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FGF1-FGF21 chimeric protein and application of same to treatment of diabetes

1. The technology of FGF1-FGF21 and FGF21, applied in the field of protein, can solve the problems of loss of cell division and proliferation, weak binary complexes, etc., and achieve the prospect of high-efficiency medicine, long-term effect, and maintain the effect of hypoglycemia

Inactive Publication Date: 2018-10-12
黄志锋 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The inventor jumped out of the framework of prior art research, and after long-term research, unexpectedly discovered a long-acting FGF21 agonist, which is a chimeric protein of FGF1-FGF21, but does not include all parts of FGF1-FGF21 , not only the introduction of limited mutations, but it can only form a weak binary complex with FGFR to start the signaling pathway of metabolic regulation, and basically lose the function of promoting cell division and proliferation. At the same time, only one A small part of FGF21 also provides long-acting pharmacological effects such as hypoglycemia

Method used

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  • FGF1-FGF21 chimeric protein and application of same to treatment of diabetes
  • FGF1-FGF21 chimeric protein and application of same to treatment of diabetes
  • FGF1-FGF21 chimeric protein and application of same to treatment of diabetes

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Embodiment 1

[0027]Example 1 Preliminary research on the FGF1-FGF21 chimeric protein of the present invention and its activity

[0028] Cloning, expression and purification of FGF1-FGF21 chimeric protein (abbreviated as FGF1) by conventional means ΔHBS -FGF21 C -tail ). Briefly, the full-length human wild-type FGF1 (abbreviated as FGF1 WT , 1-155) cDNA fragments were cloned into the pET30a expression vector, and then three mutations (i.e. encoding FGF1 ΔHS ), and then introduce the gene encoding the C tail (C-tail, Gly142-Ser182) part of FGF21 to obtain a chimeric construct (the amino acid sequence of the chimeric protein encoded by it is shown in SEQ ID NO: 1). The expression vector with the chimeric construct was transformed into Escherichia coliBL21(DE3), cultured at 37°C, when A 600 When reaching 0.5, add 1mM IPTG to continue culturing for 4 hours. After lysing, the cells were purified by anion exchange chromatography column (Source Q, GE Healthcare, Piscataway, NJ) and gel exclu...

Embodiment 2

[0034] Embodiment 2 FGF1 of the present invention ΔHS in vivo activity studies

[0035] (1) Normal mice

[0036] Daily administration of FGF1 to normal C57BL / 6J mice WT and FGF1 ΔHBS -FGF21 C-tail (2.0mg / kg body weight), lasted for 20 days, respectively used Ki6 immunohistochemical staining and Western blotting to analyze the hyperplasia of the mouse liver. FGF1 WT was observed to cause significant hyperplasia in mice, while FGF1 ΔHBS -FGF21 C-tail Hyperplasia did not appear relative to the PBS control group.

[0037] (2) FGF1 ΔHBS -FGF21 C-tail Effects on blood glucose levels and insulin sensitivity in db / db mice

[0038] Diabetic model (db / db) mice (C57BLKS / J-lepr db / lepr db ) and its control mice with normal phenotype (db / m) were purchased from Model Animal Research Center of Nanjing University.

[0039] In db / db mice, daily subcutaneous injections of FGF1 WT and FGF1 ΔHBS -FGF21 C-tail (0.5mg / kg body weight), last for 4 weeks, measure blood glucose within ...

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Abstract

The invention provides a FGF1-FGF21 chimeric protein. The FGF1-FGF21 chimeric protein comprises a FGF1 mutant and a C-tail of FGF21. The FGF1-FGF21 chimeric protein reduces the side effects of mitogenesis and proliferation, and has long-acting blood-sugar-reducing and lipid-lowering activities and other activities.

Description

technical field [0001] The invention belongs to the field of protein technology, in particular, the invention relates to a long-acting FGF21 agonist, which is a FGF1-FGF21 chimeric protein. In addition, the present invention also relates to the application of the protein, such as the application of treating diabetes. Background technique [0002] There are 18 family members in Fibroblast Growth Factor (FGF), which are divided into 5 paracrine and 1 endocrine subfamilies. The role of FGF is achieved by interacting with FGF receptors (FGF Receptor, FGFR) with tyrosine kinase activity on the cell surface, causing receptor dimerization and further activating downstream cascade signals. Among them, fibroblast growth factor 21 (FGF21) is a member of the endocrine-acting FGF19 subfamily. [0003] Due to its advantages in metabolism and safety, FGF21 is expected to be a drug for diabetes, obesity and dyslipidemia. However, its in vivo drug efficacy and half-life are not ideal, so...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00C12N15/62A61K38/18A61K47/42A61P3/10A61P3/06A61P3/04
CPCC07K14/50A61K38/00A61P3/04A61P3/06A61P3/10C07K2319/31
Inventor 黄志锋牛建楼赵龙伟穆萨·穆罕默迪
Owner 黄志锋
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