CN106432471B - A kind of novel Africa xenopus glucagon-like-peptide-1 (GLP-1) conjugation peptide and its application - Google Patents

A kind of novel Africa xenopus glucagon-like-peptide-1 (GLP-1) conjugation peptide and its application Download PDF

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CN106432471B
CN106432471B CN201611152536.0A CN201611152536A CN106432471B CN 106432471 B CN106432471 B CN 106432471B CN 201611152536 A CN201611152536 A CN 201611152536A CN 106432471 B CN106432471 B CN 106432471B
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glu
pro
gly
lys
ser
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CN106432471A (en
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韩京
傅俊杰
崔旭
周凤
费颖颖
张莹
司鹏斌
胡月
卫婷
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Jiangsu Normal University
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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
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

The present invention relates to a kind of novel Africa xenopus glucagon-like-peptide-1 (GLP-1) conjugation peptide and its synthetic method and applications.It is introduced by the C-terminal in Africa xenopus GLP-1 and promotees spiral sequence, while carrying out PEGylated modification, obtain hypoglycemic activity holding and the Africa xenopus GLP-1 analog with longer pharmacological action time.Africa xenopus GLP-1 analog synthesis yield of the invention is high, at low cost, and the half-life period of analog significantly extends, and bioactivity is significantly improved.

Description

A kind of novel Africa xenopus glucagon-like-peptide-1 (GLP-1) conjugation peptide and its Using
Technical field
The present invention relates to a kind of novel Africa xenopus glucagon-like-peptide-1 (GLP-1) conjugation peptide and its applications.
Background technique
Diabetes (Diabetes Mellitus) are a kind of related with inherent cause and relevant to a variety of environmental factors Chronic systemic disease is the generation of the sugar due to caused by the absolute or relative deficiency of internal insulin secretion, fat, protein It thanks to disorder, insulin-dependent diabetes mellitus (1 type) and Non-Insulin Dependent Diabetes Mellitus (2 type) can be divided into, wherein 2 type patients account for 80% or more of diabetes cases.Diabetes are a kind of global high morbidities, are predicted according to the World Health Organization, complete by 2025 World diabetic is up to 300,000,000.The recent report on Epidemiological of China shows that diabetes mellitus in China illness rate is up to 9.7%, much higher than the average illness rate 6.4% in the whole world, estimate that China's diabetes number of patients is more than 9000 by this illness rate Ten thousand, and there is also about 1.5 hundred million potential risk of diabetes crowds.At present for the treatment of type 1 diabetes, research direction is exploitation Convenient drug administration, effective insulin preparation and substitute.And the treatment for diabetes B, clinical treatment means mainly make With oral hypoglycemic drug, traditional sulfonylurea and biguanides oral hypoglycemic agents offer limited effectiveness, oral diabetes drug is in treatment 2 In patients with type Ⅰ DM disease maximum deficiency be can not reverting diabetes the cause of disease, i.e., " temporary solution do not know this ", the life for beta Cell of islet Long, differentiation is proliferated without obvious effect.
Glucagon-like-peptide-1 (glucagon like peptide-1, GLP-1) is one kind of Intestinal L cells secretion Polypeptide incretin.Since Mojsov discovery GLP-1 in 1987 has strong pancreotropic hormone release action, related life Object and chemical research deepen continuously.GLP-1 can control the blood glucose of type 2 diabetic patient by number of mechanisms, work as blood sugar concentration When raising, by specifically being combined with GLP-1 high receptor, stimulate insulin secretion, the generation of glucagon suppression makes Postprandial blood sugar reduces and maintains constant level.In physiological conditions, the effect that GLP-1 stimulates insulin secretion depends on blood glucose Because of continuous release hypoglycemia will not occur for concentration.In addition to adjusting blood glucose, the most significant function of GLP-1 is to promote β cell again Raw and reparation, increases beta Cell of islet quantity.Furthermore GLP-1, which also has, adjusts nervous function, delay gastric emptying and reduces appetite etc. Effect.However endogenous or exogenous GLP-1 in vivo can be rapidly by DPP IVs (DPP-IV) and neutral restriction endonuclease (NEP 24.11) degrades and loses bioactivity, and Half-life in vivo only has two minutes or so, therefore natural GLP-1 is difficult to obtain Clinical use.
Although remarkable result of the GLP-1 in diabetes B treatment, recognized by people, it in vivo too short half The phase of declining limits the possibility of its direct patent medicine.DPP-IV is the major protein enzyme for making natural GLP-1 inactivation, and action site is Ala8-Glu9Between peptide bond.Another main metabolic enzyme of natural GLP-1 is NEP 24.11, and about 50% GLP-1 is in vivo It can be degraded by NEP24.11, there is the restriction enzyme site of multiple NEP 24.11, mainly Thr on GLP-1 peptide chain11-Phe12、Asp15- Val16、Ser18-Tyr19、Glu27-Phe28And Trp31-Leu32Site.Therefore, only displacement Individual amino acids can not resist NEP 24.11 degradations, and multiple amino acid replacements may be such that the hypoglycemic activity of compound declines.At present major part long-acting GLP-1 by The research of body agonist is modified both for the structure of GLP-1, and which has limited the research and development of -1 receptor stimulating agent of novel glp-1. Simultaneously as being difficult to resist NEP by the means of amino acid modification there are more 24.11 restriction enzyme site of NEP on natural GLP-1 24.11 degradation.
GLP-1 function and effect in the mammalian body are similar with people GLP-1, so being tied for mammal GLP-1 Structure modification is expected to discovery -1 analog of novel glp-1.Extend polypeptide at present, the method for protein drug half-life period is based primarily upon three kinds Principle: 1, increasing the molecular weight of protein drug, reduces glomerular filtration rate；2, using Free drug and mating type drug in blood The characteristics of balance is formed in slurry, slow release sequestered protein drug makes the balance of mating type drug and Free drug to trip Release drug direction is mobile；3, the immunogenicity for reducing heterologous protein, to reduce its internal clearance rate.
According to the above prompt, it is presumed that increasing polypeptide molecular weight if macro-radical can be introduced on peptide chain The immunogenicity for reducing polypeptide simultaneously, can significantly extend the half-life period of polypeptide.So we are first in Africa xenopus GLP- 1 C-terminal, which introduces, promotees spiral sequence, has increased its hypoglycemic activity, has further designed the PEGylated conjunction object of macromolecular, pass through maleimide Amine is connected with the Africa xenopus GLP-1 analog that cysteine changes structure, to extend the in vivo bioactivity effect of analog Time and increase its hypoglycemic, anti-obesity activity.
Summary of the invention
The present invention relates to a kind of Africa xenopus glucagon-like-peptide-1 (GLP-1) analogs.It is characterized in that its structure For following form:
His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6- Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19- Xaa20-Xaa21-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser
(SEQ.ID NO:1)
Wherein:
Xaa1:Ala, Leu, Val, Met, Ile, Tyr, Phe, Arg, Asn, Lys, Thr, Asp, His, Trp, Gln, Glu, Ser or Gly；
Xaa2:Cys (S-PEG anolog) or Thr；
Xaa3:Cys (S-PEG anolog) or Glu；
Xaa4:Cys (S-PEG anolog) or Tyr；
Xaa5:Cys (S-PEG anolog) or Leu；
Xaa6:Cys (S-PEG anolog) or Glu；
Xaa7:Cys (S-PEG anolog) or Glu；
Xaa8:Cys (S-PEG anolog) or Lys；
Xaa9:Cys (S-PEG anolog) or Ala；
Xaa10:Cys (S-PEG anolog) or Ala；
Xaa11:Cys (S-PEG anolog) or Lys；
Xaa12:Cys (S-PEG anolog) or Glu；
Xaa13:Cys (S-PEG anolog) or Phe；
Xaa14:Cys (S-PEG anolog) or Ile；
Xaa15:Cys (S-PEG anolog) or Glu；
Xaa16:Cys (S-PEG anolog) or Trp；
Xaa17:Cys (S-PEG anolog) or Leu；
Xaa18:Cys (S-PEG anolog) or Ile；
Xaa19:Cys (S-PEG anolog) or Lys；
Xaa20:Cys (S-PEG anolog) or Gly；
Xaa21:Cys (S-PEG anolog) or Lys；
On condition that the sequence is not His-Xaa1-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu- Tyr-Leu-Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro- Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2
Wherein Cys (S-PEG anolog) is selected from
Here, n is selected from 30~80.
It is preferred that the molecular weight of S-PEG anolog is~2000.
In one embodiment, the present invention relates to the Africa xenopus GLP-1 analogs with following sequence:
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Cys(S-PEG anolog)-Glu-Tyr- Leu-Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:2)
In one embodiment, the present invention relates to the Africa xenopus GLP-1 analogs with following sequence:
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Cys(S-PEG anolog)-Tyr- Leu-Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:3)
In one embodiment, the present invention relates to the Africa xenopus GLP-1 analogs with following sequence:
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Cys(S-PEG anolog)- Leu-Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:4)
In one embodiment, the present invention relates to the Africa xenopus GLP-1 analogs with following sequence:
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Cys(S-PEG anolog)-Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro- Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:5)
In one embodiment, the present invention relates to the Africa xenopus GLP-1 analogs with following sequence:
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Cys (S-PEG anolog)-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:6)
In one embodiment, the present invention relates to the Africa xenopus GLP-1 analogs with following sequence:
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys- Cys(S-PEG anolog)-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:7)
In one embodiment, the present invention relates to the Africa xenopus GLP-1 analogs with following sequence:
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys- Ala-Cys(S-PEG anolog)-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:8)
In one embodiment, the present invention relates to the Africa xenopus GLP-1 analogs with following sequence:
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys- Ala-Ala-Lys-Glu-Phe-Cys(S-PEG anolog)-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:9)
In one embodiment, the present invention relates to the Africa xenopus GLP-1 analogs with following sequence:
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys- Ala-Ala-Lys-Glu-Phe-I le-Glu-Trp-Cys(S-PEG anolog)-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:10)
In one embodiment, the present invention relates to the Africa xenopus GLP-1 analogs with following sequence:
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys- Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Cys(S-PEG anolog)-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:11)
The present invention also provides a kind of pharmaceutical compositions, including therapeutically effective amount at least one above compound or its medicine Acceptable salt and pharmaceutically acceptable carrier or diluent on.
Invention further provides above compound or its pharmaceutically acceptable salt and pharmaceutically acceptable loads The utilization of body or diluent in the drug that preparation is used for diabetes and obesity.
The present invention also provides the preparation methods of above compound, including biological expression, liquid phase synthesis and synthesis in solid state system Preparation Method.
A kind of synthetic method of Africa xenopus glucagon-like-peptide-1 (GLP-1) analog, it is characterized in that will MPEG2000-MAL is dissolved with methanol/water (v/v=1:1, pH 7.0), and the Africa xenopus that equimolar cysteine changes structure is added Glucagon-like-peptide-1 (GLP-1) analog, is stirred to react at room temperature, and after reaction, the direct system of reaction solution is for liquid phase Sterling is lyophilized to obtain in chromatogram purification.
Above compound chemical property provided by the invention is stablized, be not easy by intracorporal dipeptidyl peptidase IV (DPP-IV) and The immunogenicity of neutral endonucleases, compound reduces, and is not easy by glomerular filtration, the internal drop of all compounds Sugared action time significantly extends, and curative effect could be generated by overcoming natural GLP-1 and having to last for intravenous drip or continuous subcutaneous infusion Defect.In addition, above compound provided by the invention or compound are used to drop as pharmaceutical composition prepared by effective component When hypoglycemia and weight reducing treatments, existing significant long-acting hypoglycemic effect, there are also apparent antiobesity actions.
The present invention has the advantages that
1, peptide is conjugated in a kind of PEG- Africa xenopus glucagon-like-peptide-1 (GLP-1) proposed, is a kind of with completely new The GLP-1 analog of structure, biological half-life, more natural GLP-1 significantly extended, and hypoglycemic activity is also significantly better than naturally GLP-1 can be used for diabetes and fat treatment in addition, it also has good fat-reducing effect.
2, Africa xenopus GLP-1 analog synthesis process according to the present invention is simple, and at low cost, polypeptide crude product purity is big It in 80%, is greatly improved compared with conventional solid synthetic method, and easy to automate, large-scale, this makes it be more suitable for work Industry metaplasia produces.
Therefore Africa xenopus GLP-1 analog provided by the invention, synthesis cycle is short, high income, purifying crude are easy, raw Produce it is at low cost, be easy to industrial automation production.The Africa xenopus GLP-1 analog being prepared is more steady than natural GLP-1 Fixed, hypoglycemic effect time and hypoglycemic activity are better than natural GLP-1, and also have good fat-reducing effect, are suitable as The active constituent for treating diabetes and slimming medicine.
Detailed description of the invention
General description is done to the present invention above, following accompanying drawings is for illustrating specific embodiments of the present invention.Wherein:
Exenatide is shown in Fig. 1 and temperature of the Africa xenopus GLP-1 analog in rat plasma applies degradation figure；
Exenatide and Africa xenopus GLP-1 analog is shown in the intracorporal abdominal cavity sugar of db/db model mice in Fig. 2 Tolerance test blood glucose figure；
Exenatide and Africa xenopus GLP-1 analog is shown in the intracorporal non-fasting of db/db model mice in Fig. 3 Hypoglycemic tests blood glucose figure；
The weight that Exenatide and Africa xenopus GLP-1 the analog mouse in losing weight experiment is shown in Fig. 4 increases Dosage；
Specific embodiment
Following abbreviation is used in this specification:
DMF: dimethylformamide；DCM: methylene chloride；Fmoc:N-9- fluorenylmethyloxycarbonyl；DIC:N, N '-diisopropyl carbon Diimine；HOBT:1- hydroxyl-benzotriazole；TFA: trifluoroacetic acid；EDT: dimercaptoethane；HPLC: high performance liquid chromatography； ESI-MS: electrospray ionization mass spectrum；LC-MS: LC-MS mass spectrum；Gly: glycine；Ser: serine；Ala: alanine；Thr: Soviet Union Propylhomoserin；Val: valine；Ile: isoleucine；Leu: leucine；Tyr: tyrosine；Phe: phenylalanine；His: histidine； Pro: proline；Asp: asparatate；Met: methionine；Glu: glutamic acid；Trp: tryptophan；Lys: lysine；Arg: essence Propylhomoserin；Asn: asparagine；Gln: glutamine；Cys: cysteine.
The present invention is to be illustrated by the following example, but these embodiments do not do any restrictions solution of the invention It releases.
Embodiment 1
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Cys(S-PEG anolog)-Glu-Tyr- Leu-Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
The synthesis in solid state (0.1mmol) of (SEQ.ID NO:2)
(1) swelling of resin
Fmoc-Rink amide-MBHA Resin 0.262g (substitution amount 0.382mmol/g) is weighed, it is molten through 7mL DCM Swollen 2min, suction filtration removes DCM, then is swollen 30min with 10mL DCM, finally uses DCM, DMF 7mL to rinse well respectively.
(3) removing of Fmoc protecting group
The resin being swollen is put into reactor, 20% piperidines of 7mL/DMF (V/V) solution is added, in the reactor 180 degree of round-trip shaking reaction 5min, filter off solution after reaction by 25 DEG C of reaction temperature；Add 7mL20% piperidines/DMF (V/V) solution in the reactor 180 degree shake back and forth reaction 15min, 25 DEG C of reaction temperature.Solution is filtered off after reaction, is used DMF washes clean.Obtain sloughing the resin of the Fmoc protecting group of initial connection.
(4) synthesis of Ser-Rink amide-MBHAResin
By Ser (0.4mmol), DIC (0.4mmol), HOBT (0.4mmol) is dissolved in 5mLDMF, then this solution is added In resin above, 180 degree shakes back and forth in the reactor reacts 90min, and 25 DEG C of reaction temperature.Reaction is filtered out after reaction Liquid is washed resin 3 times with 7mLDMF.
(5) detection of coupling efficiency
With the coupling efficiency of ninhydrin method detection resin, chromogenic reaction is that feminine gender can enter next coupling cycles.
Ninhydrin method: taking a small amount of resin particle ethanol washing, is put into transparent vials and 5% ninhydrin ethyl alcohol, KCN is added Each 2 drop of pyridine solution (2ml 0.001M KCN is diluted in 98ml pyridine), 80% phenol ethanol solution, heats 5 points in 100 DEG C Clock, if the aobvious blue of resin is the positive.
(6) extension of peptide chain
According to the sequence of peptide chain, repeats above-mentioned deprotection and be sequentially connected corresponding amino acid the step of coupling until peptide Chain synthesis finishes, and obtains the resin for being connected with compound.
(7) on resin polypeptide cracking
The resin obtained above for being connected with compound is put into reaction flask, it is each that decomposition agent Reagent K (TFA/ benzene is added Methyl sulfide/water/phenol/EDT, 82.5:5:5:5:2.5, V/V) 5mL, then it is stirred to react 2h at normal temperature.It takes out after reaction Filter adds a small amount of TFA washing three times, merging filtrate, filtrate decompression concentration.It is white by being precipitated in a large amount of ice ether of concentration filtrate addition Color flocculent deposit, refrigerated centrifuge obtain the crude product of target polypeptides, ultimate yield 92.2%.
(8)Gly8-Cys17(S-PEG analog)-xGLP (7~36)-Ex-NH2
By mPEG2000- MAL is dissolved with methanol/water (v/v=1:1, pH 7.0), is added equimolar (7) step obtains half Cystine changes Africa xenopus glucagon-like-peptide-1 (GLP-1) analog of structure, is stirred to react at room temperature, after reaction, The direct system of reaction solution is for liquid chromatography purification, chromatographic condition are as follows: C18 reversed-phase column (320mm × 28mm, 5 μm)；Mobile phase A: 0.1%TFA/ water (V/V), Mobile phase B: methanol (V/V)；Eluent gradient: Mobile phase B 40%~90%, 20min；Flow velocity is 8mL/min Detection wavelength is 214nm, and sterling is lyophilized to obtain in the solution of collection.Since PEG is mixture, molecular weight 226.1+ 44n, n=40, the average theory relative molecular mass of compound are 6265.9 here.ESI-MS m/z:calu[M+5H]5+ 1254.2 [M+6H]6+1045.3；found[M+5H]5+1254.1 [M+6H]6+1045.6。
Embodiment 2~10
According to method described in embodiment 1, the Africa xenopus pancreas for obtaining embodiment 2~10 according to corresponding sequent synthesis is high - 1 (GLP-1) analog of blood glucose element sample peptide, confirms respective molecular weight by ESI-MS.
Embodiment 2
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Cys(S-PEG anolog)-Tyr- Leu-Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:3)
Average theory relative molecular mass is 6237.9.ESI-MS m/z:calu[M+5H]5+1248.6 [M+6H]6+ 1040.6；found[M+5H]5+1248.8 [M+6H]6+1040.7。
Embodiment 3
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Cys(S-PEG anolog)- Leu-Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:4)
Average theory relative molecular mass is 6203.9.ESI-MS m/z:calu[M+5H]5+1241.8 [M+6H]6+ 1034.9；found[M+5H]5+1242.0 [M+6H]6+1035.2。
Embodiment 4
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Cys(S-PEG anolog)-Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro- Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:5)
Average theory relative molecular mass is 6253.8.ESI-MS m/z:calu[M+5H]5+1251.7 [M+6H]6+ 1043.3；found[M+5H]5+1250.9 [M+6H]6+1043.5。
Embodiment 5
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Cys (S-PEG anolog)-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:6)
Average theory relative molecular mass is 6238.8.ESI-MS m/z:calu[M+5H]5+1248.8 [M+6H]6+ 1040.8；found[M+5H]5+1248.5 [M+6H]6+1040.2。
Embodiment 6
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys- Cys(S-PEG anolog)-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:7)
Average theory relative molecular mass is 6295.9.ESI-MS m/z:calu[M+5H]5+1260.2 [M+6H]6+ 1050.3；found[M+5H]5+1261.1 [M+6H]6+1050.9。
Embodiment 7
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys- Ala-Cys(S-PEG anolog)-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:8)
Average theory relative molecular mass is 6295.9.ESI-MS m/z:calu[M+5H]5+1260.2 [M+6H]6+ 1050.3；found[M+5H]5+1260.8 [M+6H]6+1050.5。
Embodiment 8
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys- Ala-Ala-Lys-Glu-Phe-Cys(S-PEG anolog)-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:9)
Average theory relative molecular mass is 6253.8.ESI-MS m/z:calu[M+5H]5+1251.7 [M+6H]6+ 1043.3；found[M+5H]5+1251.5 [M+6H]6+1043.2。
Embodiment 9
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys- Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Cys(S-PEG anolog)-Ile-Lys-Gly-Lys-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:10)
Average theory relative molecular mass is 6253.8.ESI-MS m/z:calu[M+5H]5+1251.7 [M+6H]6+ 1043.3；found[M+5H]5+1252.6 [M+6H]6+1043.9。
Embodiment 10
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys- Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Cys(S-PEG anolog)-Pro-Ser- Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(SEQ.ID NO:11)
Average theory relative molecular mass is 6238.8.ESI-MS m/z:calu[M+5H]5+1248.8 [M+6H]6+ 1040.8；found[M+5H]5+1248.9 [M+6H]6+1040.6。
Embodiment 11
Stability experiment of the Africa xenopus GLP-1 analog to rat plasma
Rat eye takes blood, and blood is fitted into the centrifuge tube containing heparin, and 3000rpm is centrifuged 10 minutes, takes supernatant blood plasma Blood plasma is incubated as temperature, using LC-MS come the response signal of detection compound.The Exenatide (control) and Africa xenopus of 100ul The blood plasma of GLP-1 analog and 100ul is placed in 37 DEG C of water-baths after vortex mixed, and temperature is incubated 24 hours, 0,1,2,4,8,12, 24,36,48,72h time points took 10ul, and 20ul acetonitrile precipitation is added, and 14000rpm centrifugation takes supernatant into LC-MS, calculates each The peak area at a time point, makes attenuation curve.As shown in Figure 1, the plasma half-life of Exenatide is 4h or so, and it is African The plasma half-life of Xenopus laevis GLP-1 analog is all at 36 hours or more.
Embodiment 12
The abdominal cavity sugar tolerance of Africa xenopus GLP-1 analog is tested
6 week old db/db diabetic mices, it is adaptive feeding one week, random to be grouped, every group six.Mouse is in fasting 18h, positive control Exenatide (25nmol/kg), negative control physiological saline and Africa xenopus are given in the abdominal cavity 30min in advance GLP-1 analog (25nmol/kg), 0min give in abdominal cavity glucose (1g/kg), in 0,15,30,60,120min blood glucose meter Monitor blood glucose level.As shown in Fig. 2, the hypoglycemic activity of Africa xenopus GLP-1 analog is suitable with Exenatide, illustrate PEGylated Do not have an impact the glycemic control of Africa xenopus GLP-1 analog.
Embodiment 13
The non-fasting hypoglycemic of Africa xenopus GLP-1 analog is tested
Seven week old db/db diabetic mices, adaptive feeding one week, the blood glucose value of blood glucose meter measurement mouse was higher than It is random to be grouped after 20mmol/L, every group six.It is divided into positive controls Exenatide (25nmol/kg), negative control group is raw Manage salt water, compound group SEQ.ID NO:5, SEQ.ID NO:6, SEQ.ID NO:10 (25nmol/kg).Mouse free water, Diet, 0h give compound, measure blood glucose with blood glucose meter 0,1,2,3,4,6,8,10,12,16,20,24,36,48h, make When m- blood glucose curve, detection each group mouse blood sugar is restored to the time of 8.35mmol/L.As shown in figure 3, the blood glucose of compound group The stable time is all significantly better than positive control Exenatide, their glucostasis times are above for 24 hours.
Embodiment 14
The losing weight of Africa xenopus GLP-1 analog is tested
6 week old db/db diabetic mices, it is adaptive feeding one week, random to be grouped, every group 6.Mouse is 2 times a day It gives positive control Exenatide (25nmol/kg), negative control physiological saline, gives SEQ.ID NO administration group 1 day 1 time: 5, SEQ.ID NO:6 (25nmol/kg), treatment cycle 20 days, the weight of the mouse of detection in every two days.As shown in figure 4, chemical combination Object energy SEQ.ID NO:5, SEQ.ID NO:6 enough significantly inhibit the body weight increase of mouse, and the effect of its weight loss is better than sun Property control Exenatide, show Africa xenopus GLP-1 analog have it is good treatment diabetes and weight-reducing it is medicinal before Scape.
<110>Jiangsu Normal University
<120>a kind of novel Africa xenopus glucagon-like-peptide-1 (GLP-1) conjugation peptide and its application
<160> 10
<210> 1
<211> 39
<212> PRT
<213>artificial sequence
<220>
<221>construct is synthesized
<222> (2)..(2)
<223>the 2nd Xaa are Ala, Leu, Val, Met, Ile, Tyr, Phe, Arg, Asn, Lys, Thr, Asp, His, Trp, Gln, Glu, Ser or Gly
<220>
<221>construct is synthesized
<222> (11)..(11)
<223>the 11st Xaa are Cys (S-PEG anolog) or Thr
<220>
<221>construct is synthesized
<222> (12)..(12)
<223>the 12nd Xaa are Cys (S-PEG anolog) or Glu
<220>
<221>construct is synthesized
<222> (13)..(13)
<223>the 13rd Xaa are Cys (S-PEG anolog) or Tyr
<220>
<221>construct is synthesized
<222> (14)..(14)
<223>the 14th Xaa are Cys (S-PEG anolog) or Leu
<220>
<221>construct is synthesized
<222> (15)..(15)
<223>the 15th Xaa are Cys (S-PEG anolog) or Glu
<220>
<221>construct is synthesized
<222> (16)..(16)
<223>the 16th Xaa are Cys (S-PEG anolog) or Glu
<220>
<221>construct is synthesized
<222> (17)..(17)
<223>the 17th Xaa are Cys (S-PEG anolog) or Lys
<220>
<221>construct is synthesized
<222> (18)..(18)
<223>the 18th Xaa are Cys (S-PEG anolog) or Ala
<220>
<221>construct is synthesized
<222> (19)..(19)
<223>the 19th Xaa are Cys (S-PEG anolog) or Ala
<220>
<221>construct is synthesized
<222> (20)..(20)
<223>the 20th Xaa are Cys (S-PEG anolog) or Lys
<220>
<221>construct is synthesized
<222> (21)..(21)
<223>the 21st Xaa are Cys (S-PEG anolog) or Glu
<220>
<221>construct is synthesized
<222> (22)..(22)
<223>the 22nd Xaa are Cys (S-PEG anolog) or Phe
<220>
<221>construct is synthesized
<222> (23)..(23)
<223>the 23rd Xaa are Cys (S-PEG anolog) or Ile
<220>
<221>construct is synthesized
<222> (24)..(24)
<223>the 24th Xaa are Cys (S-PEG anolog) or Glu
<220>
<221>construct is synthesized
<222> (25)..(25)
<223>the 25th Xaa are Cys (S-PEG anolog) or Trp
<220>
<221>construct is synthesized
<222> (26)..(26)
<223>the 26th Xaa are Cys (S-PEG anolog) or Leu
<220>
<221>construct is synthesized
<222> (27)..(27)
<223>the 27th Xaa are Cys (S-PEG anolog) or Ile
<220>
<221>construct is synthesized
<222> (28)..(28)
<223>the 28th Xaa are Cys (S-PEG anolog) or Lys
<220>
<221>construct is synthesized
<222> (29)..(29)
<223>the 29th Xaa are Cys (S-PEG anolog) or Gly
<220>
<221>construct is synthesized
<222> (30)..(30)
<223>the 30th Xaa are Cys (S-PEG anolog) or Lys
<400> 1
His Xaa Glu Gly Thr Tyr Thr Asn Val Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10 15
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30 35
<210> 2
<211> 39
<212> PRT
<213>artificial sequence
<220>
<221>construct is synthesized
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Cys (S-PEG anolog) Glu Tyr Leu Glu Glu Lys Ala Ala
1 5 10 15
Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30 35
<210> 3
<211> 39
<212> PRT
<213>artificial sequence
<220>
<221>construct is synthesized
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Cys (S-PEG anolog) Tyr Leu Glu Glu Lys Ala Ala
1 5 10 15
Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30 35
<210> 4
<211> 39
<212> PRT
<213>artificial sequence
<220>
<221>construct is synthesized
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Cys (S-PEG anolog) Leu Glu Glu Lys Ala Ala
1 5 10 15
Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30 35
<210> 5
<211> 39
<212> PRT
<213>artificial sequence
<220>
<221>construct is synthesized
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Cys (S-PEG anolog) Glu Glu Lys Ala Ala
1 5 10 15
Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30 35
<210> 6
<211> 39
<212> PRT
<213>artificial sequence
<220>
<221>construct is synthesized
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Ley Glu Glu Cys (S-PEG anolog) Ala Ala
1 5 10 15
Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30 35
<210> 7
<211> 39
<212> PRT
<213>artificial sequence
<220>
<221>construct is synthesized
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Ley Glu Glu Lys Cys (S-PEG anolog) Ala
1 5 10 15
Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Lys Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30 35
<210> 8
<211> 39
<212> PRT
<213>artificial sequence
<220>
<221>construct is synthesized
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Ley Glu Glu Lys Ala Ala
1 5 10 15
Lys Glu Phe Cys (S-PEG anolog) Glu Trp Leu Ile Lys Gly Lys Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30 35
<210> 9
<211> 39
<212> PRT
<213>artificial sequence
<220>
<221>construct is synthesized
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Ley Glu Glu Lys Ala Ala
1 5 10 15
Lys Glu Phe Cys (S-PEG anolog) Glu Trp Leu Ile Lys Gly Lys Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30 35
<210> 10
<211> 39
<212> PRT
<213>artificial sequence
<220>
<221>construct is synthesized
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Ley Glu Glu Lys Ala Ala
1 5 10 15
Lys Glu Phe Ile Glu Trp Cys (S-PEG anolog) Ile Lys Gly Lys Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30 35
<210> 11
<211> 39
<212> PRT
<213>artificial sequence
<220>
<221>construct is synthesized
His Gly Glu Gly Thr Tyr Thr Asn Asp Val Thr Glu Tyr Ley Glu Glu Lys Ala Ala
1 5 10 15
Lys Glu Phe Ile Glu Trp Leu Ile Lys Gly Cys (S-PEG anolog) Pro Ser Ser Gly Ala Pro Pro Pro Ser
20 25 30 35

Claims (5)

1. a kind of Africa xenopus glucagon-like-peptide-1 (GLP-1) analog, which is characterized in that its structure is one of following formula institute Show:
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Cys(S-PEG anolog)-Glu-Tyr-Leu- Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-G1y-Lys-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Pro-Ser-NH2；
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Cys(S-PEG anolog)-Tyr-Leu- Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Pro-Ser-NH2；
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Cys(S-PEG anolog)-Leu- Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Pro-Ser-NH2；
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Cys(S-PEG anolog)- Glu-Glu-Lys-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Pro-Ser-NH2；
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Cys(S- PEGanolog)-Ala-Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Pro-Ser-NH2；
His-Gly-Glu-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys-Cys (S-PEG anolog)-Ala-Lys-Glu-Phe-Tle-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser- G1y-Ala-Pro-Pro-Pro-Ser-NH2；
His-Gly-Glu-Gly-Thr-Tyr-Thr-Ash-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys-Ala- Cys(S-PEGanolog)-Lys-G1u-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser-Gly- Ala-Pro-Pro-Pro-Ser-NH2；
His-Gly-Glu-Gly-Thr-Tyr-Thr-Ash-Asp-Val-Thr-Glu-Tyr-Leu-G1u-Glu-Lys-Ala- Ala-Lys-Glu-Phe-Cys(S-PEG anolog)-Glu-Trp-Leu-Ile-Lys-Gly-Lys-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Pro-Ser-NH2；
His-Gly-Glu-Gly-Thr-Tyr-Thr-Ash-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys-Ala- Ala-Lys-Glu-Phe-Ile-Glu-Trp-Cys(S-PEG anolog)-Ile-Lys-Gly-Lys-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Pro-Ser-NH2；
His-Gly-Glu-Gly-Thr-Tyr-Thr-Ash-Asp-Val-Thr-Glu-Tyr-Leu-Glu-Glu-Lys-Ala- Ala-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Ile-Lys-Gly-Cys(S-PEG anolog)-Pro-Ser-Ser- Gly-Ala-Pro-Pro-Pro-Ser-NH2；
Wherein Cys (S-PEG analog) is selected from
Here: n is selected from 30~80.
2. a kind of Africa xenopus glucagon-like-peptide-1 (GLP-1) analog according to claim 1, feature exist In the molecular weight of S-PEG analog is 2000.
3. a kind of pharmaceutical composition, Africa xenopus glucagon-like peptide-described in the claim 1 including therapeutically effective amount 1 (GLP-1) analog or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
4. Africa xenopus glucagon-like-peptide-1 (GLP-1) analog described in claim 1 or its is pharmaceutically acceptable Salt and pharmaceutically acceptable carrier in preparation for the utilization in diabetes and fat drug.
5. the preparation method of the analog of Africa xenopus glucagon-like-peptide-1 (GLP-1) described in claim 1, including life Object expression, liquid phase synthesis and solid phase synthesis preparation method thereof.
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