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A novel anti-metabolism FGF analogue and its application

A technology of analogues and drugs, applied in the field of new FGF analogues for anti-metabolic disorders, which can solve problems such as hidden dangers

Active Publication Date: 2021-10-22
无锡代达康健生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the above clinical studies, in addition to observing some common gastrointestinal symptoms, nausea and erythema at the injection site, it was also found that FGF19 mutant NGM282 can significantly increase cholesterol levels after injection, and many studies have shown that elevated cholesterol levels are metabolic diseases. One of the significant high-risk factors for metabolic diseases, which is a huge risk for the treatment of metabolic diseases
In addition, FGF19 can also cause symptoms such as anorexia and loss of appetite, which have certain hidden dangers in the future treatment process. Therefore, how to optimize FGF19 to reduce its side effects is a key issue in promoting the application of FGF19 in the treatment of various diseases.

Method used

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  • A novel anti-metabolism FGF analogue and its application
  • A novel anti-metabolism FGF analogue and its application
  • A novel anti-metabolism FGF analogue and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Construction, expression and purification of recombinant proteins

[0035] (1) Construction of FGF19-1, FGF19-2, FGF19-3 and FGF19-4 expression vectors

[0036] According to the computer simulation replacement and Escherichia coli codon preference, 4 kinds of novel FGF19 genes were designed. The nucleotide sequence is shown in SEQ ID NO.6), FGF19-3 (the nucleotide sequence is shown in SEQ ID NO.7), FGF19-4 (the nucleotide sequence is shown in SEQ ID NO.8). These four genes were sent to Shanghai Jierui Biological Co., Ltd. for synthesis, and NdeI and BamHI restriction sites were designed at both ends of each gene. The four synthetic vectors containing their respective target gene fragments and pET30a(+) were double-enzyme-digested with NdeI and BamHI respectively, and after the digestion was completed, the required target fragments were recovered from the gel. The four target fragments were ligated with the prokaryotic expression vector pET30a(+) using T4 DN...

Embodiment 2

[0040] Example 2: Detection of half-life of recombinant protein in vivo

[0041] In vivo half-life detection of five proteins NGM282, FGF19-1, FGF19-2, FGF19-3 and FGF19-4.

[0042] Twenty-five rabbits with a body weight of about 2 kg were selected and randomly divided into 5 groups. Each group was subcutaneously injected with 5 kinds of proteins NGM282, FGF19-1, FGF19-2, FGF19-3 and FGF19-4, the dose was 30mg / kg, after administration, 0h, 1h, 3h, 5h, 7h, 24h, in the ear About 800 μL of blood was collected from the marginal vein. Centrifuge at 12000r / m for 10min, take the supernatant and store it at -20°C for later use. The in vivo half-life of five proteins was determined by ELISA indirect method: NGM282, FGF19-1, FGF19-2, FGF19-3 and FGF19-4 proteins (2μg / mL, 0.2μg / mL, 200ng / mL, 20ng / mL and 2ng / mL) to establish the standard curve of protein concentration respectively, the diluted standard protein and serum were coated on the microtiter plate, and the content of the targe...

Embodiment 3

[0045] Example 3: Effects of recombinant protein on body weight, diet, blood lipids and diabetes-related indicators

[0046] The four proteins FGF19-1, FGF19-2, FGF19-3 and FGF19-4 were prepared according to the method of Example 1.

[0047] 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 42 model mice whose values ​​were relatively close to the mean value were randomly divided into saline injection group (Saline), NGM282 group, FGF19-1 group, FGF19-2 group, FGF19-3 group and FGF19-4 group, with 6 mice 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...

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Abstract

The invention discloses a novel FGF19 analogue and application thereof, belonging to the technical field of medicine. The present invention is modified on the basis of FGF19 mutant NGM282. Compared with NGM282, the obtained novel FGF19 analog has a longer-acting and more stable effect, and can better improve liver damage and correct metabolic disorders, obesity, overweight, Metabolic syndrome, diabetes, dyslipidemia and other diseases, and the side effects of increased cholesterol and decreased diet caused by the treatment of the original FGF19 mutant NGM282 did not appear during the treatment.

Description

technical field [0001] The invention relates to a novel anti-metabolism disorder FGF analogue and application thereof, belonging to the technical field of medicine. Background technique [0002] Fibroblast growth factor 19 (FGF19) is a newly discovered metabolic regulator, which stimulates intestinal secretion and expression after bile acid secretion into the intestinal tract. After being secreted by the intestinal tract, FGF19 can enter the liver with the circulation and combine with FGFR4 in the liver to act. It has a hormone-like effect and plays an important role in metabolic regulation, such as regulating bile acid metabolism, regulating gallbladder filling, improving energy metabolism and reducing blood pressure. body mass, blood sugar improvement, etc. Since many previous studies have shown that FGF19 has a mitogenic effect, FGFR4 can promote the proliferation of FGF19 in the liver and has a tumor-promoting effect. In 2014, a study found that the N-terminal domain o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/50C12N15/12A61K38/18A61P3/10A61P3/04A61P3/00A61P1/16A61P35/00A61P9/10A61P29/00
CPCC07K14/50A61P3/10A61P3/04A61P3/00A61P1/16A61P35/00A61P9/10A61P29/00A61K38/00Y02A50/30A61K9/0019A61K9/0053A61K38/1825
Inventor 朱升龙陈永泉王振
Owner 无锡代达康健生物医药科技有限公司
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