CN115960201B - GLP-1 analogue and preparation method thereof - Google Patents
GLP-1 analogue and preparation method thereof Download PDFInfo
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- CN115960201B CN115960201B CN202111176443.2A CN202111176443A CN115960201B CN 115960201 B CN115960201 B CN 115960201B CN 202111176443 A CN202111176443 A CN 202111176443A CN 115960201 B CN115960201 B CN 115960201B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention relates to the technical field of polypeptides, and discloses a GLP-1 analogue and a preparation method thereof. The GLP-1 analogue provided by the invention has an amino acid sequence shown as SEQ ID NO.1, and the 2 nd cysteine and the 13 th cysteine of the sequence shown as SEQ ID NO.1 form intramolecular disulfide bonds. Experiments show that the GLP-1 analogue has high-efficiency and durable hypoglycemic effect and can be widely used in development of diabetes medicines.
Description
Technical Field
The invention relates to the technical field of polypeptides, in particular to a GLP-1 analogue and a preparation method thereof.
Background
Type 2 diabetes is a chronic metabolic disease caused by insufficient insulin secretion or insulin resistance in the body, and currently worldwide diabetic patients are predicted to be 4 hundred million. GLP-1 receptor agonists have been increasingly used in recent years to lower blood glucose by entering the blood to bind with GLP-1 receptor, and by promoting insulin synthesis and secretion of islets, inhibiting glucagon secretion, enhancing the utilization of glucose by peripheral tissues, and reducing hepatic glucose output, thereby lowering blood glucose.
Human glucagon-like peptide-1 (GLP-1) is incretin produced by L cells of the ileum and colon, the activity of GLP-1 (1-37) is extremely low, GLP-1 (7-37) with biological activity is formed after removing N-terminal 6 peptide, and the sequence of human GLP-1 (7-37) is as follows:
HAEGT FTSDV SSYLE GQAAK EFIAW LVKGRG
7 11 16 21 26 31 32 37
however, human GLP-1 (7-37) is secreted into the blood and has a half-life of only 3 to 5 minutes because it is extremely easily degraded by DDP-IV and cleared by glomerular filtration.
Therefore, development of a novel drug with a durable and effective hypoglycemic effect has been a goal pursued in the art.
Disclosure of Invention
In view of the above, the invention aims to provide a GLP-1 analogue and a preparation method thereof, wherein the GLP-1 analogue has a remarkable hypoglycemic effect.
In order to achieve the above object, the present invention provides the following technical solutions:
a GLP-1 analogue which is at least one of I) to III):
i) A polypeptide having an amino acid sequence shown in SEQ ID NO.1, wherein the 2 nd cysteine and the 13 th cysteine of the sequence shown in SEQ ID NO.1 form intramolecular disulfide bonds; or (b)
II) a polypeptide having the same or similar function as I) obtained by substitution, deletion or addition of one or more amino acids in the polypeptide of I); or (b)
III) a polypeptide having at least 90% homology to the amino acid sequence shown in I) and having the same or similar function as I).
Preferably, the GLP-1 analog is: 6-7 common amino acids are additionally added at the C end of the amino acid sequence shown in SEQ ID NO.1, and the 2 nd cysteine and the 13 th cysteine form intramolecular disulfide bonds.
In a specific embodiment of the invention, the amino acid sequence of the GLP-1 analogue is the amino acid sequence shown in any one of SEQ ID NO.2 or SEQ ID NO.3, and the 2 nd cysteine and the 13 th cysteine of the sequence shown in any one of SEQ ID NO.2 or SEQ ID NO.3 form an intramolecular disulfide bond.
Experiments show that the GLP-1 analogue provided by the invention has better blood sugar control capability and longer effect compared with the existing product after optimization.
Meanwhile, the invention also provides a preparation method of the GLP-1 analogue, which comprises the steps of synthesizing linear polypeptide according to the amino acid sequence of the GLP-1 analogue by adopting a liquid phase synthesis, solid phase synthesis or solid-liquid combination synthesis process, and oxidizing to form disulfide bonds to obtain the GLP-1 analogue.
In the specific embodiment of the invention, the GLP-1 analogue is synthesized by a solid phase synthesis process, the method for purifying the linear polypeptide adopts an HPLC method, and the disulfide bond is formed by oxidizing ammonium bicarbonate or DMSO.
The blood glucose reduction experiment result shows that the GLP-1 analogue provided by the invention is effective for reducing blood glucose for a long time; based on the excellent technical effect, the invention provides application of the GLP-1 analogue in preparing a medicament for treating or preventing diabetes.
According to the application, the invention also provides a medicament for preventing or treating diabetes, which takes the GLP-1 analogue as an active ingredient, and can further comprise pharmaceutically acceptable auxiliary materials and/or medicinal ingredients for treating other diseases without affecting the activity of the GLP-1 analogue as a further preferable scheme.
The medicine can be prepared into any clinical dosage form, mainly comprises oral dosage forms or injection dosage forms, wherein the injection dosage forms comprise transfusion forms, and the dosage forms comprise but are not limited to tablets, granules, pills, oral liquid, freeze-dried powder, injection, capsules and microcapsules.
According to the technical scheme, the amino acid sequence is optimized on the basis of human GLP-1, an intramolecular disulfide bond is formed, and a GLP-1 analogue is prepared from the difference of the two aspects of sequence and spatial configuration and human GLP-1, so that the analogue has high-efficiency and lasting hypoglycemic effect, and can be widely used in development of diabetes medicines.
Drawings
FIG. 1 is a graph showing the hypoglycemic effect of GLP-1 analogues of the present invention;
FIG. 2 is a line graph of the average blood glucose over time for the composition of example 4 of the present invention.
Detailed Description
The embodiment of the invention discloses a GLP-1 analogue and a preparation method thereof, and a person skilled in the art can refer to the content of the GLP-1 analogue and appropriately improve the technological parameters. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention. The GLP-1 analogues and methods of preparing the same have been described in the preferred embodiments, and it will be apparent to those skilled in the relevant art that the GLP-1 analogues and methods of preparing the same described herein can be modified or suitably altered and combined to practice and use the present technology without departing from the spirit, scope and scope of the invention.
In the invention, in the specific embodiment, the experiment is compared, except for the due differences of each group, other experiment conditions, raw materials, reagents and the like which are not explicitly mentioned are kept consistent, and the comparability of the comparison experiment is ensured.
In the invention, the amino acid sequence shown in SEQ ID NO.1 is as follows:
HCEGTFTSDVSSCYLEKQAAKEFIAXLVK。
wherein amino acid x=trp or Tyr at position 26.
The GLP-1 analogue provided by the invention is further optimized on the basis of the amino acid sequence shown in SEQ ID NO.1, and the obtained polypeptide has high-efficiency and durable hypoglycemic effect and can be widely used in development of diabetes medicines.
In some embodiments, the GLP-1 analogue provided by the invention is additionally added with 6-7 common 20 amino acids at the C end of the amino acid sequence shown in SEQ ID NO.1, and the 2 nd cysteine and the 13 th cysteine form intramolecular disulfide bonds.
In some specific embodiments, the GLP-1 analogue is additionally provided with 7 common amino acids at the C end of the amino acid sequence shown in SEQ ID NO.1, the amino acid sequence of the obtained polypeptide is shown in SEQ ID NO.2, and the 2 nd cysteine and the 13 th cysteine form intramolecular disulfide bonds.
SEQ ID NO.2 sequence is as follows:
HCEGTFTSDVSSCYLEKQAAKEFIAWLVKAECHYGR。
in some specific embodiments, the GLP-1 analogue is additionally provided with 6 common amino acids at the C end of the amino acid sequence shown in SEQ ID NO.1, the amino acid sequence of the obtained polypeptide is shown in SEQ ID NO.3, and the 2 nd cysteine and the 13 th cysteine form intramolecular disulfide bonds.
SEQ ID NO.3 sequence is as follows:
HCEGTFTSDVSSCYLEKQAAKEFIAYLVKFSQERG。
the GLP-1 analogue provided by the invention and a preparation method thereof are further described below.
Example 1: preparation of GLP-1 analogues
The solid-phase polypeptide synthesis method by Fmoc strategy was carried out with a polypeptide synthesizer according to the manufacturer's instructions. Sequentially synthesizing according to the amino acid sequence shown in SEQ ID NO.2, removing protecting groups and resin to obtain a GLP-1 analogue intermediate crude product, dissolving the GLP-1 analogue intermediate crude product with water, purifying by adopting a preparative HPLC (high performance liquid chromatography) and a C8 column, and using acetonitrile/water (V/V) =90: and 10, concentrating and freeze-drying to obtain a pure GLP-1 analogue intermediate product with free sulfhydryl groups. Dissolving a GLP-1 analogue intermediate pure product with water, oxidizing with ammonium bicarbonate or DMSO to form disulfide bonds, purifying to obtain a GLP-1 analogue, wherein the sequence of the GLP-1 analogue is as follows:
the broken line represents the intramolecular disulfide bond formed by the two cysteines.
SEQ ID NO.2:
HCEGTFTSDVSSCYLEKQAAKEFIAWLVKAECHYGR
EXAMPLE 2 preparation of GLP-1 analog
The solid-phase polypeptide synthesis method by Fmoc strategy was carried out with a polypeptide synthesizer according to the manufacturer's instructions. Sequentially synthesizing according to the amino acid sequence shown in SEQ ID NO.3, removing protecting groups and resin to obtain a GLP-1 analogue intermediate crude product, dissolving the GLP-1 analogue intermediate crude product with water, purifying by adopting a preparative HPLC (high performance liquid chromatography) and a C8 column, and using acetonitrile/water (V/V) =90: and 10, concentrating and freeze-drying to obtain a pure GLP-1 analogue intermediate product with free sulfhydryl groups. Dissolving a GLP-1 analogue intermediate pure product with water, oxidizing with ammonium bicarbonate or DMSO to form disulfide bonds, purifying to obtain a GLP-1 analogue, wherein the sequence of the GLP-1 analogue is as follows:
the broken line represents the intramolecular disulfide bond formed by the two cysteines.
SEQ ID NO.3:
HCEGTFTSDVSSCYLEKQAAKEFIAYLVKFSQERG。
Example 3: blood sugar lowering experiment
Grouping:
24 normal mice were divided into 4 groups, 6 groups each, blank group, positive control group, drug 1 group, drug 2 group.
Dosing regimen:
the blank group injection medicine is normal saline;
the positive control group injection medicine is liraglutide;
the injection medicine of the medicine 1 group is GLP-1 analogue prepared in the embodiment 1 of the invention;
the drug 2 group injection drug is GLP-1 analogue prepared in the embodiment 2 of the invention.
Each group of mice was fasted for 12 hours before administration, fasting blood glucose of each group of mice was measured, then 200 μl of physiological saline was injected subcutaneously into the blank group, 200 μl of liraglutide was injected into the positive control group, 200 μl of 0.2mg/ml of the GLP-1 analogue prepared in example 1 of the present invention was injected into the drug 1 group, 200 μl of the GLP-1 analogue prepared in example 2 of the present invention was injected into the drug 2 group, 0.2mg/ml of the GLP-1 analogue prepared in example 2 of the present invention was injected into the drug 2 group, and 200mg of glucose/mouse was infused into the stomach immediately after administration of each group of mice, and 200mg of glucose/mouse was infused into the stomach repeatedly every 12 hours. Sugar tolerance was measured 6h, 24h, 36h and 48h after administration, blood glucose levels at 15min, 30min and 60min were measured, and the blood glucose level AUC (mg/dL.min) was calculated. The results are shown in FIG. 1.
The blood sugar measurement method comprises the following steps: a blood glucose meter.
Fig. 1 illustrates:
after 4 hours of administration, the medicine 1 group and the medicine 2 group have the effect of reducing blood sugar;
after 24 hours of administration, the positive control group has no blood glucose reducing effect;
after 48 hours of administration, the drug 1 group and the drug 2 group still have obvious blood glucose reducing effect, and especially the blood glucose reducing effect of the drug 2 group is more obvious.
EXAMPLE 4 preparation of GLP-1 analog-containing compositions
(1) Preparation of composition A
TABLE 1 composition A composition
GLP-1 analog prepared in example 1 | 10mg |
N- (8- (2-hydroxybenzoyl) amino) octanoic acid sodium salt | 30mg |
Fish oil | 20mg |
The preparation method comprises the following steps:
10mg of the GLP-1 analog prepared in example 1, 30mg of sodium N- (8- (2-hydroxybenzoyl) amino) octoate and 20mg of fish oil were mixed, and the mixture was filled into a capsule and coated. Weighing Eudragit L30D, talcum powder and polyethylene glycol, dissolving with dichloromethane and isopropanol to obtain coating solution, and spraying the coating solution onto the surface of capsule to obtain enteric capsule. The flow rate of the coating liquid is 1.5ml/min, the coating temperature is 35 ℃, and the coating weight is increased by 10%. Wherein, eudragit L30D: talc powder: polyethylene glycol=9: 1:1 (weight ratio), dichloromethane: isopropanol=10:1 (volume ratio).
(2) Composition B
TABLE 2 composition of composition B
GLP-1 analog prepared in example 1 | 12mg |
N- (8- (2-hydroxybenzoyl) amino) octanoic acid sodium salt | 120mg |
Fish oil | 84mg |
The preparation method comprises the following steps:
12mg of the GLP-1 analog prepared in example 1, 120mg of sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and 84mg of fish oil were mixed, and filled into a capsule and coated. Weighing Eudragit L30D, talcum powder and polyethylene glycol, dissolving with dichloromethane and isopropanol to obtain coating solution, and spraying the coating solution onto the surface of capsule to obtain enteric capsule. The flow rate of the coating liquid is 1.2ml/min, the coating temperature is 33 ℃, and the weight of the coating is increased by 10%.
(3) Composition C
TABLE 3 composition C composition
GLP-1 analog prepared in example 2 | 7mg |
N- (8- (2-hydroxybenzoyl) amino) octanoic acid sodium salt | 35mg |
Fish oil | 21mg |
The preparation method comprises the following steps:
7mg of the GLP-1 analog prepared in example 2, 35mg of sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and 21mg of fish oil were mixed, and filled into a capsule and coated. Weighing Eudragit L30D, talcum powder and polyethylene glycol, dissolving with dichloromethane and isopropanol to obtain coating solution, and spraying the coating solution onto the surface of capsule to obtain enteric capsule. The flow rate of the coating liquid is 0.5ml/min, the coating temperature is 30 ℃, and the weight of the coating is increased by 8%.
(4) Composition D
TABLE 4 composition D composition
GLP-1 analog prepared in example 2 | 15mg |
N- (8- (2-hydroxybenzoyl) amino) octanoic acid sodium salt | 300mg |
Fish oil | 30mg |
The preparation method comprises the following steps:
15mg of the GLP-1 analog prepared in example 2, 300mg of sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and 30mg of fish oil were mixed, and filled into a capsule and coated. Weighing Eudragit L30D, talcum powder and polyethylene glycol, dissolving with dichloromethane and isopropanol to obtain coating solution, and spraying the coating solution onto the surface of capsule to obtain enteric capsule. The flow rate of the coating liquid is 0.8ml/min, the coating temperature is 45 ℃, and the weight of the coating is increased by 5%.
Comparative example 1 preparation of composition E (placebo)
TABLE 5 composition E composition
GLP-1 analog prepared in example 2 | 0mg |
N- (8- (2-hydroxybenzoyl) amino) octanoic acid sodium salt | 30mg |
Fish oil | 20mg |
The preparation method comprises the following steps:
30mg of sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and 20mg of fish oil are mixed, and the mixture is filled into a capsule and coated. Weighing Eudragit L30D, talcum powder and polyethylene glycol, dissolving with dichloromethane and isopropanol to obtain coating solution, and spraying the coating solution onto the surface of capsule to obtain enteric capsule. The flow rate of the coating liquid is 1.0ml/min, the coating temperature is 40 ℃, and the weight of the coating is increased by 7%.
EXAMPLE 5 oral composition hypoglycemic experiments
Group I:
the healthy beagle dogs are randomly divided into 5 groups, 15 beagle dogs are adopted, the weight of the beagle dogs is 10-12 kg, double cross administration is adopted, each group comprises 6 beagle dogs, the elution period is 1-2 weeks, and the group is (1) group A; (2) group B; (3) group C; (4) group D; group (5) E.
Dosage of administration:
group a oral composition a prepared in example 4;
group B oral composition B prepared in example 4;
group C oral composition C prepared in example 4;
group D oral composition D prepared in example 4;
group E orally administrated composition E prepared in comparative example 1.
Blood glucose monitoring:
each group of animals was fasted overnight for 12 hours, fasting blood glucose was measured, and then each group was orally administered one capsule of the corresponding group. After 30min of administration, each group of animals was given 8g/kg of glucose by gastric lavage. Blood glucose levels were measured for each group of animals at 0h, 0.5h, 1h, and 1.5h, respectively, after glucose administration. Blood glucose was measured using a glucometer. Each blood glucose value on the axis is the average blood glucose value of 6 beagle dogs in the corresponding group at the corresponding time. The experimental results are shown in FIG. 2.
Conclusion:
composition A, composition B, composition C, and composition D all showed hypoglycemic effects.
The foregoing is only for the understanding of the method of the present invention and the core idea thereof, and it should be noted that it will be apparent to those skilled in the art that several improvements and modifications can be made to the present invention without departing from the principle of the invention, and these improvements and modifications also fall within the protection scope of the claims of the invention.
Sequence listing
<110> Hefei Tianhui hatching technology Co.Ltd
<120> GLP-1 analog and process for producing the same
<130> MP21015111
<160> 3
<170> SIPOSequenceListing 1.0
<210> 1
<211> 29
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<220>
<221> UNSURE
<222> (26)..(26)
<223> Xaa=Trp or Tyr
<220>
<221> UNSURE
<222> (26)..(26)
<223> The 'Xaa' at location 26 stands for Gln, Arg, Pro, or Leu.
<400> 1
His Cys Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Cys Tyr Leu Glu
1 5 10 15
Lys Gln Ala Ala Lys Glu Phe Ile Ala Xaa Leu Val Lys
20 25
<210> 2
<211> 36
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<400> 2
His Cys Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Cys Tyr Leu Glu
1 5 10 15
Lys Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Ala Glu Cys
20 25 30
His Tyr Gly Arg
35
<210> 3
<211> 35
<212> PRT
<213> Artificial sequence (Artificial Sequence)
<400> 3
His Cys Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Cys Tyr Leu Glu
1 5 10 15
Lys Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Phe Ser Gln
20 25 30
Glu Arg Gly
35
Claims (8)
1. GLP-1 analogue, characterized in that it is a polypeptide having an amino acid sequence shown as SEQ ID NO.2 or SEQ ID NO.3, and having cysteines at position 2 and 13 forming intramolecular disulfide bonds.
2. The method for preparing a GLP-1 analog according to claim 1, wherein the GLP-1 analog is obtained by synthesizing a linear polypeptide according to the amino acid sequence of the GLP-1 analog by liquid phase synthesis, solid phase synthesis or solid-liquid combination synthesis process, and then oxidizing to form disulfide bonds.
3. The method of claim 2, wherein the oxidation to form disulfide bonds uses ammonium bicarbonate or DMSO oxidation to form disulfide bonds.
4. The GLP-1 analogue of claim 1, which is prepared by the preparation method of claim 2 or 3.
5. Use of a GLP-1 analogue of claim 1 for the preparation of a medicament for the treatment or prevention of type II diabetes.
6. A medicament for preventing or treating type II diabetes mellitus, which comprises the GLP-1 analogue of claim 1 as an active ingredient.
7. The medicament according to claim 6, further comprising pharmaceutically acceptable excipients and/or pharmaceutical ingredients for the treatment of other diseases without affecting the GLP-1 analogue activity.
8. The medicament according to claim 6 or 7, wherein the medicament is in an oral or injectable form.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1812808A (en) * | 2003-06-03 | 2006-08-02 | 诺沃挪第克公司 | Stabilized pharmaceutical peptide compositions |
CN104262481A (en) * | 2013-08-09 | 2015-01-07 | 天津药物研究院有限公司 | Preparing method and applications of long-acting GLP-1 analogues modified with side chains |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN1812808A (en) * | 2003-06-03 | 2006-08-02 | 诺沃挪第克公司 | Stabilized pharmaceutical peptide compositions |
CN104262481A (en) * | 2013-08-09 | 2015-01-07 | 天津药物研究院有限公司 | Preparing method and applications of long-acting GLP-1 analogues modified with side chains |
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