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Glucagon-like peptide-1 analogs and uses thereof

A technology for recombining microorganisms and nucleic acid molecules, which is applied in the field of biomedicine, can solve problems such as inactivation, and achieve the effect of reducing the dosage

Active Publication Date: 2020-04-28
INST OF ANIMAL SCI OF CHINESE ACAD OF AGRI SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the active GLP-1 produced by the body itself is easily degraded and inactivated by dipeptide peptidase IV (DPP-4). In order to improve the biological activity of GLP-1, maintain a long-term effective plasma concentration, and exert its therapeutic The role of diabetes, domestic and foreign researchers focus on the development of long-acting GLP-1 analogs

Method used

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  • Glucagon-like peptide-1 analogs and uses thereof
  • Glucagon-like peptide-1 analogs and uses thereof
  • Glucagon-like peptide-1 analogs and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1. Design and preparation of glucagon-like peptide-1 analogs

[0038] The function research of GIP shows that the function of GIP (1-42) is identical with GIP (1-30) function, and the identical amino acid of GIP (1-30) and GLP-1 (7-36) reaches 80%, therefore the present invention When designing subsequent amino acid mutations, the sequences of GIP(1-30) and GLP-1(7-36) should be considered comprehensively, and the common sequence of the two should be retained, and the difference between GLP-1(7-36) and GIP(1-30) should be considered. The sequence of GIP(1-30) was replaced with different combinations of amino acids.

[0039] GLP-1(7-36): HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR

[0040] GIP (1-30): YAEGTFISDYSIAMDKI HQQDFVNWLLAQK

[0041] The amino acid sequence of the GLP-1 analog designed in the present invention is shown in Formula 1.

[0042] Formula 1:

[0043] Xaa 1 -Ser-Glu-Gly-Thr-Phe-Xaa 7 -Ser-Asp-Xaa 10 -Ser-Xaa 12 -Xaa 13 -Xaa 14 -Xaa 15 -Xaa 16 -Xaa ...

Embodiment 2

[0050] Example 2, GLP-1 analog yeast transformation, expression screening and purification

[0051] Add 20 μl of the series of recombinant plasmids constructed in Example 1 to 100 μl of GS115 competent yeast, gently blow twice to mix the recombinant plasmids and competent yeast evenly, place on ice, add the mixture into a pre-cooled electric shock cup, and carry out Electric shock, add 1ml of pre-cooled 1M sorbitol immediately after electric shock; transfer the transformed bacteria solution into a 1.5ml centrifuge tube, put it in a 29°C incubator for 3 hours; Place them on the YPDS plate and culture them in an incubator at 29°C, and use the PCR method to identify the success of the recombination.

[0052] Single clones on plates with different Zeocin concentrations were picked and inoculated in 100ml BMGY liquid medium, cultured continuously at 29°C and 220rpm for three days, centrifuged at 13000rpm for 40min, and the supernatant was collected. The collected supernatant was a...

Embodiment 3

[0055] Example 3, Functional Verification of GLP-1 Analogues

[0056] GLP-1 has a wide range of physiological functions, and the most convenient and quick detection index is the ability to lower blood sugar in the body. Therefore, 6-week-old male C57 mice were used as the experimental subjects in this experiment, and there were 12 mice in each experimental group. All mice were injected with glucose solution at 2 g / kg body weight. The mice in the experimental group were injected with GLP-1 analogues (SGP-1, SGP-5, SGP-13, SGP-19 or SGP-23 at a concentration of 2 mmol / L) at the same time as the glucose injection; the mice in the control group were injected with 0.1 mL of normal saline , the positive control group was injected with Exendin-4 (EX), GLP-1, GIP (concentration is 2mmol / L), and the GLP-1 analogue and the control injection were injected with 10nmol / kg mouse body weight at 0 and 20 hours after injection respectively. and 40min to detect the blood glucose levels of mic...

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Abstract

The invention discloses a glucagon-like peptide-1 (GLP-1) analogue, and applications thereof. The general formula of the amino acid sequence of the glucagon-like peptide-1 analogue is Xaa1-Ser-Glu-Gly-Thr-Phe-Xaa7-Ser-Asp-Xaa10-Ser-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30. According to a preparation method, the second site amino acid Ala of GLP-1 is replaced by Ser, and the amino acids at other sites are changed, so that the glucagon-like peptide-1 (GLP-1) analogue possesses both the biological functions of GLP-1 and GIP, the using amount is reduced, and the glucagon-like peptide-1 (GLP-1) analogue is capable of reducing blood sugar.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a glucagon-like peptide-1 analogue and its application. Background technique [0002] Glucagon-like peptide-1 (GLP-1) has a wide range of physiological effects: GLP-1 promotes the biosynthesis and secretion of insulin; increases the number of islet β cells in the pancreas that respond to glucose, That is, more islet β cells can participate in the production of insulin; GLP-1 inhibits glucagon secretion; GLP-1 inhibits the apoptosis of islet β cells and promotes the proliferation and differentiation of islet β cells; GLP-1 inhibits gastric emptying and gastric acid secretion; the effect of GLP-1 on the feeding center; the effect of GLP-1 on the heart and blood pressure; GLP-1 reduces endogenous gluconeogenesis. Because of the extensive physiological effects of GLP-1, GLP-1 may become an ideal therapeutic drug for diabetes, especially those obese patients with type 2 diabetes. However, t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605C12N15/16A61K38/26A61P3/10
CPCA61K38/00C07K14/605
Inventor 李奎裴杨莉杨述林安翠平齐传翔
Owner INST OF ANIMAL SCI OF CHINESE ACAD OF AGRI SCI
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