CN106349346A - Protein kinase inhibitor polypeptide and application - Google Patents
Protein kinase inhibitor polypeptide and application Download PDFInfo
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- CN106349346A CN106349346A CN201610766461.9A CN201610766461A CN106349346A CN 106349346 A CN106349346 A CN 106349346A CN 201610766461 A CN201610766461 A CN 201610766461A CN 106349346 A CN106349346 A CN 106349346A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
The invention relates to the field of medicines and in particular relates to polypeptide which has pathology function of inhibiting protein kinase to treat cerebral apoplexy. The sequence is SEQ ID NO:1 and is a brand new sequence. By adopting the protein kinase inhibitor polypeptide, the polypeptide has an obvious curative effect on rat cerebral infarction model, can be used as an effective candidate treatment method of clinical cerebral apoplexy and has a potential new medicine devolvement value.
Description
Technical field
The present invention relates to kinases inhibitor polypeptide and its application are and in particular to have the pathology work(of suppression protein kinase
Can, the polypeptide for the treatment of apoplexy.
Background technology
Apoplexy (stroke) is the general name of cerebral infarction, cerebral hemorrhage and subarachnoid hemorrhage, is a kind of unexpected onset
Cerebral blood circulation obstacle disease, its Common Mechanism is axoneuron and glial cell ischemic hypoxia is dead, and Chinese medicine claims
Be apoplexy, be the common refractory disease of serious harm human health and life security, clinical manifestation to flutter suddenly dusk, no
Save occurrences in human life or occur suddenly facial hemiparalysiss, hemiplegia, stiff tongue to say that not smoothgoing, dysnoesia is principal character.
China occurs Patients with Stroke to reach 2,000,000 people every year according to statistics, sickness rate up to 1,20/,100,000. existing paralytic
7000000, wherein 4,500,000 patients lose different degrees of work capacity because disabled, or even can't take care of oneself, and disability rate is up to
75%.Acute stroke unit is the core concept of current clinical treatment, and its drug treatment is an important ring, at present both at home and abroad still without
The Therapeutic Method determining mitigating nerve injury, for many years uniquely by U.S. fda ratify for apoplexy medicine only in a organized way
Plasminogen activator (t-pa).The Therapeutic Method of research apoplexy and exploitation medicine are significant.
Protein kinase (pkc) is a kind of protein phosphorylation enzyme being widely present in vertebratess body, almost sees various
In histoorgan, especially abundant with central nervous system.Increasing result of study shows, pkc damages in ischemic brain at present
There is during wound considerable effect.Compared with thrombolytic agent, although protein kinase c can not stay for dredging apoplexy
Thrombosis, but it can be used for the damage repaired hemorrhagic apoplexy and cause when filling again. using experimental apoplexy model, choosing
The research of the inhibitor of selecting property polypeptide and agonist finds there is pkc ε hypotype in the ischemic preconditioning stage, in tissue injury's stage
There is pkc δ hypotype, and occur in their brain neutrophilic granulocytes typically when reperfusion injury occurs.Additionally, research
Find that pkc ε protects rat brain damage by adjusting cerebral blood flow, propose pkc ε be probably treat ischemia injury target spot it
One.At present, the inhibitor of pkc δ hypotype is current to the research of damage during minimizing Reperfu- sion and the effect strengthening thrombolytic agent
The study hotspot of scientist, great Research Prospects.But, do not have the inhibitor medicaments of pkc δ hypotype to list at this stage.
Content of the invention
Goal of the invention
The present invention provides brand-new sequence, this sequence kinases inhibitor polypeptide, has good curative effect to apoplexy.
Technical scheme
Kinases inhibitor polypeptide is it is characterised in that its sequence is seq id no:1.
Application in treatment apoplexy medicine for the kinases inhibitor polypeptide.
Beneficial effect
Using solid-phase synthesis chemosynthesis kinases inhibitor polypeptide, this polypeptide has brand-new sequence, this polypeptide
Can be used for treating cerebral infarction.Set up rat cerebral infarction model, its pharmacological evaluation result shows, polypeptide of the present invention can
Improve the Neurological deficits of cerebral infarction model rat, reduce rat cerebral infarction area, reduce degree of cerebral edema and rat brain
Pkc δ kinase activity in tissue, compared with model group, has significant difference.It can be seen that, polypeptide of the present invention is to rat cerebral infarction mould
Type curative effect substantially, can be used as the effective candidate therapeutics of apoplexy.
Specific embodiment
Polypeptide is by Shanghai raw work gill synthesis.
Embodiment 1
The impact to rat cerebral infarction model cerebral infarct size for the kinases inhibitor polypeptide.
Take the sd male rat of 8-12w, set up rat cerebral infarction model, observe kinases inhibitor polypeptide to rat brain
The impact of cerebral infarction models.Rat anesthesia, takes and escribes mouth on the right side of cervical region, separates right side external carotid artery (eca) and internal carotid artery
(ica), separate eca trunk, ligation, cut-out at its far-end 1.5cm.The ligature of lifting eca stump, with vascular clamp in cca
Separate at eca, interim for eca folder closed, ligature between vascular clamp and eca stump together with stitching thread, it's not serious.Using 0.2-
0.3mm nylon wire silica gel line support catheter embolus, by eca stump inlet wire nearby, tightens stitching thread, unclamps vascular clamp, promote Buddhist nun
Imperial line enters people ica, enters people away from ica and eca crotch.During about 1.8-1.9cm, there is stop sense, show that bolt line has passed past in brain
Tremulous pulse (mca), reaches the initial part of anterior cerebral artery (aca).The record thromboembolism time started, stitching thread on eca is tightened.Thromboembolism
90min afterwards, nylon wire is extracted.100 rat model machines are divided into 5 groups after setting up by model, treatment group and matched group.Each group is equal
Subcutaneous injection relative medicine is given in the same day (first day) nylon wire when extracting, subsequently, 2 times/d, common 10d；The subcutaneous note for the treatment of group
Penetrate polypeptide of the present invention, dosage be respectively 40,20,10mg/kg, matched group urokinase, dosage be 1000u/kg.14d after modeling
Take cerebral tissue, section, 2%ttc dyeing, incubation, fixing after, take pictures and use image analysis system calculate brain piece infarct size and
Brain piece volume, calculates cerebral infarct volume percentage ratio, cerebral infarct volume percentage ratio=brain piece infarct size/brain piece area according to formula
× 100%, to evaluate the impact to rat cerebral infarction model for the polypeptide of the present invention.
The impact to rat cerebral infarction rat model cerebral infarct volume for table 1 polypeptide of the present invention
| Medicine | Dosage | Number of animals (n) | Rat cerebral infarction percent by volume (%) | |
| Model group | —— | —— | 20 | 46.73±7.30 |
| Positive group | Urokinase | 1000u/kg | 20 | 17.65±8.51** |
| Experimental group | Polypeptide of the present invention | 20mg/kg | 20 | 11.92±6.64** |
| Polypeptide of the present invention | 10mg/kg | 20 | 15.26±4.83** | |
| Polypeptide of the present invention | 5mg/kg | 20 | 18.49±3.19** |
*P < 0.05,**P < 0.01 is compared with model group
Polypeptide of the present invention is to rat cerebral infarction model result as shown in Table 1: polypeptide of the present invention can reduce rat cerebral infarction
Volume, is in dose dependent when dosage is in 10-40mg/kg, compared with model group, has significant difference.
Embodiment 2
The impact to pkc δ kinase activity in rat cerebral infarction model cerebral tissue for the kinases inhibitor polypeptide.
Take the sd male rat of 8-12w, set up rat cerebral infarction model, observe kinases inhibitor polypeptide to rat brain
The impact of cerebral infarction models.Modeling method is shown in embodiment 1.Model set up after 100 rat model machines are divided into 5 groups, treatment group and
Matched group.Each group all gives subcutaneous injection relative medicine in the same day (first day) nylon wire when extracting, subsequently, 2 times/d, common 10d；
Treatment group's subcutaneous injection polypeptide of the present invention, dosage be respectively 40,20,10mg/kg, matched group urokinase, dosage be 1000u/kg.
14d after modeling, eyeball takes blood, centrifugation, takes supernatant blood plasma, is measured in cerebral tissue using elisa test kit (promega company)
Pkc δ kinase activity, evaluates the impact to rat cerebral infarction model for the polypeptide of the present invention with this.
The impact to pkc δ kinase activity in rat cerebral infarction model cerebral tissue for table 2 polypeptide of the present invention
*P < 0.05,**P < 0.01 is compared with model group
Polypeptide of the present invention is to rat cerebral infarction model result as shown in Table 2: polypeptide of the present invention can reduce cerebral infarction model
Rat pkc δ kinase activity, is in dose dependent when dosage is in 10-40mg/kg, compared with model group, has statistics poor
Different.
Embodiment 3
The impact to rat cerebral infarction model Neurological deficits for the kinases inhibitor polypeptide.
Take the sd male rat of 8-12w, set up rat cerebral infarction model, observe kinases inhibitor polypeptide to rat brain
The impact of cerebral infarction models.Modeling method is shown in embodiment 1.Model set up after 100 rat model machines are divided into 5 groups, treatment group and
Matched group.Each group all gives subcutaneous injection relative medicine in the same day (first day) nylon wire when extracting, subsequently, 2 times/d, common 10d；
Treatment group's subcutaneous injection polypeptide of the present invention, dosage be respectively 40,20,10mg/kg, matched group urokinase, dosage be 1000u/kg.
After modeling, 14d observes Neurological deficits, with Neurological deficits for metrics evaluation polypeptide of the present invention to rat cerebral infarction
The impact of plug model.Brain function defect degree index, is described as: 0 point-impassivity functional impairment symptom, it is hanging that rat is carried tail
When two forelimbs earthward stretch；1 point-slight neurologic impairment, rat carried tail hanging when focus offside forelimb be in flexing,
Raise, take on interior receipts, elbow joint stretches；The focal neurologic impairment of 2 points-moderate, oriented paralysis side rotates sign；3 points-severe
Focal neurologic impairment, oriented focus offside tumble sign；4 points-no spontaneous activity and human-subject test declines.
The impact to rat cerebral infarction model Neurological deficits for table 3 polypeptide of the present invention
*P < 0.05,**P < 0.01 is compared with model group
Polypeptide of the present invention is to rat cerebral infarction model result as shown in Table 3: polypeptide of the present invention can improve cerebral infarction model
The Neurological deficits of rat, are in dose dependent when dosage is in 10-40mg/kg, compared with model group, have statistics
Difference.
Embodiment 4
The impact to rat cerebral infarction model cerebral edema for the kinases inhibitor polypeptide.Take the sd male rat of 8-12w, build
Vertical rat cerebral infarction model, observes the impact to rat cerebral infarction model for the kinases inhibitor polypeptide.Modeling method is shown in enforcement
Example 1.100 rat model machines are divided into 5 groups after setting up by model, treatment group and matched group.Each group is all in the same day (first day) Buddhist nun
Imperial line gives subcutaneous injection relative medicine when extracting, subsequently, 2 times/d, common 10d；Treatment group's subcutaneous injection polypeptide of the present invention, dosage
Be respectively 40,20,10mg/kg, matched group urokinase, dosage be 1000u/kg.After modeling, 14d takes cerebral tissue, with cerebral tissue
Water content evaluates the impact to rat cerebral infarction model for the kinases inhibitor polypeptide.Brain water content=(wet quality-dry
Quality)/wet quality × 100%.
The impact to rat cerebral infarction model cerebral edema for table 4 polypeptide of the present invention
*P < 0.05,**P < 0.01 is compared with model group
Polypeptide of the present invention is to rat cerebral infarction model result as shown in Table 4: polypeptide of the present invention can improve cerebral infarction model
The Neurological deficits of rat, are in dose dependent when dosage is in 10-40mg/kg, compared with model group, have statistics
Difference.
sequence listing
<110>Suzhou Pu Luoda bio tech ltd
<120>kinases inhibitor polypeptide and its application
<130>
<160> 1
<170> patent in version 3.3
<210> 1
<211> 65
<212> prt
<213>artificial sequence
<400> 1
gly ala glu lys lys gln gln met ala arg glu tyr arg glu lys ile
1 5 10 15
glu thr glu leu arg asp ile cys asn asp val leu ser leu leu glu
20 25 30
lys phe leu ile pro asn ala ser gln ala glu ser lys val phe tyr
35 40 45
leu lys met lys gly asp tyr tyr arg tyr leu ala glu val ala ala
50 55 60
gly
65
Claims (2)
1. kinases inhibitor polypeptide is it is characterised in that its sequence is seq id no:1.
2. application in treatment apoplexy medicine for the kinases inhibitor polypeptide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610766461.9A CN106349346A (en) | 2016-08-30 | 2016-08-30 | Protein kinase inhibitor polypeptide and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610766461.9A CN106349346A (en) | 2016-08-30 | 2016-08-30 | Protein kinase inhibitor polypeptide and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106349346A true CN106349346A (en) | 2017-01-25 |
Family
ID=57856701
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610766461.9A Pending CN106349346A (en) | 2016-08-30 | 2016-08-30 | Protein kinase inhibitor polypeptide and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106349346A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298884A (en) * | 1999-12-03 | 2001-06-13 | 上海博道基因技术有限公司 | Human cyclic adenylicacid dependent protein kinase inhibitor-9 and polynucleotide for coding said polypeptide |
| CN104059130A (en) * | 2014-06-27 | 2014-09-24 | 苏州普罗达生物科技有限公司 | ST2 protein inhibitor related polypeptide and application thereof |
-
2016
- 2016-08-30 CN CN201610766461.9A patent/CN106349346A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298884A (en) * | 1999-12-03 | 2001-06-13 | 上海博道基因技术有限公司 | Human cyclic adenylicacid dependent protein kinase inhibitor-9 and polynucleotide for coding said polypeptide |
| CN104059130A (en) * | 2014-06-27 | 2014-09-24 | 苏州普罗达生物科技有限公司 | ST2 protein inhibitor related polypeptide and application thereof |
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Application publication date: 20170125 |