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Fusion protein for treating diabetes and/or obesity

A fusion protein and protein technology, which is applied in the fusion of peptide/protein components, animal/human proteins, and prolonging the life of plasma, can solve the problems of easy degradation and aggregation, high cost, toxic and side effects, etc., and improve the hypoglycemic activity , weight loss, high solubility effect

Pending Publication Date: 2022-03-01
TIANJIN INST OF IND BIOTECH CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, the PEG method has high production costs, which will lead to a decrease in drug activity; in recent years, it has been found that PEG-modified proteins and their degradation products are easy to accumulate in the kidney, which interferes with the normal kidney filtration; and people will produce certain antibodies to PEG. , indicating that it has certain immunogenicity
[0014] The cytotoxicity and complement activation of Fc can sometimes cause certain damage to the body; Fc fusion proteins are mostly in the form of dimers, and excessive molecular weight will affect the rate of drug molecules passing through the mucosa; Albumin fusion proteins are fermented and purified Degradation and polymerization are prone to occur during storage and storage, which will lead to loss of activity and may cause toxic and side effects; Albumin and Fc need to be expressed by yeast or mammalian cells, which takes a long cycle and high cost

Method used

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  • Fusion protein for treating diabetes and/or obesity
  • Fusion protein for treating diabetes and/or obesity
  • Fusion protein for treating diabetes and/or obesity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: Linking GLP-1 to different ABD domains

[0057] 1. Vector construction

[0058] The fusion protein gene of ABD and GLP-1 was obtained by whole gene synthesis, wherein GLP-1 was connected to the N-terminal or C-terminal of ABD and connected to pET-24d to construct pET-24d-GLP-ABD-X-Ln or pET-24d-ABD-GLP-X-Ln (X represents GS linking peptide or EA linking peptide; n=0, 1, 2, 3 repeats of GGGGS or EAAAK); all target proteins contain His at the N-terminus -tag and TEV protease cleavage site, MKHHHHHHPMSDYDIPTTENLYFQ (SEQ ID NO.34).

[0059] GLP-1 sequence (31 amino acids) :

[0060] HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO. 1)

[0061] or HSEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO.2)

[0062] GA3 sequence (SEQ ID NO.3)

[0063] LAEAKVLANRELDKYGVSDYYKNLINNAKTVEGVKALIDEILAALP

[0064] ABD035 sequence (SEQ ID NO.4)

[0065] LAEAKVLANRELDKYGVSDFYKRLINKAKTVEGVEALKLHILAALP

[0066] ABDCon sequence (SEQ ID NO.5)

[0067] LKEAKEKAIEELKKAGITSDYYFDLINKAKT...

Embodiment 2

[0112] Example 2: Linking exenatide (Ex) to different ABD domains

[0113] 1. Vector construction

[0114] The fusion protein genes of various ABD and Ex were obtained by whole gene synthesis, and exenatide (Ex) was connected to the N-terminal or C-terminal of ABD, and then connected to the expression vector pET-24d, etc., to construct pET-24d- Ex-ABD-X-Ln or pET-24d-ABD-Ex-X-Ln (X represents GS-linked peptide or EA-linked peptide; n=0, 1, 2, 3 repeats of GGGGS or EAAAK); in all purposes The N-terminus of the protein all contains a His-tag and a TEV protease cleavage site, MKHHHHHHPMSDYDIPTTENLYFQ (SEQ ID NO.34).

[0115] Exenatide (Ex) sequence (39 amino acids): (SEQ ID NO. 24)

[0116] HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS

[0117] Ex-GA3-GS-L2 sequence (SEQ ID NO. 25)

[0118] HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGSGGGGSGGGGSLAEAKVLANRELDKYGVSDYYKNLINNAKTVEGVKALIDEILAALP

[0119] Ex-GA3-GS-L3 sequence (SEQ ID NO. 26)

[0120] HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPS...

Embodiment 3

[0129] Example 3: Linking GLP-1 or Exenatide Ex to DARPin protein

[0130] 1. Vector Construction

[0131] Link GLP-1 or Ex to the N-terminus of DARPin by gene fusion, synthesize all the genes by whole gene synthesis, and link them with the expression vector pET-28a to construct the expression vector pET-28a-GLP-DARPin -GS-L3 or pET-28a-Ex-DARPin-GS-L3, etc.;

[0132] The two DARPins were connected in series, and GLP-1 was linked to its N-terminus to construct the expression vector pET-28a-GLP-DARPin-DARPin-GS-L3. The two DARPins are linked by GTGPTPTPTGSGPTPTPTGGS (SEQ ID NO.35) sequence.

[0133] The N-terminals of all target proteins contain His-tag and TEV protease cleavage site, MGSSHHHHHHSSGENLYFQ (SEQ ID NO.36).

[0134] DARPin sequence: (SEQ ID NO.30)

[0135] DLGKKLLEAARAGQDDEVRELLKAGADVNAKDYFSHTPLHLAARNGHLKIVEVLLKAGADVNAKDFAGKTPLHLAANEGHLEIVEVLLKAGADVNAQDIFGKTPADIAADAGHEDIAEVLQKAA

[0136] GLP-DARPin-GS-L3 sequence; (SEQ ID NO. 31)

[0137] HGEGTFTSDVSSYLEG...

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Abstract

The invention relates to a fusion protein for treating diabetes and / or obesity. The structure of the fusion protein is GLP-1 or an analogue and a derivative thereof-connecting peptide-albumin binding protein, the albumin binding protein comprises an ABD structural domain (GA3, ABD035, ABDon) or a DARPin capable of targeting HSA (human serum albumin). The bottleneck problem that the half-life period of GLP-1 or Ex is short is solved by connecting the GLP-1 or Ex with an ABD structural domain or DARPin protein, so that the GLP-1 or Ex can be better applied clinically. According to the present invention, the test results show that the albumin binding protein significantly prolongs the half-life period of GLP-1 or Ex, and improves the hypoglycemic activity in mice. The modified GLP-1 or Ex has a certain body weight reducing effect and can be used for treating or assisting in treating obesity.

Description

technical field [0001] The invention belongs to the field of biotechnology, and specifically relates to a series of novel GLP-1 receptor agonists with extended half-life and improved activity, which are mainly used in the field of diabetes treatment or obesity treatment. Background technique [0002] With the improvement of people's living standards, changes in diet structure, and the reduction of physical labor, the number of diabetic patients is gradually increasing. [0003] Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia. It has become one of the diseases that seriously threaten human health, and its incidence is increasing year by year. In 2017, there were 420 million people with diabetes worldwide, and this number is expected to reach 630 million by 2045. The total number of people with diabetes in my country has exceeded 114 million, and more than 90% of people with type 2 diabetes have diabetes, and among them, obese people account fo...

Claims

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Application Information

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IPC IPC(8): C07K19/00A61K38/22A61K38/26A61K47/64A61P3/10A61P3/04
CPCC07K14/605C07K14/57563A61P3/10A61P3/04C07K2319/31A61K38/00
Inventor 谭焕波邹培建苏文成
Owner TIANJIN INST OF IND BIOTECH CHINESE ACADEMY OF SCI
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