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FGF1 (Fibroblast Growth Factor 1) mutant and medicinal application thereof

A technology of mutants and drugs, applied in the field of protein, can solve the problems of induced hyperplasia and achieve the effect of convenient industrialization

Active Publication Date: 2017-07-18
黄志锋 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, as a paracrine protein, FGF1 interacts with heparin and FGFR to form a tight ternary complex to initiate a series of downstream complex signaling pathways, including the effects of promoting cell division and proliferation. Therefore, frequent injection FGF1 will undoubtedly have the hidden danger of inducing hyperplasia and even tumor in vivo

Method used

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  • FGF1 (Fibroblast Growth Factor 1) mutant and medicinal application thereof
  • FGF1 (Fibroblast Growth Factor 1) mutant and medicinal application thereof
  • FGF1 (Fibroblast Growth Factor 1) mutant and medicinal application thereof

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Effect test

Embodiment 1

[0028] Example 1 FGF1 of the present invention △HS and its in vitro activity

[0029] Cloning, expression and purification of FGF1 by conventional means △HS . Briefly, the full-length human wild-type FGF1 (abbreviated as FGF1 WT , positions 1-155) were cloned into the pET30a expression vector, and then the three mutations Lys127Asp, Lys128Gln and Lys133Val were introduced using the QuikChange XL site-directed mutagenesis kit (Stratagene, La Jolla, CA). The expression vector with the mutant was transformed into Escherichia coli BL21(DE3), cultivated at 37°C, when A 600 When reaching 0.5, add 1 mM IPTG to continue culturing for 4 hours. After lysing, the cells were purified by cation-exchange chromatography and gel-exclusion chromatography (GE Healthcare, Piscataway, NJ) to obtain FGF1 with a purity >98%. △HS . Other control proteins can also be prepared in a similar manner.

[0030] Detected by SPR biosensor chip (BIAcore 2000 system (GE Healthcare, Piscataway, NJ)), com...

Embodiment 2

[0034] Example 2 FGF1 of the present invention △HS in vivo activity studies

[0035] (1) Normal mice

[0036] everyday to normal C57BL / 6J Mice administered FGF1WT and FGF1 △HS (0.5 mg / kg body weight), for 3 months, with PCNA and Ki67 ( figure 2 A) Immunohistochemical staining and Western blotting ( figure 2 B) Mouse livers were analyzed for hyperplasia. FGF1 WT was observed to cause hyperplasia in mice, while FGF1 △HS Hyperplasia did not appear relative to the PBS control group.

[0037] (2) FGF1 WT and FGF1 △HS right db / db Effects on Blood Glucose Levels and Insulin Sensitivity in Mice

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

[0039] exist db / db In mice, rapid injection of FGF1 WT and FGF1 △HS (0.5 mg / kg body weight) can significantly reduce blood sugar levels, and the effect can basical...

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Abstract

The invention provides an FGF1 (Fibroblast Growth Factor 1) mutant. The amino acid sequence of the mutant has mutation of Lys127, Lys128 and / or Lys133 on the basis of SEQ ID NO:1, and the mutant has a function of reducing cell division promotion and proliferation of a FGF1, but still has the activity of reducing blood sugar and the like.

Description

technical field [0001] The invention belongs to the technical field of proteins, and in particular, the invention relates to FGF1 mutants, which reduce the side effects of FGF1 promoting cell division and proliferation, but have activities such as hypoglycemia. 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. [0003] Among them, FGF1 can produce important hypoglycemic and insulin-sensitizing functions in db / db, ob / ob and other type 2 diabetic mouse models, and even large doses will not cause hypoglycemia (see Nature Review Drug Discovery, 2016 ; Nature Medicine, 2016; Proc Natl Acad Sci U S A, 2016; Diabetes, 2016; Nature, 2015, etc.). [0004] However,...

Claims

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Application Information

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IPC IPC(8): C07K14/50C12N15/12A61K38/19A61P3/10A61P3/04A61P29/00
CPCA61K38/00C07K14/50A61K38/18A61P3/04A61P3/10A61P29/00
Inventor 黄志锋李校堃周洁宋林涛赵龙伟陈紫璐
Owner 黄志锋
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