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Fusion protein for treating metabolic diseases as well as preparation method and application thereof

A fusion protein and metabolic disease technology, applied in the field of medicine, can solve problems such as lowering blood sugar

Active Publication Date: 2021-08-17
JIANGNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] FGF21 can decompose fat, reduce body weight, and improve lipid metabolism, but it has no function of lowering blood sugar; although GIP can promote insulin secretion, it can also stimulate the increase of glucagon. If GIP is mutated, it retains the function of stimulating insulin secretion, The novel GIP will complement the biological activity shown by FGF21

Method used

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  • Fusion protein for treating metabolic diseases as well as preparation method and application thereof
  • Fusion protein for treating metabolic diseases as well as preparation method and application thereof
  • Fusion protein for treating metabolic diseases as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Construction, expression and purification of recombinant proteins

[0039] (1) Construction of GIP-FGF21-1 and GIP-FGF21-2 expression vectors

[0040] According to the computer simulation replacement and the codon preference of E. coli, two new fusion protein genes were designed, and their amino acid sequences were shown in the sequence table as GIP-FGF21-1 (SEQ ID NO: 5), GIP-FGF21-2 ( Shown in SEQ ID NO: 6). The two genes were sent to Shanghai Jierui Biological Co., Ltd. for synthesis, and two restriction sites, NdeI and BamHI, were designed at both ends of each gene. The two synthetic vectors and pET30a(+) containing their respective target gene fragments were double-digested with NdeI and BamHI respectively. After the enzyme digestion was completed, the respective target fragments were recovered from the gel. The four target fragments were ligated with the prokaryotic expression vector pET30a(+) using T4 DNA ligase. The ligation reaction system was 10 μ...

Embodiment 2

[0044] Example 2: Effects of recombinant protein on body weight, diet, blood lipid and diabetes-related indicators

[0045] The four proteins FGF21 (shown in SEQ ID NO: 7), GIP-1 (shown in SEQ ID NO: 3), GIP-FGF21-1, and GIP-FGF21-2 were prepared according to the method in Example 1.

[0046] Take 50 SPF 8-week-old male db / db mice, weigh them after pre-feeding for 1 week, fast for 6 hours the next day, take blood from the tail vein to measure the fasting blood glucose of the mice, remove abnormal weight, and screen blood glucose and body weight 30 model mice whose values ​​were relatively close to the mean value were randomly divided into saline injection group (Saline), FGF21 group, GIP-1 group, GIP-FGF21-1 group, GIP-FGF21-2 group, 6 in each group. At about 8:30 every morning, the corresponding test substance was given to the experimental group once, intraperitoneally, at a dose of 2 mg / kg, and the normal saline group was injected with the same volume of normal saline, and t...

Embodiment 3

[0050] Embodiment 3: the impact of recombinant protein on non-alcoholic steatohepatitis (NASH) related indicators

[0051] The four proteins FGF21, GIP-1, GIP-FGF21-1 and GIP-FGF21-2 were prepared according to the method of Example 1. Take 60 8-week-old male C57BL / 6 mice of SPF grade, pre-feed for 1 week, and then feed them with methionine-choline-deficient MCD diet. After 8 weeks of feeding, remove the abnormal body weight, and screen the model mice whose blood sugar and body weight are relatively close to the average Thirty rats were randomly divided into saline injection group (Saline), FGF21 group, GIP-1 group, GIP-FGF21-1 group, GIP-FGF21-2 group, 6 rats in each group. At about 8:30 every morning, the corresponding test substance was given to the experimental group once, intraperitoneally, at a dose of 2 mg / kg, and the normal saline group was injected with the same volume of normal saline, and the administration continued for 8 weeks. Free to eat and drink during the exp...

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Abstract

The invention belongs to the technical field of medicines, and relates to a fusion protein for treating metabolic diseases and a preparation method and application thereof. The general formula of the fusion protein is R1-L-R2 or R2-L-R1, wherein R1 is FGF21 protein, an FGF21 protein analogue or an analogue peptide with a FGF21 protein biological function, R2 is GIP, mutant GIP or an analogue peptide with a GIP biological function, and L is a connecting peptide. As a therapeutic drug or a pharmaceutical composition, the fusion protein disclosed by the invention can be used for treating diseases related to hyperglycemia and hyperlipidemia, such as diabetes, obesity, steatohepatitis or cardiovascular diseases, and the therapeutic effect is obviously superior to that of original FGF21 and GIP.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a fusion protein for treating metabolic diseases, a preparation method and application thereof. Background technique [0002] Fibroblast growth factor (FGF) 21 is a new member of the FGF family. The FGF21 gene is mainly expressed in the liver and fat. FGF21 can promote HepG2 cells and 3T3-L1 adipocytes to consume glucose in vitro, and can reduce blood sugar in animals. and triglyceride, and will not produce side effects such as hypoglycemia and tumorigenesis (Kharitonenkov A, et al.FGF21 as a novel metabolic regulator. J ClinInvest2005; 115:1627–35. state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007;148:774–81). FGF21 is safe, effective and does not rely on insulin to regulate the blood sugar level in the organism, so it is expected to become a new type of drug for the treatment of type II diabetes. However, multiple clinical trials have fo...

Claims

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Application Information

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IPC IPC(8): C07K19/00C12N15/62A61K38/18A61K38/22A61P3/04A61P3/10A61P3/06A61P1/16A61P9/10A61P35/00
CPCC07K14/50C07K14/57563A61P3/04A61P3/10A61P3/06A61P1/16A61P9/10A61P35/00C07K2319/00A61K38/00C07K14/645A61K38/1825
Inventor 朱升龙陈永泉
Owner JIANGNAN UNIV
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