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Long-acting enterocrinin polypeptide analogue for treating type 2 diabetes and application of long-acting enterocrinin polypeptide analogue

A technology of analogs and drugs, applied in the field of pharmaceuticals, can solve the problems of short half-life of liraglutide, inconvenient clinical use, and failure to meet clinical standards, and achieve the effect of facilitating clinical promotion and application and prolonging the half-life

Inactive Publication Date: 2014-09-10
HEFEI TIANHUI BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the serum half-life of GLP-1(7-37) is only 3-5 minutes, and multiple injections per day are very inconvenient in clinical use
[0003] At present, many studies have used GLP-1 analog fusion protein technology to solve the retention time of GLP-1 analogs in the body. However, the existing technology is still far from the ideal clinical goal, and generally has not yet reached the clinical goal. Standard, Liraglutide recently produced by Novo Norisk is a GLP-1 analogue, which modifies GLP-1 with palmitic acid, and was launched in the United States in 2009
However, liraglutide also has the problem of short half-life, and its dosage form still needs daily injections

Method used

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  • Long-acting enterocrinin polypeptide analogue for treating type 2 diabetes and application of long-acting enterocrinin polypeptide analogue
  • Long-acting enterocrinin polypeptide analogue for treating type 2 diabetes and application of long-acting enterocrinin polypeptide analogue
  • Long-acting enterocrinin polypeptide analogue for treating type 2 diabetes and application of long-acting enterocrinin polypeptide analogue

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: the solid-phase synthesis of polypeptide

[0040] Using the solid-phase polypeptide synthesis method of the Fmoc strategy, the CS336X instrument produced by CSBio Company was used to synthesize the polypeptide of the present invention. The method of synthesis was carried out according to the manufacturer's instruction manual. The "Fmoc strategy" described herein refers to a synthetic method for synthesizing polypeptides by sequentially condensing amino-terminal Fmoc-protected amino acids in the presence of coupling reagents using polymer resin as a solid-phase reaction substrate. For its specific method, see Fmoc solid phase peptide synthesis: a practical approach, 2000, Oxford University Press.

[0041] The prepared polypeptide was purified using HPLC C18 semi-preparative column, and the mobile phase was acetonitrile. The polypeptide freeze-dried powder is obtained by desalting and freeze-drying. The polypeptides included in the patent of the present inv...

Embodiment 2

[0042] Example 2: Hypoglycemic Function of GLP-1 Analogs

[0043] In this embodiment, the polypeptides used are as follows:

[0044] SEQ ID NO4: HAEGTFTSDVSSYLEGQAAKEFIAWLCKGRGGC—aminocaproic acid;

[0045] SEQ ID NO5: HAEGTFTSDVSSYLEGQAAK EFIAWLVKCRGAAC—amino caprylic acid;

[0046] SEQ ID NO 6: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRCVVVVVC—aminocapric acid

[0047] Dissolve 1 mg of each of the above polypeptides in 1 ml of normal saline to make a polypeptide solution, and inject the polypeptide solution subcutaneously into mice (200 μl / mouse, 6 mice / group, purchased from the Shanghai Experimental Animal Center of the Chinese Academy of Sciences). After 30 minutes of administration, 400 Micrograms of glucose were injected into each mouse. The blood glucose of the mice was measured at 2 hours, 24 hours, 48 ​​hours, 72 hours and 96 hours after the glucose injection (note: the same dose of glucose was given again two hours before each blood glucose measurement), and the results were ...

Embodiment 3

[0049] Example 3: Stability determination of GLP-1 analogs in human serum

[0050] In this embodiment, the polypeptides used are as follows:

[0051] SEQ ID NO4: HAEGTFTSDVSSYLEGQAAKEFIAWLCKGRGGC—aminocaproic acid;

[0052] SEQ ID NO5: HAEGTFTSDVSSYLEGQAAK EFIAWLVKCRGAAC—amino caprylic acid;

[0053] SEQ ID NO 6: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRCVVVVVC—aminocapric acid

[0054] (1) Serum preparation: Three blood samples were taken from volunteers with a vacuum blood collection needle (BD Biosciences, Franklin Lakes, NJ), and then immediately centrifuged at 13,000 rpm for 20 minutes on a centrifuge, and the upper layer of serum was taken for later use.

[0055] (2) Dissolve 0.1 mg of each of the above three polypeptides and GLP-1 standard (purchased from Shanghai Shenggong Company, its sequence is: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG) in 0.5 ml of normal saline, and add to 1 ml of rat serum after fully dissolving ( Purchased from Invitrogen Company), the serum was marked as blank ...

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Abstract

The invention discloses a long-acting enterocrinin polypeptide analogue for treating type 2 diabetes and an application of the long-acting enterocrinin polypeptide analogue, and provides an analogue of GLP-1 (Glucagon-Like Peptide-1) with longer half-life period and an application of the analogue. The analogue of the GLP-1 has a following general formula A: HAEGTFTSDVSSYLEGQAAKEFIAWLX27KX29RX31n1YCZ. In the general formula A, X27 is valine or cysteine, X29 is glycine or cysteine, X31 is glycine or cysteine, and at least one of X27, X29 and X31 is cysteine; n1X1 represents n1Ys, n1 is equal to 1-10, and Y is glycine, alanine or valine; Z represents amino saturated fatty acid; and two cysteines contained in the general formula A both form disulfide bonds. The analogue of the GLP-1, provided by the invention, is capable of effectively increasing the blood half-life period of the GLP-1 and overcoming the current situation that the analogue can not be clinically used due to short half-life period, and has an application prospect in the fields of drugs for treating diabetes and adiposis.

Description

technical field [0001] The invention relates to the field of pharmaceutical technology, in particular to a GLP-1 analogue and its application in the preparation of medicines for diabetes, obesity and / or diabetes, obesity-related diseases and obesity prevention. Background technique [0002] GLP-1 (glucagon-likepeptide-1, hereinafter referred to as: GLP-1) involved in the present invention is a polypeptide composed of 37 amino acids mainly secreted by small intestinal L cells, and its active form is GLP-1(7-37) OH and GLP-1(7-36)NH2 (Mojsov S, J Clin Invest. 1987 Feb;79(2):616-9). GLP-1 significantly reduces blood sugar after meals, can stimulate the production of insulin, and can also achieve a certain weight loss effect, and will not cause hypoglycemia (Drucker D J, Diabetes.1998Feb; 47(2): 159-69) . Recent studies have also shown that GLP-1 has a role in pancreatic regeneration (Drucker D J, 2003Dec; 144(12):5145-8). In addition, because GLP-1 is a fully humanized polyp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/04
CPCA61K38/26C07K14/605A61K38/00
Inventor 李瑛高井珍伊原
Owner HEFEI TIANHUI BIOTECH CO LTD
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