CN104262481B - A kind of preparation method and applications of the analog of extended GLP-1 1 of side chain modification - Google Patents
A kind of preparation method and applications of the analog of extended GLP-1 1 of side chain modification Download PDFInfo
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Abstract
The invention discloses the analogs of GLP 1 to have general formula A：7HAEGT FX13SDV SSY X20E X22QAA X26EFIAW LVKGR G37Formula A, wherein, X13The lysine (K nX) modified for threonine or side chain, X20The lysine (K nX) modified for leucine or side chain, X22The lysine (K nX) modified for glycine or side chain, X26For lysine (the K NH of unprotected side chain modification2) or side chain modification lysine (K nX)；X13、X20, X22And X26In have and only one be lysine K nX, wherein n=4~10, X be glycine, alanine or valine.The analogs of this GLP 1 can be effectively increased GLP 1 blood halflife, the present situation for overcoming it can not clinically be used because of half-life short, be had wide application prospects in diabetes, obesity treatment drugs field.The invention also discloses the preparation method and applications of the analogs of GLP 1.
Description
Technical field
The present invention relates to the related drug field of diabetes, and specifically, the present invention relates to a kind of pancreas with side chain is high
The GLP-1 analogs of half-life period inside (GLP-1) class of blood glucose element sample peptide -1.The invention further relates to the system of the GLP-1 analogs
Preparation Method and its application in diabetes medicament is prepared.
Background technology
GLP-1 of the present invention (glucagon-likepeptide-1, hereinafter referred to as：GLP-1 it is) mainly by small intestine L
A kind of polypeptide of 37 amino acid composition of cell secretion, its activity form is GLP-1 (7-37) OH and GLP-1 (7-36) NH2
(Mojsov S,J Clin Invest.1987Feb；79(2):616-9).GLP-1 substantially lowers people with postprandial blood glucose, can pierce
Swash the generation of insulin, while certain fat-reducing effect can also be played, and will not cause hypoglycemia (Drucker D J,
Diabetes.1998Feb；47(2):159-69).Recent research also show GLP-1 have pancreas palingenesis (Drucker D J,
2003Dec；144(12):5145-8).In addition, because GLP-1 is full-length human polypeptide, have as clinical medicine in safety
There is greater advantage.However, GLP-1 (7-37) serum half-life is only 3-5 minutes, daily multiple injection administration makes in clinic
It is very inconvenient in.
There are many researchs to solve GLP-1 analogs in vivo using GLP-1 analog fusions technology at present
RT (CN90101167.3, CN200710018734.2, CN200410054397.9, CN01820232.2,
CN200380110152.7, CN200510039265.3, CN200610127237.1, CN200910009642.7), however, existing
Some technologies also have very big distance with clinical preferably target, are generally all also not reaching to clinical criteria, nearest Novo Norisk
The Liraglutide of production is GLP-1 analogs, and it has carried out the modification of palmitic acid to GLP-1, and is listed in 2009 in the U.S..
But Liraglutide, there is also the problem of half-life short, its formulation still needs to inject daily.
Therefore, presently, there are to solving the demand of the short method of GLP-1 Half-life in vivo.
The content of the invention
Unless otherwise noted, " Fmoc strategies " as described herein refers to using fluoropolymer resin as solid phase reaction matrix, will
The amino acid of aminoterminal Fmoc protections is condensed successively in the presence of coupling reagent, so as to the synthetic method of synthesis polypeptide.It has
Body method is referring to Fmoc solid phase peptide synthesis:a practical approach,2000,Oxford
University Press.
It is an object of the invention to for clinically GLP-1 analogs, RT is shorter, it is necessary to note daily in vivo
Penetrate the scarce limit of administration, there is provided a kind of longer GLP-1 of half-life period analog.
It is a further object to provide a kind of GLP-1 analogs answering in the medicine for preparing treatment diabetes
With, and application of the GLP-1 analogs in the medicine for preparing treatment and/or prevention obesity.
A further object of the present invention is to provide a kind of Pharmaceutical composition using GLP-1 analogs as active ingredient, its
Include above-mentioned GLP-1 analogs.Wherein, described pharmaceutical composition also includes one or more pharmaceutically acceptable auxiliary materials,
And described pharmaceutical composition is preferably injection, more preferably freeze-dried powder or solution injection.
For realizing that the technical scheme of above-mentioned purpose is as follows：
On the one hand, the present invention provides a kind of GLP-1 analogs, and the GLP-1 analogs have general formula：
7HAEGT FX13SDV SSY X20E X22QAA X26EFIAW LVKGR G37
Wherein, X13The lysine (K-nX) modified for threonine or side chain, X20The lysine modified for leucine or side chain
(K-nX), X22The lysine (K-nX) modified for glycine or side chain, X26For lysine (K-NH2) or side chain modification lysine
(K-nX)；X13、X20, X22And X26In have and only one be side chain modification lysine (K-nX), wherein n=4~10, X is sweet
Propylhomoserin, alanine or valine.
The described GLP-1 analogs with formula, there is general formula I：
7HAEGT FTSDV SSYLE GQAAK(nX)EFIAW LVKGR G37
(I)
Wherein n=4~10, preferably n=5~8；X is glycine, alanine or valine；
Preferably, the GLP-1 analogs are：
SEQ ID NO1:7HAEGT FTSDV SSYLE GQAAK(GGGGG)EFIAW LVKGR G37；
SEQ ID NO2:7HAEGT FTSDV SSYLE GQAAK(GGGGG G)EFIAW LVKGR G37；Or
SEQ ID NO3:7HAEGT FTSDV SSYLE GQAAK(GGGGG GG)EFIAW LVKGR G37；Or
SEQ ID NO4:7HAEGT FTSDV SSYLE GQAAK(GGGGG GGG)EFIAW LVKGR G37；Or
SEQ ID NO5:7HAEGT FTSDV SSYLE GQAAK(AAAAA)EFIAW LVKGR G37；
SEQ ID NO6:7HAEGT FTSDV SSYLE GQAAK(AAAAA A)EFIAW LVKGR G37；Or
SEQ ID NO7:7HAEGT FTSDV SSYLE GQAAK(AAAAA AA)EFIAW LVKGR G37；Or
SEQ ID NO8:7HAEGT FTSDV SSYLE GQAAK(AAAAA AAA)EFIAW LVKGR G37；Or
SEQ ID NO9:7HAEGT FTSDV SSYLE GQAAK(VVVVV)EFIAW LVKGR G37；
SEQ ID NO10:7HAEGT FTSDV SSYLE GQAAK(VVVVV V)EFIAW LVKGR G37；Or
SEQ ID NO11:7HAEGT FTSDV SSYLE GQAAK(VVVVV VV)EFIAW LVKGR G37；Or
SEQ ID NO12:7HAEGT FTSDV SSYLE GQAAK(VVVVV VVV)EFIAW LVKGR G37。
The GLP-1 analogs with formula in addition, it is possible to have general formula II：
7HAEGT FTSDV SSYLE K(nX)QAAK EFIAW LVKGR G37
(II)
Wherein n=4~10, preferably n=5~8；X is glycine, alanine or valine；
Preferably, the GLP-1 analogs are：
SEQ ID NO13:7HAEGT FTSDV SSYLE K(GGGGG)QAAK EFIAW LVKGR G37；
SEQ ID NO14:7HAEGT FTSDV SSYLE K(GGGGG G)QAAK EFIAW LVKGR G37；Or
SEQ ID NO15:7HAEGT FTSDV SSYLE K(GGGGG GG)QAAK EFIAW LVKGR G37；Or
SEQ ID NO16:7HAEGT FTSDV SSYLE K(GGGGG GGG)QAAK EFIAW LVKGR G37；Or
SEQ ID NO17:7HAEGT FTSDV SSYLE K(AAAAA)QAAK EFIAW LVKGR G37；
SEQ ID NO18:7HAEGT FTSDV SSYLE K(AAAAA A)QAAK EFIAW LVKGR G37；Or
SEQ ID NO19:7HAEGT FTSDV SSYLE K(AAAAA AA)QAAK EFIAW LVKGR G37；Or
SEQ ID NO20:7HAEGT FTSDV SSYLE K(AAAAA AAA)QAAK EFIAW LVKGR G37；Or
SEQ ID NO21:7HAEGT FTSDV SSYLE K(VVVVV)QAAK EFIAW LVKGR G37；
SEQ ID NO22:7HAEGT FTSDV SSYLE K(VVVVV V)QAAK EFIAW LVKGR G37；Or
SEQ ID NO23:7HAEGT FTSDV SSYLE K(VVVVV VV)QAAK EFIAW LVKGR G37；Or
SEQ ID NO24:7HAEGT FTSDV SSYLE K(VVVVV VVV)QAA KEFIAW LVKGR G37。
The GLP-1 analogs with formula, it is possible to have general formula III：
7HAEGT FTSDV SSY K(nX)E GQAAK EFIAW LVKGR G37
(III)
Wherein n=4~10, preferably n=5~8；X is glycine, alanine or valine；
Preferably, the GLP-1 analogs are：
SEQ ID NO25:7HAEGT FTSDV SSYK(GGGGG)E GQAAK EFIAW LVKGR G37；
SEQ ID NO26:7HAEGT FTSDV SSYK(GGGGG G)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO27:7HAEGT FTSDV SSYK(GGGGG GG)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO28:7HAEGT FTSDV SSYK(GGGGG GGG)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO29:7HAEGT FTSDV SSYK(AAAAA)E GQAAK EFIAW LVKGR G37；
SEQ ID NO30:7HAEGT FTSDV SSYK(AAAAA A)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO31:7HAEGT FTSDV SSYK(AAAAA AA)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO32:7HAEGT FTSDV SSYK(AAAAA AAA)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO33:7HAEGT FTSDV SSYK(VVVVV)E GQAAK EFIAW LVKGR G37；
SEQ ID NO34:7HAEGT FTSDV SSYK(VVVVV V)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO35:7HAEGT FTSDV SSYK(VVVVV VV)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO36:7HAEGT FTSDV SSYK(VVVVV VVV)E GQAA KEFIAW LVKGR G37。
The GLP-1 analogs with formula, it is possible to have general formula IV：
7HAEGT FK(nX)SDV SSYLE GQAAK EFIAW LVKGR G37
(IV)
Wherein n=4~10, preferably n=5~8；X is glycine, alanine or valine；
Preferably, the GLP-1 analogs are：
SEQ ID NO37:7HAEGT FK(GGGGG)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO38:7HAEGT FK(GGGGG G)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO39:7HAEGT FK(GGGGG GG)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO40:7HAEGT FK(GGGGG GGG)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO41:7HAEGT FK(AAAAA)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO42:7HAEGT FK(AAAAA A)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO43:7HAEGT FK(AAAAA AA)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO44:7HAEGT FK(AAAAA AAA)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO45:7HAEGT FK(VVVVV)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO46:7HAEGT FK(VVVVV V)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO47:7HAEGT FK(VVVVV VV)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO48:7HAEGT FK(VVVVV VVV)SDV SSYLE GQAA KEFIAW LVKGR G37。
On the other hand, the present invention provides the preparation method of above-mentioned GLP-1 analogs, and the preparation method includes Fmoc strategies
Solid phase peptide synthssis.
Another aspect, the present invention provide above-mentioned GLP-1 analogs and are preparing treatment diabetes, obesity and its relevant disease
With the application in the medicine of prevention obesity.
Also, the present invention also provides a kind of pharmaceutical composition, and described pharmaceutical composition includes above-mentioned GLP-1 analogs and one
Kind or a variety of pharmaceutically acceptable auxiliary materials.
Described pharmaceutical composition is preferably injection, more preferably freeze-dried powder or solution injection.
It is the detailed description of the present invention below：
(1) GLP-1 analogs
The formula of GLP-1 analogs of the present invention is as follows：
Formula：
7HAEGT FX13SDV SSY X20E X22QAA X26EFIAW LVKGR G37
7HAEGT FTSDV SSYLE GQAAK EFIAW LVKGR G37For people source GLP-1 sequences, above-mentioned formula A's
GLP-1 analogs are artificial sequence, are modified respectively in the amino acids of the 13rd, 20,22 or 26, by the bad ammonia with side chain
Sour K-nX instead of original amino acid.Wherein n=4~10, X can be Gly, Ala, Val.
Sporting the lysine K-nX formulas with side chain based on 26 amino acids is preferably：
Formula I：
7HAEGT FTSDV SSYLE GQAAK(nX)EFIAW LVKGR G37
Wherein n=4~10, preferably n=5~8；X is glycine, alanine or valine；
Sporting the lysine K-nX formulas with side chain based on 22 amino acids is preferably：
Formula II：
7HAEGT FTSDV SSYLE K(nX)QAAK EFIAW LVKGR G37
Wherein n=4~10, preferably n=5~8；X is glycine, alanine or valine；
Sporting the lysine K-nX formulas with side chain based on 20 amino acids is preferably：
General formula III：
7HAEGT FTSDV SSY K(nX)E GQAAK EFIAW LVKGR G37
Wherein n=4~10, preferably n=5~8；X is glycine, alanine or valine；
Sporting the lysine K-nX formulas with side chain based on 13 amino acids is preferably：
Formula IV：
7HAEGT FK(nX)SDV SSYLE GQAAK EFIAW LVKGR G37
Wherein n=4~10, preferably n=5~8；X is glycine, alanine or valine.
(2) Pharmaceutical composition of the invention
Can being made jointly with one or more pharmaceutically acceptable auxiliary materials containing GLP-1 analogs for the present invention is medicinal
Composition, these auxiliary materials include：Water-soluble filler, PH conditioning agents, stabilizer, water for injection, osmotic pressure regulator etc..
Water-soluble filler auxiliary material of the present invention is selected from following one kind or one kind：Mannitol, low molecule dextrorotation
Glucosides, sorbierite, polyethylene glycol, glucose, lactose, galactolipin etc..
PH conditioning agents are selected from following one kind or one kind：Citric acid, phosphoric acid, lactic acid, tartaric acid, hydrochloric acid etc. are non-volatile
Acid and potassium hydroxide, sodium hydroxide or potassium hydroxide or ammonium hydroxide, sodium carbonate or potassium carbonate or ammonium carbonate salts, bicarbonate
The physiologically acceptable organic or inorganic acid such as sodium or saleratus or bicarbonate ammonium salt and alkali and salt etc..
Stabilizer is selected from following one kind or one kind：EDTA-2Na, sodium thiosulfate, sodium pyrosulfite, sodium sulfite,
Dipotassium hydrogen phosphate, sodium acid carbonate, sodium carbonate, arginine, glutamic acid, Macrogol 6000, Macrogol 4000, dodecyl sulphur
Sour sodium or trishydroxymethylaminomethane etc..It is preferred that sodium pyrosulfite, dipotassium hydrogen phosphate, arginine, Macrogol 6000, three hydroxyl first
Base aminomethane.
Osmotic pressure regulator is one or two kinds of combinations of sodium chloride, potassium chloride.
(3) preparation method of injection
The Pharmaceutical composition of the present invention can by muscle, it is intravenous, be subcutaneously injected by way of being administered, preferable formulation
For freeze-dried powder or solution injection.
The preparation method of freeze drying injection：Take GLP-1 analog solution appropriate, add water-soluble filler, stably
Agent, osmotic pressure regulator etc., addition water for injection is appropriate, and regulation pH value makes its dissolving to 4-8, is diluted with water to debita spissitudo,
0.1-0.5% activated carbons are added, 10-20 minutes are stirred at 0-10 DEG C, decarburization is degerming using filtering with microporous membrane, and filtrate is entered
Row packing, using freeze-drying, white loose block is made, seals and produces, each specification contains GLP-1 analogs in 5 μ
Between g to 1mg.
The preparation method of parenteral solution：Take GLP-1 analogs solution or appropriate freeze-dried powder, add water-soluble filler, stably
Agent, osmotic pressure regulator etc., addition water for injection is appropriate, and regulation pH value makes its dissolving to 4-8, is diluted with water to debita spissitudo,
0.1-0.5% activated carbons are added, 10-20 minutes are stirred at 0-10 DEG C, decarburization is degerming using filtering with microporous membrane, and filtrate is entered
Row packing, seals and produces, each specification contains GLP-1 analogs between 5 μ g to 1mg.
(4) purposes of Pharmaceutical composition
The GLP-1 analogs of the present invention, which can be used in, prepares Remedies for diabetes aspect.Specifically, combination of the invention
Thing can be administered in the form of vein, muscle or subcutaneous injection agent.Although dosage according to treatment target, administering mode, symptom and it is other because
Element and change, GLP-1 analogs of the invention are effective in comparatively wide dosage range.In the treatment of adult, dosage
Scope is in 5 μ g/ people -- 1mg/ people, once a day or per several days single administrations.Actual dose should be by doctor according to relevant feelings
Condition determines, it is anti-to the individual of medicine that these situations include the condition of patient, method of administration, age, body weight, patient
Should, order of severity of patient symptom etc., therefore above-mentioned dosage range is not the scope limiting the invention in any way.
The problem of GLP-1 analogs of the present invention overcome GLP-1 half-life shorts, the GLP-1 analogs provided are in body
Interior half-life period can reach more than 15~75 hours, and the half-life period (half-life period is only 3-5 minutes) for the GLP-1 being relatively administered alone is bright
It is aobvious to extend, greatly facilitate its clinical expansion and application.
Brief description of the drawings
Hereinafter, embodiments of the invention are described in detail with reference to accompanying drawing, wherein：
Fig. 1 is the hypoglycemic experiment of analog containing GLP-1 (SEQ ID NO1-12) in embodiment 2；Wherein, Fig. 1-A are represented
The hypoglycemic experiment of GLP-1 analogs (SEQ ID NO1-6), wherein corresponding to each time point seven data strips from a left side to
The right side represents SEQ1-6 and control successively；Fig. 1-B represent the hypoglycemic experiment of GLP-1 analogs (SEQ ID NO7-12), wherein right
SEQ7-12 and control should be from left to right represented successively in seven data strips at each time point；
Fig. 2 is the hypoglycemic experiment of analog containing GLP-1 (SEQ ID NO13-24) in embodiment 3；Wherein, Fig. 2-A tables
Show GLP-1 analogs (SEQ ID NO13-18) hypoglycemic experiment, wherein corresponding to each time point seven data strips from
It is left-to-right to represent SEQ13-18 and control successively；Fig. 2-B represent the hypoglycemic reality of GLP-1 analogs (SEQ ID NO19-24)
Test, wherein from left to right representing SEQ19-24 and control successively corresponding to seven data strips at each time point；
Fig. 3 is the hypoglycemic experiment of analog containing GLP-1 (SEQ ID NO25-36) in embodiment 4；Wherein, Fig. 3-A tables
Show GLP-1 analogs (SEQ ID NO25-30) hypoglycemic experiment, wherein corresponding to each time point seven data strips from
It is left-to-right to represent SEQ25-30 and control successively；Fig. 3-B represent the hypoglycemic reality of GLP-1 analogs (SEQ ID NO31-36)
Test, wherein from left to right representing SEQ30-36 and control successively corresponding to seven data strips at each time point；
Fig. 4 is the hypoglycemic experiment of analog containing GLP-1 (SEQ ID NO37-48) in embodiment 5, wherein, Fig. 4-A tables
Show GLP-1 analogs (SEQ ID NO37-42) hypoglycemic experiment, wherein corresponding to each time point seven data strips from
It is left-to-right to represent SEQ37-42 and control successively；Fig. 4-B represent the hypoglycemic reality of GLP-1 analogs (SEQ ID NO43-48)
Test, wherein from left to right representing SEQ43-48 and control successively corresponding to seven data strips at each time point；
Fig. 5 is the figure that stability of the GLP-1 analogs in human serum is described in embodiment 6；
Fig. 6 is the figure that stability of the GLP-1 analogs in human serum is described in embodiment 7.
Fig. 7 is the figure that stability of the GLP-1 analogs in human serum is described in embodiment 8.
Embodiment
The present invention is further described in detail with reference to embodiment, the embodiment provided is only for explaining
The bright present invention, the scope being not intended to be limiting of the invention.
Below in an example, the various processes and method not being described in detail are conventional methods as known in the art.
Embodiment 1:The synthesis in solid state of polypeptide
Using the solid-phase peptide synthesis of Fmoc strategies, the CS 336X types instrument produced using CSBio companies carries out this
The synthesis of the polypeptide of invention.The method of synthesis is carried out according to the instrument specification of manufacturer.
Obtained polypeptide is purified using HPLC C18 semi-preparative columns, mobile phase is acetonitrile.It is dry through desalination and freezing
It is dry to obtain more peptide freeze-dried powders.
Embodiment 2：The related function of blood sugar reduction of GLP-1 analogs (formula I)
In the present embodiment, the polypeptide of use is as follows：
SEQ ID NO1:7HAEGT FTSDV SSYLE GQAAK(GGGGG)EFIAW LVKGR G37；
SEQ ID NO2:7HAEGT FTSDV SSYLE GQAAK(GGGGG G)EFIAW LVKGR G37；
SEQ ID NO3:7HAEGT FTSDV SSYLE GQAAK(GGGGG GG)EFIAW LVKGR G37；
SEQ ID NO4:7HAEGT FTSDV SSYLE GQAAK(GGGGG GGG)EFIAW LVKGR G37；
SEQ ID NO5:7HAEGT FTSDV SSYLE GQAAK(AAAAA)EFIAW LVKGR G37；
SEQ ID NO6:7HAEGT FTSDV SSYLE GQAAK(AAAAA A)EFIAW LVKGR G37；
SEQ ID NO7:7HAEGT FTSDV SSYLE GQAAK(AAAAA AA)EFIAW LVKGR G37；
SEQ ID NO8:7HAEGT FTSDV SSYLE GQAAK(AAAAA AAA)EFIAW LVKGR G37；
SEQ ID NO9:7HAEGT FTSDV SSYLE GQAAK(VVVVV)EFIAW LVKGR G37；
SEQ ID NO10:7HAEGT FTSDV SSYLE GQAAK(VVVVV V)EFIAW LVKGR G37；
SEQ ID NO11:7HAEGT FTSDV SSYLE GQAAK(VVVVV VV)EFIAW LVKGR G37；
SEQ ID NO12:7HAEGT FTSDV SSYLE GQAAK(VVVVV VVV)EFIAW LVKGR G37；
Each 1mg of aforementioned polypeptides is dissolved in 1ml physiological saline polypeptide solution is made, this polypeptide solution is subcutaneously injected in mouse
(200 μ l/, 6/group, purchased from Chinese Academy of Sciences's Shanghai Experimental Animal Center), by 400 microgram glucose injections after being administered 30 minutes
In every mouse.The blood glucose of 2 hours, 24 hours, 48 hours, 72 hours and 96 hours measure mouse after glucose injection
(note：Glucose of the blood glucose the first two hour again to same dose is surveyed every time), as a result see Fig. 1, wherein pair in the present embodiment
It is identical with other test groups to mouse subcutaneous injection physiological saline, dosage 1ml, the injection of glucose according to (blank).
Embodiment 3：The related function of blood sugar reduction of GLP-1 analogs (formula II).
In the present embodiment, the polypeptide of use is as follows：
SEQ ID NO13:7HAEGT FTSDV SSYLE K(GGGGG)QAAK EFIAW LVKGR G37；
SEQ ID NO14:7HAEGT FTSDV SSYLE K(GGGGG G)QAAK EFIAW LVKGR G37；
SEQ ID NO15:7HAEGT FTSDV SSYLE K(GGGGG GG)QAAK EFIAW LVKGR G37；
SEQ ID NO16:7HAEGT FTSDV SSYLE K(GGGGG GGG)QAAK EFIAW LVKGR G37；
SEQ ID NO17:7HAEGT FTSDV SSYLE K(AAAAA)QAAK EFIAW LVKGR G37；
SEQ ID NO18:7HAEGT FTSDV SSYLE K(AAAAA A)QAAK EFIAW LVKGR G37；
SEQ ID NO19:7HAEGT FTSDV SSYLE K(AAAAA AA)QAAK EFIAW LVKGR G37；
SEQ ID NO20:7HAEGT FTSDV SSYLE K(AAAAA AAA)QAAK EFIAW LVKGR G37；
SEQ ID NO21:7HAEGT FTSDV SSYLE K(VVVVV)QAAK EFIAW LVKGR G37；
SEQ ID NO22:7HAEGT FTSDV SSYLE K(VVVVV V)QAAK EFIAW LVKGR G37；
SEQ ID NO23:7HAEGT FTSDV SSYLE K(VVVVV VV)QAAK EFIAW LVKGR G37；
SEQ ID NO24:7HAEGT FTSDV SSYLE K(VVVVV VVV)QAA KEFIAW LVKGR G37；
Each 1mg of aforementioned polypeptides is dissolved in 1ml physiological saline polypeptide solution is made, this polypeptide solution is subcutaneously injected in mouse
(200 μ l/, 6/group, purchased from Chinese Academy of Sciences's Shanghai Experimental Animal Center), by 400 microgram glucose injections after being administered 30 minutes
In every mouse.The blood glucose of 2 hours, 24 hours, 48 hours, 72 hours and 96 hours measure mouse after glucose injection
(note：Glucose of the blood glucose the first two hour again to same dose is surveyed every time), as a result see Fig. 2, wherein pair in the present embodiment
It is identical with other test groups to mouse subcutaneous injection physiological saline, dosage 1ml, the injection of glucose according to (blank).
Embodiment 4：The related function of blood sugar reduction of GLP-1 analogs (general formula III)
In the present embodiment, the polypeptide of use is as follows：
SEQ ID NO25:7HAEGT FTSDV SSYK(GGGGG)E GQAAK EFIAW LVKGR G37；
SEQ ID NO26:7HAEGT FTSDV SSYK(GGGGG G)E GQAAK EFIAW LVKGR G37；
SEQ ID NO27:7HAEGT FTSDV SSYK(GGGGG GG)E GQAAK EFIAW LVKGR G37；
SEQ ID NO28:7HAEGT FTSDV SSYK(GGGGG GGG)E GQAAK EFIAW LVKGR G37；
SEQ ID NO29:7HAEGT FTSDV SSYK(AAAAA)E GQAAK EFIAW LVKGR G37；
SEQ ID NO30:7HAEGT FTSDV SSYK(AAAAA A)E GQAAK EFIAW LVKGR G37；
SEQ ID NO31:7HAEGT FTSDV SSYK(AAAAA AA)E GQAAK EFIAW LVKGR G37；
SEQ ID NO32:7HAEGT FTSDV SSYK(AAAAA AAA)E GQAAK EFIAW LVKGR G37；
SEQ ID NO33:7HAEGT FTSDV SSYK(VVVVV)E GQAAK EFIAW LVKGR G37；
SEQ ID NO34:7HAEGT FTSDV SSYK(VVVVV V)E GQAAK EFIAW LVKGR G37；
SEQ ID NO35:7HAEGT FTSDV SSYK(VVVVV VV)E GQAAK EFIAW LVKGR G37；
SEQ ID NO36:7HAEGT FTSDV SSYK(VVVVV VVV)E GQAA KEFIAW LVKGR G37；
Each 1mg of aforementioned polypeptides is dissolved in 1ml physiological saline polypeptide solution is made, this polypeptide solution is subcutaneously injected in mouse
(200 μ l/, 6/group, purchased from Chinese Academy of Sciences's Shanghai Experimental Animal Center), by 400 microgram glucose injections after being administered 30 minutes
In every mouse.The blood glucose of 2 hours, 24 hours, 48 hours, 72 hours and 96 hours measure mouse after glucose injection
(note：Glucose of the blood glucose the first two hour again to same dose is surveyed every time), as a result see Fig. 3, wherein pair in the present embodiment
It is identical with other test groups to mouse subcutaneous injection physiological saline, dosage 1ml, the injection of glucose according to (blank).
Embodiment 5：The related function of blood sugar reduction of GLP-1 analogs (formula IV)
In the present embodiment, the polypeptide of use is as follows：
SEQ ID NO37:7HAEGT FK(GGGGG)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO38:7HAEGT FK(GGGGG G)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO39:7HAEGT FK(GGGGG GG)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO40:7HAEGT FK(GGGGG GGG)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO41:7HAEGT FK(AAAAA)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO42:7HAEGT FK(AAAAA A)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO43:7HAEGT FK(AAAAA AA)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO44:7HAEGT FK(AAAAA AAA)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO45:7HAEGT FK(VVVVV)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO46:7HAEGT FK(VVVVV V)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO47:7HAEGT FK(VVVVV VV)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO48:7HAEGT FK(VVVVV VVV)SDV SSYLE GQAA KEFIAW LVKGR G37；
Each 1mg of aforementioned polypeptides is dissolved in 1ml physiological saline polypeptide solution is made, this polypeptide solution is subcutaneously injected in mouse
(200 μ l/, 6/group, purchased from Chinese Academy of Sciences's Shanghai Experimental Animal Center), by 400 microgram glucose injections after being administered 30 minutes
In every mouse.The blood glucose of 2 hours, 24 hours, 48 hours, 72 hours and 96 hours measure mouse after glucose injection
(note：Glucose of the blood glucose the first two hour again to same dose is surveyed every time), as a result see Fig. 4, wherein pair in the present embodiment
It is identical with other test groups to mouse subcutaneous injection physiological saline, dosage 1ml, the injection of glucose according to (blank).
Embodiment 6：Stability Determination of the GLP-1 analogs in human serum
In the present embodiment, the polypeptide of use is as follows：
SEQ ID NO1:7HAEGT FTSDV SSYLE GQAAK(GGGGG)EFIAW LVKGR G37；
SEQ ID NO4:7HAEGT FTSDV SSYLE GQAAK(GGGGG GGG)EFIAW LVKGR G37；
Three parts of volunteer's blood sample is taken with vacuum blood taking needle (BD Biosciences, Franklin Lakes, NJ), is then stood
Centrifuged 20 minutes in 13000rpm on centrifuge, take upper serum standby.
Above-mentioned two polypeptides and GLP-1 standard items (are purchased from Shanghai Sheng Gong companies, its sequence is：
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG) each 0.1mg is dissolved in 0.5ml physiological saline, is fully separately added into after dissolving
It is blank group (0.1mg GLP-1 are dissolved in 0.5ml physiological saline), NO1 experimental groups by serum marker into 1ml serum
(0.1mg sequences are SEQ ID for (0.1mg sequences are that SEQ ID NO1 peptide is dissolved in 0.5ml physiological saline) and NO4 experimental groups
NO4 peptide is dissolved in 0.5ml physiological saline).After 37 DEG C are incubated 0,0.1,0.3,2.5,5,10,15 and 24h, 50 μ l are taken respectively
Serum mixture, each group serum is examined with GLP-1 enzyme-linked immunologic detecting kits (being purchased from ALPCO Immunoassays)
Survey, in reading light absorption value on SpectraMax M5 ELIASAs, calculate in different blood serum samples GLP-1 analogs in different time
The concentration of point, is as a result shown in Fig. 5.Wherein circle represents blank group, and inverted triangle represents NO1 experimental groups, and positive triangle represents NO4 experiments
Group.As a result the half-life period of No1 and No4 experimental groups is shown>24h.
Embodiment 7：Stability Determination of the GLP-1 analogs in human serum
In the present embodiment, the polypeptide of use is as follows：
SEQ ID NO17:7HAEGT FTSDV SSYLE K(AAAAA)QAAK EFIAW LVKGR G37；
SEQ ID NO20:7HAEGT FTSDV SSYLE K(AAAAA AAA)QAAK EFIAW LVKGR G37；
Three parts of volunteer's blood sample is taken with vacuum blood taking needle (BD Biosciences, Franklin Lakes, NJ), is then stood
Centrifuged 20 minutes in 13000rpm on centrifuge, take upper serum standby.
Aforementioned polypeptides and GLP-1 standard items (are purchased from Shanghai Sheng Gong companies, its sequence is：SEQ ID NO49,
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG) each 0.1mg is dissolved in 0.5ml physiological saline, is fully separately added into after dissolving
It is blank group (0.1mg GLP-1 are dissolved in 0.5ml physiological saline), NO.17 experimental groups (0.1mg by serum marker into serum
Sequence is that SEQ ID NO17 peptide is dissolved in 0.5ml physiological saline) and NO20 experimental groups (0.1mg sequences are SEQ ID
NO2520 peptide is dissolved in 0.5ml physiological saline).It is incubated 0,0.5 in 37 DEG C, Isosorbide-5-Nitrae, after 8,12,24,48,72 and 96h, respectively
50 μ l serum mixtures are taken, with GLP-1 enzyme-linked immunologic detecting kits (being purchased from ALPCO Immunoassays) to each group serum
Detected, in reading light absorption value on SpectraMax M5 ELIASAs, calculate in different blood serum samples GLP-1 analogs not
With the concentration at time point, Fig. 6 is as a result seen.Wherein inverted triangle represents blank group, and empty circles represent NO.17 experimental groups, filled circles
Circle represents NO.20 experimental groups.As a result the half-life period for showing No.17 and No.20 experimental groups is 48h.
Embodiment 8：Stability Determination of the GLP-1 analogs in human serum
In the present embodiment, the polypeptide of use is as follows：
SEQ ID NO33:7HAEGT FTSDV SSYK(VVVVV)E GQAAK EFIAW LVKGR G37；
SEQ ID NO36:7HAEGT FTSDV SSYK(VVVVV VVV)E GQAA KEFIAW LVKGR G37；
Three parts of volunteer's blood sample is taken with vacuum blood taking needle (BD Biosciences, Franklin Lakes, NJ), is then stood
Centrifuged 20 minutes in 13000rpm on centrifuge, take upper serum standby.
Aforementioned polypeptides and GLP-1 standard items (are purchased from Shanghai Sheng Gong companies, its sequence is：SEQ ID NO49,
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG) each 0.1mg is dissolved in 0.5ml physiological saline, is fully separately added into after dissolving
It is blank group (0.1mg GLP-1 are dissolved in 0.5ml physiological saline), NO.33 experimental groups (0.1mg by serum marker into serum
Sequence is that SEQ ID NO33 peptide is dissolved in 0.5ml physiological saline) and NO36 experimental groups (0.1mg sequences are SEQ ID NO36
Peptide be dissolved in 0.5ml physiological saline).0,0.5 is incubated in 37 DEG C, Isosorbide-5-Nitrae, after 8,12,24 and 48h, takes 50 μ l serum to mix respectively
Compound, each group serum is detected with GLP-1 enzyme-linked immunologic detecting kits (being purchased from ALPCO Immunoassays), in
Light absorption value is read on SpectraMax M5 ELIASAs, calculates in different blood serum samples GLP-1 analogs in the dense of different time points
Degree, is as a result shown in Fig. 7.Wherein inverted triangle represents blank group, empty circles No.33 experimental groups, and solid circles represent No.36 realities
Test group.As a result the half-life period for showing No.33 and No.36 experimental groups is 24h.
Claims (15)
1. a kind of GLP-1 analogs, the GLP-1 analogs formula is as follows：
7HAEGT FX13SDV SSY X20E X22QAA X26EFIAW LVKGR G37
Wherein, X13The lysine (K-nX) modified for threonine or side chain, X20Lysine (the K- modified for leucine or side chain
NX), X22The lysine (K-nX) modified for glycine or side chain, X26For the lysine (K-NH of unprotected side chain modification2) or side chain repair
The lysine (K-nX) of decorations；X13、X20, X22And X26In have and only one be side chain modification lysine (K-nX), wherein n=5
~8, X are glycine, alanine or valine.
2. GLP-1 analogs as claimed in claim 1, it is characterised in that the GLP-1 analogs formula is shown in formula I：
7HAEGT FTSDV SSYLE GQAAK(nX)EFIAW LVKGR G37
(I)
Wherein n=5~8；X is glycine, alanine or valine.
3. GLP-1 analogs as claimed in claim 2, are selected from：
SEQ ID NO 1:7HAEGT FTSDV SSYLE GQAAK(GGGGG)EFIAW LVKGR G37；
SEQ ID NO 2:7HAEGT FTSDV SSYLE GQAAK(GGGGG G)EFIAW LVKGR G37；Or
SEQ ID NO 3:7HAEGT FTSDV SSYLE GQAAK(GGGGG GG)EFIAW LVKGR G37；Or
SEQ ID NO 4:7HAEGT FTSDV SSYLE GQAAK(GGGGG GGG)EFIAW LVKGR G37；Or
SEQ ID NO 5:7HAEGT FTSDV SSYLE GQAAK(AAAAA)EFIAW LVKGR G37；
SEQ ID NO 6:7HAEGT FTSDV SSYLE GQAAK(AAAAA A)EFIAW LVKGR G37；Or
SEQ ID NO 7:7HAEGT FTSDV SSYLE GQAAK(AAAAA AA)EFIAW LVKGR G37；Or
SEQ ID NO 8:7HAEGT FTSDV SSYLE GQAAK(AAAAA AAA)EFIAW LVKGR G37；Or
SEQ ID NO 9:7HAEGT FTSDV SSYLE GQAAK(VVVVV)EFIAW LVKGR G37；
SEQ ID NO 10:7HAEGT FTSDV SSYLE GQAAK(VVVVV V)EFIAW LVKGR G37；Or
SEQ ID NO 11:7HAEGT FTSDV SSYLE GQAAK(VVVVV VV)EFIAW LVKGR G37；Or
SEQ ID NO 12:7HAEGT FTSDV SSYLE GQAAK(VVVVV VVV)EFIAW LVKGR G37。
4. GLP-1 analogs as claimed in claim 1, it is characterised in that the GLP-1 analogs formula is formula II institutes
Show：
7HAEGT FTSDV SSYLE K(nX)QAAK EFIAW LVKGR G37
(II)
Wherein n=5~8；X is glycine, alanine or valine.
5. GLP-1 analogs as claimed in claim 4, are selected from：
SEQ ID NO 13:7HAEGT FTSDV SSYLE K(GGGGG)QAAK EFIAW LVKGR G37；
SEQ ID NO 14:7HAEGT FTSDV SSYLE K(GGGGG G)QAAK EFIAW LVKGR G37；Or
SEQ ID NO 15:7HAEGT FTSDV SSYLE K(GGGGG GG)QAAK EFIAW LVKGR G37；Or
SEQ ID NO 16:7HAEGT FTSDV SSYLE K(GGGGG GGG)QAAK EFIAW LVKGR G37；Or
SEQ ID NO 17:7HAEGT FTSDV SSYLE K(AAAAA)QAAK EFIAW LVKGR G37；
SEQ ID NO 18:7HAEGT FTSDV SSYLE K(AAAAA A)QAAK EFIAW LVKGR G37；Or
SEQ ID NO 19:7HAEGT FTSDV SSYLE K(AAAAA AA)QAAK EFIAW LVKGR G37；Or
SEQ ID NO 20:7HAEGT FTSDV SSYLE K(AAAAA AAA)QAAK EFIAW LVKGR G37；Or
SEQ ID NO 21:7HAEGT FTSDV SSYLE K(VVVVV)QAAK EFIAW LVKGR G37；
SEQ ID NO 22:7HAEGT FTSDV SSYLE K(VVVVV V)QAAK EFIAW LVKGR G37；Or
SEQ ID NO 23:7HAEGT FTSDV SSYLE K(VVVVV VV)QAAK EFIAW LVKGR G37；Or
SEQ ID NO 24:7HAEGT FTSDV SSYLE K(VVVVV VVV)QAA KEFIAW LVKGR G37。
6. GLP-1 analogs as claimed in claim 1, it is characterised in that the GLP-1 analogs formula is general formula III institute
Show：
7HAEGT FTSDV SSY K(nX)E GQAAK EFIAW LVKGR G37
(III)
Wherein n=5~8；X is glycine, alanine or valine.
7. GLP-1 analogs as claimed in claim 6, are selected from：
SEQ ID NO 25:7HAEGT FTSDV SSYK(GGGGG)E GQAAK EFIAW LVKGR G37；
SEQ ID NO 26:7HAEGT FTSDV SSYK(GGGGG G)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 27:7HAEGT FTSDV SSYK(GGGGG GG)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 28:7HAEGT FTSDV SSYK(GGGGG GGG)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 29:7HAEGT FTSDV SSYK(AAAAA)E GQAAK EFIAW LVKGR G37；
SEQ ID NO 30:7HAEGT FTSDV SSYK(AAAAA A)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 31:7HAEGT FTSDV SSYK(AAAAA AA)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 32:7HAEGT FTSDV SSYK(AAAAA AAA)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 33:7HAEGT FTSDV SSYK(VVVVV)E GQAAK EFIAW LVKGR G37；
SEQ ID NO 34:7HAEGT FTSDV SSYK(VVVVV V)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 35:7HAEGT FTSDV SSYK(VVVVV VV)E GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 36:7HAEGT FTSDV SSYK(VVVVV VVV)E GQAA KEFIAW LVKGR G37。
8. GLP-1 analogs as claimed in claim 1, it is characterised in that the GLP-1 analogs formula is formula IV institutes
Show：
7HAEGT FK(nX)SDV SSYLE GQAAK EFIAW LVKGR G37
(IV)
Wherein n=5~8；X is glycine, alanine or valine.
9. GLP-1 analogs as claimed in claim 8, are selected from：SEQ ID NO 37:7HAEGT FK(GGGGG)SDV SSYLE
GQAAK EFIAW LVKGR G37；
SEQ ID NO 38:7HAEGT FK(GGGGG G)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 39:7HAEGT FK(GGGGG GG)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 40:7HAEGT FK(GGGGG GGG)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 41:7HAEGT FK(AAAAA)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO 42:7HAEGT FK(AAAAA A)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 43:7HAEGT FK(AAAAA AA)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 44:7HAEGT FK(AAAAA AAA)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 45:7HAEGT FK(VVVVV)SDV SSYLE GQAAK EFIAW LVKGR G37；
SEQ ID NO 46:7HAEGT FK(VVVVV V)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 47:7HAEGT FK(VVVVV VV)SDV SSYLE GQAAK EFIAW LVKGR G37；Or
SEQ ID NO 48:7HAEGT FK(VVVVV VVV)SDV SSYLE GQAA KEFIAW LVKGR G37。
10. the preparation method of GLP-1 analogs as claimed in any one of claims 1-9 wherein, the preparation method includes Fmoc
The Solid phase peptide synthssis of strategy.
11. GLP-1 analogs as claimed in any one of claims 1-9 wherein are preparing the application in treating diabetes medicament.
12. application of the GLP-1 analogs as claimed in any one of claims 1-9 wherein in the medicine for preparing prevention obesity.
13. a kind of pharmaceutical composition, it is similar that described pharmaceutical composition includes GLP-1 as claimed in any one of claims 1-9 wherein
Thing and one or more pharmaceutically acceptable auxiliary materials.
14. pharmaceutical composition as claimed in claim 13, it is characterised in that described pharmaceutical composition is injection.
15. pharmaceutical composition as claimed in claim 14, it is characterised in that described pharmaceutical composition is freeze-dried powder or solution
Injection.
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| CN108341880B (en) * | 2017-01-23 | 2023-07-04 | 天津药物研究院有限公司 | Chimeric polypeptides comprising glucagon-like peptide-1 and fragment analogs of glucagon and uses thereof |
| BR112021008180A2 (en) * | 2018-10-30 | 2021-08-03 | Jianning Liu | glp-1 polypeptide having glp-1 receptor agonist activity and use thereof |
| CN115960201B (en) * | 2021-10-09 | 2023-08-11 | 合肥天汇生物科技有限公司 | GLP-1 analogue and preparation method thereof |
| CN116970062B (en) * | 2022-04-29 | 2024-04-09 | 南京知和医药科技有限公司 | Ultra-long acting GLP-1 polypeptide derivative and preparation method and application thereof |
Citations (4)
| 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 | |
| CN101868476A (en) * | 2007-09-05 | 2010-10-20 | 诺沃-诺迪斯克有限公司 | Glucagon-like peptide-1 derivatives and their pharmaceutical use |
| CN102643339A (en) * | 2011-02-21 | 2012-08-22 | 天津药物研究院 | GLP-1 analogs, preparation method thereof application thereof |
| CN102796192A (en) * | 2011-05-23 | 2012-11-28 | 中国药科大学 | Human glucagon-like peptide-1 analogue |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1468258A (en) * | 2000-06-16 | 2004-01-14 | Glucagon-like peptide-1 analogs | |
| CN101868476A (en) * | 2007-09-05 | 2010-10-20 | 诺沃-诺迪斯克有限公司 | Glucagon-like peptide-1 derivatives and their pharmaceutical use |
| CN102643339A (en) * | 2011-02-21 | 2012-08-22 | 天津药物研究院 | GLP-1 analogs, preparation method thereof application thereof |
| CN102796192A (en) * | 2011-05-23 | 2012-11-28 | 中国药科大学 | Human glucagon-like peptide-1 analogue |
Non-Patent Citations (1)
| Title |
|---|
| N-terminal His7-modification of glucagon-like peptide-1(7–36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity;B D Green et al.;《Journal of Endocrinology》;20040301;第180卷;379-388 * |
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