor beta 1, improve the content of the transforming growth factor beta 1 in plasma and achieve the effect of preventing or treating cerebral infarction.
Description
Technical field:
The present invention relates to pharmaceutical field, be specifically related to the polypeptide compound for preventing or treat cerebral infarction.
Background technology:
Cerebral infarction refers to the focal neurologic impairment syndrome that the brain local blood circulation obstacle occurred suddenly causes brain tissue ischemia anoxic to cause.One of three large dead diseases in world wide are also disable reason in grownup first place.Because the cause of disease of current cerebral infarction and pathogenesis are illustrated not yet completely, and treatment means desirable is clinically limited, and not only sickness rate is very high to make it, and lethality rate, disability rate and recurrence rate are also higher, causes huge burden to individual and society.
The medicine of current prevention or treatment cerebral infarction, is mainly for control susceptible factor.As high in patient's blood coagulation, give antithrombotic treatment; As suffered from diabetes, blood sugar should being controlled in time, comprise dietary control; Then should give depressor if any hypertension, make blood pressure be down to proper level, increase if any blood cholesterol, then should control hypercholesterolemia and suitably give fat-reducing medicament.
Transforming growth factor-beta 1 (transforming growth factor-pi, TGF-β 1) be the multifunctional cytokine with potential anti-inflammatory property, its pathophysiological process by injury and recovery after number of ways participation cerebral ischemia of discovery at present.There is research to claim it by increasing expression of TGF-β 1 albumen, improving the content of TGF-β 1 in blood plasma, and then play the effect of prevention or treatment cerebral infarction in the developing of disease.But, present stage, do not have the transforming growth factor-beta 1 agonist of ripe exploitation to come out, for prevention or treatment cerebral infarction.
Summary of the invention:
The present invention seeks to the feature for existing prevention or treatment cerebral infarction medicine, design a kind of polypeptide compound, can effectively treat or prevent cerebral infarction.
Technical scheme
Transforming growth factor-beta 1 agonist polypeptide 1, is characterized in that: its sequence is HANFCLGPCPYIWSLDTQYS.Adopt the solid phase synthesis technique preparation of Fmoc protection, Rink acyl ammonia mbha resin is as carrier, and N, N-DIC is condensing agent, and trifluoroacetic acid is cutting reagent.Can a covalently bound adjuvant, adjuvant is bovine serum albumin, human serum albumin, or polyoxyethylene glycol.The application of transforming growth factor-beta 1 agonist polypeptide 1 in prevention or treatment cerebral infarction.By the prevention of multiple administering mode or treatment cerebral infarction, comprise subcutaneous or intramuscular injection, intravenous injection or intravenous drip, oral administration as pill, capsule etc., nasal spray etc.
Beneficial outcomes:
Transforming growth factor-beta 1 agonist polypeptide 1 in the present invention can promote that transforming growth factor-beta 1 is expressed by target, improves the content of transforming growth factor-beta 1 in blood plasma, reaches the effect of prevention or treatment cerebral infarction.
Embodiment
Embodiment 1
The chemical synthesis process of polypeptide
The solid phase synthesis technique preparation that polypeptide 1 is protected with Fmoc.Building-up reactions is carried out to N end from C end according to inhibitor 1 sequence, and Rink acyl ammonia mbha resin has free amino group as on carrier (can buy in Advanced Chem Tech company).In each step connection procedure, amino-acid residue all will activate, and has the HBTU of 4 times of free amino groups on carrier in activator mixture, HOBt, DIEA and Fmoc-amino acid.Be condensing agent by N, N-DIC, carry out ligation, after each amino acid whose ligation, close with the mixture of pyridine/acetic acid/N-Methylimidazole (4:2:0.5) free amino group do not connected, capping 10 minutes.Before next amino acid connects, all the Fmoc-group on carrier to be removed, go Fmoc-group to use the dimethyl formamide containing 20% piperidines, need 15 minutes.Finally, after all amino-acid residues are linked in sequence, inhibitor 1 97% trifluoroacetic acid cuts down from carrier, and cutting at room temperature carries out 2 hours.
Apply above-mentioned electrochemical conditions can synthesize and obtain polypeptide 1, sequence is HANFCLGPCPYIWSLDTQYS, and this sequence is brand-new sequence.Also the raw work synthesis in Shanghai can be entrusted.
Embodiment 2
Transforming growth factor-beta 1 agonist polypeptide 1 prevents the effect of rat cerebral infarction model
The SD rat in male 8 week age 40, is divided into 4 groups at random, is respectively: A group is blank group: physiological saline; B group is model control group: modeling+physiological saline; C group is drug intervention group: modeling+transforming growth factor-beta 1 agonist polypeptide 1 (10mg/kg/d); D is positive drug intervention group: modeling+urokinase (10mg/kg).Continuous 10 days.Set up the model of MCAO.(1) size of Infarction volume after focal cerebral ischemia in rats Reperfu-sion is observed; (2) adopt Neurological deficits, observe the rehabilitation situation of MCAO animal; (3) content of transforming growth factor-beta 1 in blood plasma is detected.
Result: the preventative cerebral infarction model rat giving polypeptide 1 group is compared with model group, cerebral infarct size reduces (P<0.01), Neurological deficits reduces (P<0.05), in blood plasma, the content of TGF-β 1 raises (P<0.05), all has statistical significance (see table 1) with model control group comparing difference.
Table 1 transforming growth factor-beta 1 agonist polypeptide 1 is to the effect of prevention rat cerebral infarction model
*p<0.05,
*p<0.01 is compared with model group
Conclusion: transforming growth factor-beta 1 agonist polypeptide 1 pair of rat cerebral infarction has prophylactic effect.
Embodiment 3
Transforming growth factor-beta 1 agonist polypeptide 1 treats the effect of rat cerebral infarction model
The SD rat in male 8 week age 40, is divided into 4 groups at random, sets up the model of MCAO, gives drug intervention respectively in modeling simultaneously, be respectively: A group is blank group: physiological saline; B group is model control group: modeling+physiological saline; C group is drug intervention group: modeling+transforming growth factor-beta 1 agonist polypeptide 1 (10mg/kg/d); D is positive drug intervention group: modeling+urokinase (10mg/kg).Continuous 10 days.(1) size of Infarction volume after focal cerebral ischemia in rats Reperfu-sion is observed; (2) adopt Neurological deficits, observe the rehabilitation situation of MCAO animal; (3) content of transforming growth factor-beta 1 in blood plasma is detected.
Result: therapeutic gives the cerebral infarction model rat of polypeptide 1 group compared with model group, cerebral infarct size reduces (P<0.01), Neurological deficits reduces (P<0.05), in blood plasma, the content of TGF-β 1 raises (P<0.01), all has statistical significance (see table 2) with model control group comparing difference.
Table 2 transforming growth factor-beta 1 agonist polypeptide 1 is to the effect for the treatment of rat cerebral infarction model
*p<0.05,
*p<0.01 is compared with model group
Conclusion: transforming growth factor-beta 1 agonist polypeptide 1 pair of rat cerebral infarction has therapeutic action.
SEQUENCE LISTING
Pu Luoda bio tech ltd, <110> Suzhou
<120> transforminggrowthfactor-β1 agonist polypeptide and preparation method thereof, application
<130>
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 20
<212> PRT
<213> artificial sequence
<400> 1
His Ala Asn Phe Cys Leu Gly Pro Cys Pro Tyr Ile Trp Ser Leu Asp
1 5 10 15
Thr Gln Tyr Ser
20
Claims (5)
1. a transforminggrowthfactor-β1 agonist polypeptide, is characterized in that: its aminoacid sequence is HANFCLGPCPYIWSLDTQYS.
2. a preparation method for polypeptide described in claim 1, is characterized in that: the solid phase synthesis technique preparation adopting Fmoc protection, Rink acyl ammonia MBHA resin is as carrier, and N, N-DIC is condensing agent, and trifluoroacetic acid is cutting reagent.
3. the preparation method of polypeptide according to claim 2, is characterized in that: a covalently bound adjuvant, adjuvant is bovine serum albumin, human serum albumin, or polyoxyethylene glycol.
4. according to the application of polypeptide in preparation prevention or treatment cerebral infarction medicine of claim.
5. the purposes of polypeptide according to claim 4, is characterized in that: prevented by multiple administering mode or treat cerebral infarction, comprises subcutaneous or intramuscular injection, intravenous injection or intravenous drip, oral administration as pill, capsule etc., nasal spray.
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| CN201410509347.9A CN104211778A (en) | 2014-09-28 | 2014-09-28 | Transforming growth factor beta 1 agonist polypeptide and preparing method and application thereof |
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| CN201410509347.9A CN104211778A (en) | 2014-09-28 | 2014-09-28 | Transforming growth factor beta 1 agonist polypeptide and preparing method and application thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1044125A (en) * | 1988-12-16 | 1990-07-25 | 安柯金两合公司 | The clone of simian transforming growth factor-beta 1 β 1 and expression |
| CN1406982A (en) * | 2001-09-06 | 2003-04-02 | 复旦大学 | Polypeptide-human protein containing transferring growth factor family characteristic sequential fragments-12.87 and polynucleotide for encoding it |
| CN101668543A (en) * | 2007-02-14 | 2010-03-10 | Tcp创新有限公司 | Tgf-beta stimulant and further agent to reduce side effects |
-
2014
- 2014-09-28 CN CN201410509347.9A patent/CN104211778A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1044125A (en) * | 1988-12-16 | 1990-07-25 | 安柯金两合公司 | The clone of simian transforming growth factor-beta 1 β 1 and expression |
| CN1406982A (en) * | 2001-09-06 | 2003-04-02 | 复旦大学 | Polypeptide-human protein containing transferring growth factor family characteristic sequential fragments-12.87 and polynucleotide for encoding it |
| CN101668543A (en) * | 2007-02-14 | 2010-03-10 | Tcp创新有限公司 | Tgf-beta stimulant and further agent to reduce side effects |
Non-Patent Citations (2)
| Title |
|---|
| GROSS CE等: "Transforming Growth Factor-b1 Reduces Infarct Size After Experimental Cerebral Ischemia in a Rabbit Model", 《STROKE》 * |
| VIEIRA AR等: "GenBank：AAQ18642.1", 《GENBANK》 * |
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Application publication date: 20141217 |