CN101041693B - Novel blood sugar lowing polypeptide and uses thereof - Google Patents
Novel blood sugar lowing polypeptide and uses thereof Download PDFInfo
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- CN101041693B CN101041693B CN2007100267597A CN200710026759A CN101041693B CN 101041693 B CN101041693 B CN 101041693B CN 2007100267597 A CN2007100267597 A CN 2007100267597A CN 200710026759 A CN200710026759 A CN 200710026759A CN 101041693 B CN101041693 B CN 101041693B
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Abstract
The present invention discloses a GLP-1 analog, specifically relating to a GLP-1 remodeling polypeptide which can promote insulin secretion and lower blood sugar so as to treat type II diabetes. The present invention provides a group of GLP-1 analog polypeptide sequence which has a general formula: HX1EGTFTSDX2SSYLEGQAAKX3FIX4WLVKGR (formula I), wherein X1 is Ala, Gly or Val; X2 is Val, Leu or Ala; X3 is Leu or Ser; X4 is Glu or Asn. The internal experiment proves that the polypeptide provided by the present invention has the advantages of longer half-life period, promoting insulin secretion, lowering blood sugar, and is superior to the effect of natural GLP-1.
Description
Technical field
The present invention relates to human glucagon-like-peptide-1 (GLP-1) analogue, specifically the present invention relates to GLP-1 and change the structure polypeptide, this polypeptide has the promotion insulin secretion in vivo, and the effect of lowering blood glucose can be used for treating type ii diabetes.
Background technology
According to report in the IDF (IDE) 2006 " Diabetes Atlas ", diabetes spread in the whole world.The whole world 2.46 hundred million people of diabetes invasion and attack at present account for 5.9% of global population, and are in developing country near 80% in patient's total number of persons, and wherein India 4,090 ten thousand, China 39,800,000.Predict in the report that as not taking any measure, the patient who suffers from diabetes will be increased to 3.8 hundred million populations in next two decades.The develop rapidly of the popular and treatment Glucovance of whole world diabetes with the annual growth by 16% in the market that makes diabetes medicament, reaches 20,000,000,000 dollars in 2006.The diabetic subject mainly is divided into two kinds of insulin-dependent diabetes mellitus (type i diabetes) and non insulin dependent diabetess (type ii diabetes), and wherein type ii diabetes accounts for more than 90% of diabetes sum.The control of type ii diabetes is an emphasis of diabetes study.Because the pathogenesis of diabetes is still very not clear and definite, at present mainly by long-term prescription with lowering blood glucose, the control complication.Treat type ii diabetes in the world based on sulfonylureas, be aided with medicines such as biguanides, alpha-glucosidase inhibitor.But, because the side effect of sulfonylureas is big, life-time service can cause beta Cell of islet depletion because of the Regular Insulin excessive secretion, takes among the diabetics of this type of medicine, has every year 10% patient to use other class medicines such as Regular Insulin instead because of the treatment inefficacy.In the finder's of boston, u.s.a hospital general in 1984 enteron aisle, exist a class to promote that polypeptide has just become the exploitation focus of treatment type ii diabetes medicine of new generation since the polypeptide (general designation GLP-1) of insulin secretion.
GLP-1 (7-36) is 36 amino acid fragments that end of the 7th beginning to the of preceding Proglucagon, be the polypeptide that 30 amino acid are formed, aminoacid sequence is as follows: HisAlaGluGlyThrPheThrSerAspValSerSerTyrLeuGluGlyGlnAlaAl aLysGluPheIleAlaTrpLeuValLysGlyArg.
GLP-1 (7-36) is by complicated machine-processed controlling blood sugar, and comprising the secretion to Regular Insulin and hyperglycemic-glycogenolytic factor (glucagon), the emptying of stomach and the insulin sensitivity of periphery are regulated.Present in addition experimentation on animals shows that GLP-1 can suppress the apoptosis of β cell, stimulates the growth and the differentiation of β cell, promotes the β transformation, thereby can solve the problem of β cell function disorder, for the treatment of type ii diabetes provides brand-new approach.Compare with the diabetes medicament that has come out in the world, GLP-1 has 4 quantum jump advantages: the one, can promote the hyperplasia of beta Cell of islet to a certain extent diabetes to be had therapeutic action.That is to say that it can effect a radical cure diabetes, and existing medicine can only disease controlling, can not effect a permanent cure.The 2nd, security is higher, and the effect of its insulin secretion accelerating depends on glucose level, and medicine just can not work when blood sugar was low, thereby the hypoglycemia of having avoided the Regular Insulin excessive secretion to cause takes place, and can use safely.The 3rd, to using the invalid patient of sulfonylureas, GLP-1 is still effective.The 4th, can reduce enterogastric peristalsis, delay stomach emptying, help to lose weight.GLP-1 can not produce antibody to human body, can improve the insulin receptor susceptibility of perienchyma, helps to treat insulin resistance.The secretion of glucagon suppression simultaneously improves patient's medium-term and long-term biochemical indicators such as glycolated hemoglobin, fructosamine.At the research of its effect of weight reducing also in extensively carrying out.
GLP-1 has the type ii diabetes of being used for the treatment of good properties, but its very short in vivo transformation period (being about 2 minutes) has been limited the possibility of its direct drug injection.Studies show that the GLP-1 degradation in vivo mainly be dipeptidyl peptidase 4 (dipeptidyl peptidase IV, DPP-IV) and neutral endopeptidase (neutralendopeptide, NEP) 24.11 rapid degraded.DPP-IV mainly is being to shear N end Ala
8And Glu
9Between peptide bond, can make GLP-1 lose most activity.NEP 24.11 in vivo can hydrolysis aromatic series amino or the N-terminal peptide bond of hydrophobic amino acid, has 6 site: Asp in the GLP-1 kind
15-Val
16, Ser
18-Tyr
19, Tyr
19-Leu
20, Glu
27-Phe
28, Phe
28-Ile
29And Trp
31-Leu
32Research and development strategy based on GLP-1 mainly contains two aspects now: the one, and the inhibitor of exploitation DDP-IV enzyme is in the hope of the degraded of the GLP-1 that produces in the body that slows down; The 2nd, the GLP-1 peptide sequence is carried out amino acid replace, obtain the GLP-1 analogue, use PEG, lipotropy long-chain etc. carries out amino acid modified to GLP-1, to obtain the longer transformation period of GLP-1.
These discover that GLP (7-15) (Exendin1-9) has very high conservative property on structure and composition, substitute His by analyzing Ala
7, Gly
10, Phe
12, Thr
13And Asp
15To the reduction degree of the activation capability of acceptor affinity and adenylyl-cyclase, these amino acid play a significant role in combination and the activation to acceptor.Same test also confirms Phe
28And Ile
29In receptors bind with activate and to play a role, analyzing these two amino acid through circular dichroism spectrum in addition has prior contribution in the secondary structure of keeping polypeptide, thereby helps combining of polypeptide and acceptor.GLP-1 (7-34) and GLP-1 (7-35) can reduce the affinity with acceptor, and GLP-1 (7-33), GLP-1 (7-22) and GLP-1 (7-20) then do not show biological activity.
Simultaneously, adopt Gly substitute for Al a8, the degraded that can resist DDP-IV, but Gly
8The insulin secretion accelerating of-GLP-1 (7-36) and hypoglycemic activity greatly reduce than GLP-1 (7-36), the AA with GLP-1 (7-37) that has
8Be replaced as D-type amino acid, as D-Ala
8-GLP-1, D-Glu
9-GLP-1, promoting insulin secretion is all well below GLP-1 (7-36) as a result.In addition, add the peptide chain of EXENDIN-4 (31-39), can return to the activity level of GLP-1 (7-36), the Degradation that can resist DDP-IV simultaneously at the C-terminal of GLP-1.GLP-1 (7-37), add 1 or several amino acid residue outside the His of the N-end of GLP-1 (7-36) or remove two amino-acid residues, then do not have promoting insulin secretion, as GLP-1 (1-37), GLP-1 (6-37), GLP-1 (8-37) does not have promoting insulin secretion.As seen many research of carrying out before does not all obtain the blood sugar reducing function and the stability that greatly improve than GLP-1 (7-36).
Summary of the invention
The object of the present invention is to provide a kind of novel glp-1-1 analogue, this polypeptide has the transformation period longer than GLP-1 in vivo, and the promotion insulin secretion that is better than GLP-1 is arranged, and the effect of lowering blood glucose can be used for the treatment of type ii diabetes.
The objective of the invention is to realize by the following technical solutions:
By the analysis to analogue or the allosteric body of GLP-1 (7-36), we find that homology or amino acid whose similar performance that the variation of a lot of peptide sequences all is based on polypeptide change, and do not analyze from the secondary structure of peptide sequence.The present invention is exactly the preliminary screening that begins to carry out polypeptide from secondary structure, and the effect that adopts interior hypoglycemic effect of body and pancreotropic hormone to produce is then estimated the biological activity of the GLP-1 analogue of the present invention's design, to obtain to have the sequence of practical application.
The present invention modifies the main action site of the DDP-IV of the topmost factor that influences GLP-1 stability, i.e. the Ala of GLP-1
8Carboxyl terminal amino acid; While has also been carried out relevant researching and analysing for the modification of the restriction enzyme site of NEP 24.11, mainly is at GLP-1 (12-15).By information biology instruments such as prodictprotein protein structure prediction software, Vector NTI DNA and sequential analysis of protein softwares, GLP-1 similar polypeptide sequence is screened analysis.According to the similar principle of secondary structure, obtain one group of GLP-1 analogue polypeptide sequence.
One group of GLP-1 analogue polypeptide sequence provided by the invention, this polypeptide has the general formula of formula I:
....,....1....,....2....,....3
HX
1EGTFTSDX
2SSYLEGQAAKX
3FIX
4WLVKGR (formula I)
X
1: Ala, Gly or Val
X
2: Val, Leu or Ala
X
3: Leu or Ser
X
4: Glu or Asn
We adopt normal rat is trial model, with the positive contrast of parent GLP-1 (7-36), identifies in vivo stability and hypoglycemic of polypeptide of the present invention, promotes insulinogenic effect.In vivo test proves, polypeptide of the present invention in vivo the transformation period longer, can stimulate the generation of Regular Insulin, the lowering blood glucose value is better than the effect of natural GLP-1.
Description of drawings
Fig. 1 is the diagram () of embodiment three polypeptide hypoglycemic activities;
Fig. 2 is the diagram (two) of embodiment three polypeptide hypoglycemic activities;
Fig. 3 is the diagrams of embodiment four rats through hypoglycemic activity after the fasting;
Fig. 4 is the diagrams of embodiment five rats through promoting insulin secretion after the fasting;
Fig. 5 is the not diagrams of hypoglycemic activity during fasting of embodiment six rats;
Fig. 6 is the not diagrams of promoting insulin secretion during fasting of embodiment seven rats.
Embodiment
Embodiment 1:
The present invention modifies the main action site of the topmost factor DDP-IV that influences GLP-1 stability, i.e. the Ala of GLP-1
8Carboxyl terminal amino acid; While has also been carried out relevant researching and analysing for the modification of the restriction enzyme site of NEP 24.11, mainly is at GLP-1 (12-15).By information biology instruments such as prodictprotein protein structure prediction software, Vector NTI DNA and sequential analysis of protein softwares, GLP-1 similar polypeptide sequence is screened analysis.According to the similar principle of secondary structure, obtain one group of GLP-1 analogue polypeptide sequence.
Primary dcreening operation GLP-1 analogue is listed below:
SEQ?NO?1
SEQ?NO?2
SEQ?NO?3
SEQ?NO?4
SEQ?NO?5
SEQ?NO?6
SEQ?NO?7
SEQ?NO?8
SEQ?NO?9
SEQ?NO?10
SEQ?NO?11
SEQ?NO?12
SEQ?NO?13
SEQ?NO?14
SEQ?NO?15
SEQ?NO?16
SEQ?NO?17
SEQ?NO?18
SEQ?NO?19
SEQ?NO?20
SEQ?NO?21
SEQ?NO?22
SEQ?NO?23
SEQ?NO?24
SEQ?NO?25
SEQ?NO?26
SEQ?NO?27
SEQ?NO?28
SEQ?NO?29
SEQ?NO?30
SEQ?NO?31
SEQ?NO?32
SEQ?NO?33
SEQ?NO?34
SEQ?NO?35
SEQ?NO?36
Obtain sequence: SEQ NO 2, SEQ NO 5, SEQ NO 6, SEQ NO 7, SEQ NO 8, SEQ NO 17, SEQ NO 18 and SEQ NO 33 by software analysis and very big similarity is arranged on secondary structure with GLP-1 (7-36).
Embodiment 2: chemically synthesized polypeptide
Adopt one of synthetic polypeptide of the present invention of solid-phase synthesis, sequence is: HGEGTFTSDLSSYLEGQAAKLFIEWLVKGR-NH
2(SEQ NO 17), other peptide sequence synthetic method is similar.
Synthesis technique
Adopt the Fmoc synthesis method, select Rink-Amide-MBHA Resin (purchase in Nankai with become company) to synthesize.Synthesis step is as follows:
The Fmoc-amino acid starting materials of 17 kinds of band Side chain protective groups---solid phase synthesis------HPLC purifying---lyophilize---the GLP analogue that takes off Side chain protective group
2. the process of solid phase synthesis
Adopt HBTU/HOBt method activated amino acid, be connected on the aminoresin, carried out for 30 steps altogether and synthesize according to sequence.
(1) plant and instrument:
Applied Biosystem Peptide synthesizer, the 433A type
Wherein: DMF=N, dinethylformamide
DIEA=N, the N-diisopropylethylamine
The NMP=N-methyl-2-pyrrolidone
The HOBT=1-hydroxybenzotriazole
HBTU=2 benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester
(3) operation
With the 1mmole scale is example; take by weighing resin 2 grams (the resin charging ratio is 0.5mmole/g); pour in the Peptide synthesizer reactor, take by weighing 4mmole from the C-end to the N-end according to the aminoacid sequence of GLP analogue and be with protecting group amino acid accordingly, and be arranged in the synthesizer.At ambient temperature, finish 30 step building-up reactionss automatically according to computer program.
Behind the end of synthesis, obtain polypeptide resin with Side chain protective group.Take out polypeptide resin, put into vacuum drier and weigh after dry 2 hours.
3. deprotection base and precipitation:
(1) plant and instrument
The magnetic agitation instrument
(3) operation
The GLP analogue polypeptide resin of band protecting group is inserted in the Erlenmeyer flask of band plug, adds lytic reagent such as following table:
Constant temperature under 25 ℃ of conditions, stirring reaction 4 hours; Filter, collect filtrate, resin washs with a small amount of trifluoroacetic acid, filters and integrates with collection liquid.Under agitation, Dropwise 5 00mL ices ether (10 ℃), obtains white precipitate, filters, and washs crude product with a small amount of ice ether, and crude product is put into the vacuum drier dried overnight.
4.HPLC purifying
(3) purifying
Prepare the pure product trifluoroacetic acid of GLP analogue salts solution (purity>95%) by the anti-phase purifying of HPLC.
1. chromatographic column:
50mm*250mm Kromasil RP-18 10 μ m 100A preparative chromatography posts
2. moving phase:
The A:0.1% trifluoroacetic acid aqueous solution
B:0.1% trifluoroacetic acid acetonitrile solution
3. go up sample solution:
Polypeptide crude product (purity about 40~50%) is used: 0.1% trifluoroacetic acid aqueous solution is made into the solution that concentration is 8.0mg/ml (pressing crude product calculates), and by 0.22 μ m membrane filtration.
4. elution requirement:
Adopt linear gradient elution, flow velocity is 120ml/min, and ultraviolet 280nm detects, gradient
5. sample collection:
During 25-35 minute, collect the wash-out main peak according to the distribution of 60ml/ bottle, and each sample liquid is carried out analyzing and testing.Merge all purity greater than 95% sample liquid.
(4) change salt
The sample liquid that purifying is good prepares the pure product acetate solution of GLP analogue (purity>95%) by the anti-phase salt that changes of HPLC.
1. chromatographic column:
50mm*250mm Kromasil RP-18 10 μ m 100A preparative chromatography posts
2. moving phase:
The A:0.5% acetic acid aqueous solution
B:0.5% acetate acetonitrile solution
3. go up sample solution:
Add the equal-volume ultrapure water to the pure solution of polypeptide.
4. elution requirement:
Adopt linear gradient elution, flow velocity is 120ml/min, and ultraviolet 280nm detects, gradient such as following table:
5. sample collection:
Collect all wash-out main peak solution.
6. remove acetonitrile:
Pour polypeptide solution into round-bottomed flask, 25 ℃, rotary evaporation under the-0.099Mpa condition is removed all acetonitriles, and remaining liq is waited until lyophilize by 0.22 μ m membrane filtration.
5. lyophilize
(2) operation
GLP analogue aqueous acetic acid is poured in the vacuum freeze drier sample disc, carried out freeze-drying, obtain required compound according to computer program.
Embodiment 3: the research trial of polypeptide hypoglycemic activity
Test materials:
1, sample:
SEQ?NO?2:HAEGTFTSDVSSYLEGQAAKLFINWLVKGR-NH2
SEQ?NO?5:HAEGTFTSDLSSYLEGQAAKLFIEWLVKGR-NH2
SEQ?NO?6:HAEGTFTSDLSSYLEGQAAKLFINWLVKGR-NH2
SEQ?NO?7:HAEGTFTSDLSSYLEGQAAKSFIEWLVKGR-NH2
SEQ?NO?8:HAEGTFTSDLSSYLEGQAAKSFINWLVKGR-NH2
SEQ?NO?17:HGEGTFTSDLSSYLEGQAAKLFIEWLVKGR-NH2
SEQ?NO?18:HGEGTFTSDLSSYLEGQAAKLFINWLVKGR-NH2
SEQ?NO?33:HVEGTFTSDASSYLEGQAAKLFIEWLVKGR-NH2
GLP-1 (7-36) positive contrast: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2
2, animal: the Wistar rat, body weight 280~300g, male, provide by preclinical medicine institute of Jilin University experimentation on animals center.
3, reagent: 1. blood sugar test kit, Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd.; 2. Regular Insulin (INS) radioimmunoassay medicine box, the Fu Rui of Beijing bio-engineering corporation.
4, instrument: 1. GF-D800 type semi-automatic biochemical analyzer, Shandong Gaomi Caihong Analytical Instrument Co., Ltd.;
2. FJ-2008 active immunity counter, Xi'an Plant No. 262.
Test method:
1, dosage design: the dosage that respectively is subjected to the reagent product is rat skin lower injection 70 μ gkg
-1, abdominal injection 20% glucose 3.5mlkg
-1
2, make up a prescription: get glucose 35g, adding distil water is to 175ml, and promptly 20%, heat sterilization, standby.Get and be subjected to reagent and GLP-1 (7-36) sample 5mg, add physiological saline 2ml dissolving and be mixed, be i.e. 2.5mg/ml; Get 0.1ml and be subjected to reagent solution to add physiological saline, be i.e. 70 μ g/ml (standby, as to face and use preceding preparation) to 3.57ml.
3, get 20 of rats, be divided into 10 groups: blank group, positive controls and 8 polypeptide test group.First eye socket blood sampling before the administration, the above-mentioned preparation of subcutaneous injection be subjected to reagent thing 1mlkg
-1, the isopyknic physiological saline of blank group subcutaneous injection, abdominal injection 20% glucose 3.5mlkg immediately
-1Respectively at 10min, 20min, 30min, 45min, the blood sampling of 60min eye socket after the administration, with 3000 rev/mins of centrifugal 10min of institute's blood sampling, get serum, end-point method is surveyed blood sugar.
The result: shown in figure one and figure two, each test polypeptide all has certain hypoglycemic activity, and is wherein obvious with the effect of SEQ NO 17 polypeptide.
Embodiment 4: hypoglycemic activity (fasting) in the body
Test sample:
Sequence is SEQ NO 17:HGEGTFTSDLSSYLEGQAAKLFIEWLVKGR-NH
2,
GLP-1 (7-36) positive contrast: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2
Test method:
Get 24 of rats, divide equally 3 groups: blank group, test group and positive controls, fasting be can't help water 16 hours, first eye socket blood sampling before the administration, the above-mentioned preparation of subcutaneous injection be subjected to reagent thing 1mlkg
-1, the isopyknic physiological saline of control group subcutaneous injection, abdominal injection 20% glucose 3.5mlkg immediately
-1Respectively at 10min, 20min, 30min, 45min, the blood sampling of 60min eye socket after the administration, with 3000 rev/mins of centrifugal 10min of institute's blood sampling, get serum, end-point method is surveyed blood sugar.
The result: behind abdominal injection glucose, with respect to the blank test group, positive control and sample experimental group can both significantly reduce the intravital blood sugar concentration of rat; Sample sets and positive controls are suitable in the effect of hypoglycemic effect, and can also reflect among the result that relative positive control of sample transformation period in the body of rat is slightly long.
Embodiment 5: promoting insulin secretion (fasting) in the body
The method of embodiment 4 described blood sugar detections obtains supernatant serum, adopts the insulin content of putting in the method mensuration serum of exempting from again.
Result: the process more complicated that Regular Insulin produces in vivo, be subjected to blood sugar concentration simultaneously, the influence of aspect such as islet cells and medicine, but in the early stage (10min) of experiment, the high-caliber secretion of Regular Insulin has all appearred in positive control and sample experimental group, reach 92.13 μ U/ml and 84.15 μ U/ml respectively, and under the similarity condition, blank test group secretion of insulin is 67.13 μ U/ml.The show sample group can promote secretion of insulin in the rat body as a result.
Embodiment 6: hypoglycemic activity in the body
Operation is as embodiment 4, and just laboratory animal does not need fasting before the experiment, and directly eye socket is got blood.In the experiment, the relative blank test group with the positive control experimental group of sample sets all can reduce intravital blood sugar concentration; Sample sets is in 30min to 45 minute, and blood sugar concentration almost has been returned to the level before the administration, is disclosed in this process of the test to have more stability and long-lasting than positive controls.
Embodiment 7: promoting insulin secretion in the body
The method of embodiment 6 described blood sugar detections obtains supernatant serum, adopts the insulin content of putting in the method mensuration serum of exempting from again.In the experiment, the insulin level in the blood of sample sets is apparently higher than the blank group, and particularly in 10min, the insulin level of two groups differs and reaches 81 μ U/ml; In 30 minutes of injection, the insulin concentration in the sample sets blood is all kept higher level with respect to the blank test group.Experiment discloses the generation that sample can promote Regular Insulin in the body effectively.
Sequence table
<110〉Zhuhai United Laboratories Ltd
<120〉a kind of novel blood sugar lowing polypeptide and application thereof
<160>1
<210>1
<211>30
<212>PRT
<213〉artificial sequence
<220>
<223〉artificial sequence description: blood sugar lowing polypeptide
<220>
<221>(2)
<223〉Xaa=Ala or Gly or Val
<220>
<221>(10)
<223〉Xaa=Val or Leu or Ala
<220>
<221>(21)
<223〉Xaa=Leu or Ser
<220>
<221>(24)
<223〉Xaa=Glu or Asn
<400>1
His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Xaa?Ser?Ser?Tyr?Leu?Glu?Gly
1 5 10 15
Gln?Ala?Ala?Lys?Xaa?Phe?Ile?Xaa?Trp?Leu?Val?Lys?Gly?Arg
20 25 30
Claims (5)
1. blood sugar lowing polypeptide, any one in its aminoacid sequence such as the following sequence:
SEQ?NO?2:HAEGTFTSDVSSYLEGQAAKLFINWLVKGR;
SEQ?NO?5:HAEGTFTSDLSSYLEGQAAKLFIEWLVKGR;
SEQ?NO?6:HAEGTFTSDLSSYLEGQAAKLFINWLVKGR;
SEQ?NO?7:HAEGTFTSDLSSYLEGQAAKSFIEWLVKGR;
SEQ?NO?8:HAEGTFTSDLSSYLEGQAAKSFINWLVKGR;
SEQ?NO?17:HGEGTFTSDLSSYLEGQAAKLFIEWLVKGR;
SEQ?NO?18:HGEGTFTSDLSSYLEGQAAKLFINWLVKGR;
SEQ?NO?33:HVEGTFTSDASSYLEGQAAKLFIEWLVKGR。
2. pharmaceutical composition, it contains blood sugar lowing polypeptide as claimed in claim 1.
3. pharmaceutical composition as claimed in claim 2, it contains pharmaceutically acceptable thinner, vehicle or carrier.
4. the described blood sugar lowing polypeptide of claim 1 is in the application that is used for preparing the medicine for the treatment of diabetes.
5. blood sugar lowing polypeptide as claimed in claim 4 is characterized in that in the application that is used for preparing the medicine for the treatment of diabetes described diabetes are type ii diabetes.
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CN102363633B (en) * | 2011-11-16 | 2013-11-20 | 天津拓飞生物科技有限公司 | Glucagon like peptide-1 mutant polypeptide and preparation method, medicinal composition and use thereof |
CN103333223A (en) * | 2012-11-22 | 2013-10-02 | 中国药科大学 | A novel blood-glucose-reducing polypeptide and applications thereof |
CN104945499B (en) * | 2014-03-31 | 2019-12-10 | 博瑞生物医药(苏州)股份有限公司 | GLP-1 analogue with modified structure and preparation method thereof |
CN104031141B (en) * | 2014-05-30 | 2016-08-24 | 天津世传生物科技有限公司 | For treating long-acting intestinal hormones polypeptide analog and the application of type 2 diabetes mellitus |
JP6984923B2 (en) * | 2017-09-19 | 2021-12-22 | イミュンワーク インク.Immunwork Inc. | Pharmaceutical constructs with enhanced binding affinity for albumin |
CN109762059B (en) * | 2019-03-28 | 2021-01-12 | 清紫生物科技(深圳)有限公司 | Novel glucagon analogue and application thereof |
CN115785249B (en) * | 2022-10-13 | 2023-07-21 | 江苏师范大学 | GLP-1 analogues and application thereof |
Citations (3)
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CN1468258A (en) * | 2000-06-16 | 2004-01-14 | Glucagon-like peptide-1 analogs | |
CN1746188A (en) * | 2004-09-06 | 2006-03-15 | 上海华谊生物技术有限公司 | Analog of GLP-1 |
CN1893980A (en) * | 2003-12-18 | 2007-01-10 | 诺沃挪第克公司 | Novel GLP-1 analogues linked to albumin-like agents |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1468258A (en) * | 2000-06-16 | 2004-01-14 | Glucagon-like peptide-1 analogs | |
CN1893980A (en) * | 2003-12-18 | 2007-01-10 | 诺沃挪第克公司 | Novel GLP-1 analogues linked to albumin-like agents |
CN1746188A (en) * | 2004-09-06 | 2006-03-15 | 上海华谊生物技术有限公司 | Analog of GLP-1 |
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