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Long-acting glucagon-like peptide-1 analogue dimer and application thereof

A technology of glucagon and analogues, applied in the application of drugs, in the field of dimer of glucagon-like peptide-1 analogues, can solve the problems of drug compliance that needs to be improved, and achieve the improvement of clinical application compliance , Avoid safety risks, hypoglycemic effect

Inactive Publication Date: 2017-04-05
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many attempts have been made over the years, only liraglutide has been developed and marketed based on the parent peptide chain of GLP-1 (7-36,7-37) so far
Although liraglutide greatly prolongs the half-life of GLP-1 in vivo, it still needs to be injected once a day, and the medication compliance still needs to be improved

Method used

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  • Long-acting glucagon-like peptide-1 analogue dimer and application thereof
  • Long-acting glucagon-like peptide-1 analogue dimer and application thereof
  • Long-acting glucagon-like peptide-1 analogue dimer and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] A. Preparation of GLP-1 analogue monomer:

[0063] 1) Synthesis: Fmoc method is adopted, and the step-by-step synthesis method is implemented according to the following steps:

[0064] a) Fmoc-Gly-resin is obtained by coupling a resin solid phase support and Fmoc-protected glycine in the presence of an activator system;

[0065] b) Connect amino acids in accordance with the amino acid sequence of the peptide sequence by solid-phase synthesis to obtain a peptide-resin conjugate with N-terminal Fmoc-protection and side chain protection; take the following protection measures for amino acids with side chains: use Boc for tryptophan, gluten Use OtBu for amino acid, Trt for glutamine for lysine, tBu for tyrosine, Trt or tBu for serine, OtBu for aspartic acid, tBu for threonine, and Trt or Boc for histidine.

[0066] c) cleavage, remove the protecting group and resin simultaneously, obtain the crude product of GLP-1 analogue monomer;

[0067] 2) Purification: Dissolve the c...

Embodiment 2

[0088] Preparation of N-terminal acylated GLP-1 analogue dimers:

[0089] 1) According to the monomer synthesis method in Example 1, a peptide-resin conjugate with N-terminal Fmoc-protection and side chain protection was synthesized;

[0090] 2) Remove the N-terminal Fmoc protecting group by conventional methods, suspend the resin-peptide conjugate in an appropriate amount of pyridine, add acetic anhydride or trifluoroacetic anhydride in an appropriate molar ratio, mix well, and place it to obtain the N-terminal histidine acyl Peptide-resin conjugates;

[0091] 3) Cleavage according to the method in Example 1 to obtain the crude peptide, purify, and lyophilize to obtain the monomeric target peptide;

[0092] 4) Prepare the dimer according to the method of Example 1.

[0093] The GLP-1 analog dimer formed by the following sequence monomers was prepared according to the above method:

[0094] GLP-1 analog dimer 3-3 formed by SEQ ID NO 3 and SEQ ID NO 3,

[0095] GLP-1 analog...

Embodiment 3

[0103] Evaluation of hypoglycemic effect of GLP-1 analog dimers 1-1, 2-2, 11-11, 16-16.

[0104] The glucose tolerance test of normal mice was used to evaluate the hypoglycemic effect of the GLP-1 analog dimer of the present invention. Methods: 30 normal mice (purchased from Shanghai Experimental Animal Center, Chinese Academy of Sciences) were randomly divided into 6 groups (blank control group, positive control group, and test group), with 5 mice in each group; The product (≥98%) was dissolved in physiological saline, and prepared as a 0.1 mg / ml sample solution. The mice in the test group were subcutaneously injected with 200 μl of the sample solution; the mice in the positive control group were injected subcutaneously with 20 μg liraglutide; the mice in the blank control group were injected subcutaneously with 200 μl saline. Glucose tolerance was measured at 4, 24, 48, 72, and 120 hours after injection. Glucose tolerance test: Orally administer glucose 2g / kg, measure the bl...

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Abstract

The invention provides a long-acting glucagon-like peptide-1 analogue dimer. The long-acting glucagon-like peptide-1 analogue dimer is characterized in that the dimer is formed by two glucagon-like peptide-1 analogue monomers, the glucagon-like peptide analogue-1 monomer is shown as a general formula Z1HX1EX2TFTSDVSSYLEGQAAKEFIX3WLVKX4RG, wherein, Z1 is H, acetyl or trifluoroacetyl; X1 is Ala, Leu, Val, Gly, Ile; X2 is Gly, Cys; X3 is Ala, Cys; and X4 is Gly, Aib. The long-acting glucagon-like peptide-1 analogue dimer has long-acting hpyerglycemic effect, can increase the clinical medication compliance, is highly homologous with endogenous GLP-1(7-37), and can avoid the security risk.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a glucagon-like peptide-1 (GLP-1) analog dimer with long-acting effect. The present invention also relates to the application of the GLP-1 analog dimer in the preparation of medicines for treating and / or preventing diabetes, obesity and Alzheimer's disease. Background technique [0002] Glucagon-like peptide-1 (GLP-1) is a gut-derived hormone synthesized primarily in L cells of the terminal jejunum, ileum, and colon and released into circulation in response to a meal. GLP-1(7-36,7-37), the major active form of GLP-1 in the systemic circulation, controls blood glucose through complex mechanisms including secretion of insulin and glucagon, gastric emptying, and regulation of peripheral insulin. The hypoglycemic effect of GLP-1(7-36,7-37) is glucose-dependent, can avoid hypoglycemia, and has the effect of inhibiting the apoptosis of islet β-cells and promoting the proliferation of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/04A61P25/28
CPCC07K14/605A61K38/00
Inventor 韩英梅赵娜夏龚珉王玉丽
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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