CN116063568A - FGF chimeric protein and application thereof in preparation of drugs for treating diabetes - Google Patents
FGF chimeric protein and application thereof in preparation of drugs for treating diabetes Download PDFInfo
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- 108090000376 Fibroblast growth factor 21 Proteins 0.000 claims abstract description 20
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- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
- C07K14/50—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- Gastroenterology & Hepatology (AREA)
- Diabetes (AREA)
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Abstract
The invention discloses an FGF chimeric protein, which comprises a first FGF chimeric protein or a second FGF chimeric protein, wherein the amino acid sequence of the first FGF chimeric protein is shown as SEQ ID NO:1 or SEQ ID NO:2, the amino acid sequence of the second FGF chimeric protein is shown as SEQ ID NO:3 or SEQ ID NO:4, discloses a pharmaceutical composition and application of the FGF chimeric protein in resisting metabolic diseases such as diabetes, non-alcoholic fatty liver and the like, wherein the FGF chimeric protein not only has good metabolic regulation function, but also has obviously improved stability and in-vivo acting time compared with FGF19 and FGF21 proteins.
Description
Technical Field
The invention relates to the technical field of biology, in particular to an FGF chimeric protein and application thereof in preparing a medicament for treating diabetes.
Background
Fibroblast growth factor 19 (FGF 19) is a newly discovered metabolic regulator and has the effects of improving energy metabolism, improving blood sugar and liver lipid accumulation of an organism and the like. Meanwhile, FGF19 has strong cell proliferation promoting capability and poor self stability, so that the drug effect, half-life and safety of FGF19 in human bodies are not ideal.
Disclosure of Invention
It is an object of the present invention to solve at least the above problems and to provide at least the advantages to be described later.
The invention also aims to provide the FGF chimeric protein and the application thereof in preparing the medicines for treating diabetes, and the residence time of the protein in a human body is improved while the blood sugar reducing effect of the protein is maintained.
To achieve these objects and other advantages and in accordance with the purpose of the invention, there is provided an FGF chimeric protein comprising a first FGF chimeric protein having an amino acid sequence as set forth in SEQ ID NO:1 or SEQ ID NO:2, the amino acid sequence of the second FGF chimeric protein is shown as SEQ ID NO:3 or SEQ ID NO: 4.
Preferably, the first FGF chimeric protein consists of a FGF1 mutant and the C-tail of FGF 19.
Preferably, the second FGF chimeric protein consists of a FGF1 mutant and the C-tail of FGF 21.
Preferably, the FGF1 mutant has any one or a combination of any plurality of Lys127Asp, lys128 gin, lys133Val mutations compared to wild-type FGF 1.
Preferably, the C-tail of FGF19 comprises positions 169-216 of the FGF19 amino acid sequence.
Preferably, the C-tail of FGF21 comprises amino acid positions 169-209 of FGF21 sequence.
A pharmaceutical composition comprising the FGF chimeric protein of any one of claims 1-6 and a pharmaceutically acceptable carrier.
Use of FGF chimeric protein in the preparation of a medicament for the treatment of diabetes.
Use of FGF chimeric protein in the preparation of a medicament for treating non-alcoholic fatty liver disease.
The invention at least comprises the following beneficial effects:
the FGF chimeric proteins comprise a first FGF chimeric protein or a second FGF chimeric protein, wherein the first FGF chimeric protein consists of an FGF1 mutant and the C tail of FGF19, and the second FGF chimeric protein consists of an FGF1 mutant and the C tail of FGF21, namely the FGF chimeric protein comprises an FGF1-FGF21 chimeric protein or an FGF1-FGF19 chimeric protein, and the invention introduces the FGF1 mutant to be chimeric with FGF21 or FGF19, so that the blood sugar reducing effect of the FGF21 and FGF19 proteins is maintained, and the residence time of the FGF21 and FGF19 proteins in a human body is improved.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1 is a schematic diagram of a chimeric FGF protein;
FIG. 2 is a graph showing the effect of a first chimeric protein and a second chimeric protein on acute hypoglycemic in mice;
FIG. 3 is a graph of blood glucose levels in mice on chronic dosing;
FIG. 4 is a graph showing the effect of a first chimeric protein and a second chimeric protein on ingestion by mice;
FIG. 5 is a graph showing the effect of a first chimeric protein and a second chimeric protein on glucose tolerance in mice;
FIG. 6 is a tissue morphology of mice;
FIG. 7 is a graph of mouse HE staining;
FIG. 8 is a graph of oil red staining and PAS staining of mice.
Detailed Description
The present invention is described in further detail below with reference to examples to enable those skilled in the art to practice the same by referring to the description.
Embodiments of the present application provide an FGF chimeric protein comprising a first FGF chimeric protein or a second FGF chimeric protein, wherein the amino acid sequence of the first FGF chimeric protein is set forth in SEQ ID NO:1 or SEQ ID NO:2, the amino acid sequence of the second FGF chimeric protein is shown as SEQ ID NO:3 or SEQ ID NO: 4. Wherein, SEQ ID NO:2 and SEQ ID NO:1, SEQ ID NO:4 and SEQ ID NO:3, compared with the FGF1, the N end is reduced by 23 amino acids, so that the proliferation promoting effect of the FGF chimeric protein is weaker, and the safety of the chimeric protein is improved.
In other embodiments, the first FGF chimeric protein consists of a FGF1 mutant and the C-tail of FGF19, forming a FGF1-FGF19 chimeric protein, the design of which is shown in figure 1.
In other embodiments, the second chimeric FGF protein consists of a FGF1 mutant and the C-tail of FGF21, forming a chimeric FGF1-FGF21 protein, the design of which is shown in figure 1.
In other embodiments, the FGF1 mutant has any one or a combination of any number of Lys127Asp, lys128 gin, lys133Val mutations compared to wild-type FGF1, wherein the mutation is expressed in a manner well known to those of skill in the art. For example, lys127 means that Lys at position 127 is mutated; and Lys128Gln means that the mutation is performed to Lys at position 128 to Gln. Mutations may be additions, deletions and/or substitutions. It is known to those skilled in the art that a polypeptide or protein having amino acid residues substituted, added and/or deleted can be produced by changing the sequence of a known polypeptide-encoding gene and introducing it into an expression vector, and these methods are widely described in the literature known in the art, such as "molecular cloning Experimental guidelines". In a specific embodiment of the invention, the mutation is a substitution. In a specific embodiment of the invention, the mutant has (only) Lys127Asp, lys128 gin and Lysl33Val mutations.
In other embodiments, the C-tail of FGF19 comprises positions 169-216 of the amino acid sequence of FGF 19.
In other embodiments, the C-tail of FGF21 comprises positions 169-209 of the amino acid sequence of FGF 21.
A pharmaceutical composition comprising the FGF chimeric protein of any one of claims 1-6 and a pharmaceutically acceptable carrier, which is capable of treating diabetes, reducing blood glucose, treating or preventing obesity, and which reduces (or even eliminates) the side effects of pro-cell proliferation, and which is also capable of long acting. In the present invention, long-acting means having a longer in vivo half-life than wild-type FGF21, FGF 19.
The application of FGF chimeric protein in preparing medicines for treating diabetes, the medicines are used for reducing blood sugar, and the medicines are used for treating diabetes, especially type 2 diabetes.
Use of FGF chimeric protein in the preparation of a medicament for treating non-alcoholic fatty liver disease.
< example >
The following examples further illustrate the invention. Unless otherwise indicated, the technical means used in the examples are conventional means well known to those skilled in the art and commercially available usual instruments and reagents, and can be referred to in the molecular cloning Experimental guidelines (3 rd edition) (scientific Press) and the relevant experimental guidelines of CFDA, and manufacturer specifications of the corresponding instruments and reagents, etc.
1. Preparation of FGF1-FGF19 chimeric proteins
Cloning, expression and purification of the FGF1-FGF19 chimeric protein (abbreviated as FGF 1) by conventional means ΔHBS -FGF19 C -tail ). Briefly, a full length human wild type FGF1 (abbreviated FGF1 WT 1-155) into pET30a expression vector, and then introducing three mutations of Lys127Asp, lys128Gln and Lys133Val (i.e., encoding FGF 1) using QuikChange XL site-directed mutagenesis kit (Stratagene, la Jolla, calif.) ΔHS ) Then, a gene encoding the C-tail (position Gly142-Ser 182) portion of FGF19 was introduced to obtain a chimeric construct (the amino acid sequence of the chimeric protein encoded by the chimeric construct is shown in SEQ ID NO: 1), wherein if the N-terminal of the FGF1 mutant is reduced by 23 amino acids, the amino acid sequence of the C-tail chimeric construct with FGF19 is as set forth in SEQ ID NO: 2. The expression vector with chimeric construct was transformed into Escherichia coli BL (DE 3), cultured at 37℃when A 600 When 0.5 was reached, 1mM IPTG was added and the culture was continued for 4 hours. After the bacterial cells are lysed, the bacterial cells are purified by anion exchange chromatography columns (Source Q, GE Healthcare, piscataway, NJ) and gel exclusion chromatography columns (GEhealthcare, piscataway, NJ) in sequence to obtain pure productsFGF1 with a degree of > 98% ΔHBS -FGF19 C -tail (protein expressed by amino acid sequence of SEQ ID NO: 1), FGF1 ΔHBSΔΝΤ -FGF19 C-tail (protein expressed by the amino acid sequence of SEQ ID NO: 2). Other control proteins can also be prepared in a similar manner.
2. Preparation of FGF1-FGF21 chimeric proteins
The preparation method of the FGF1-FGF21 chimeric protein is the same as that of the FGF1-FGF19 chimeric protein, and the FGF1 with the purity more than 98% can be obtained ΔHBS -FGF21 C-tail (protein expressed by amino acid sequence of SEQ ID NO: 3), FGF1 ΔHBSΔΝΤ -FGF21 C-tail (protein expressed by the amino acid sequence of SEQ ID NO: 4). Also, activity studies of FGF1-FGF21 chimeric proteins have been disclosed in patent application No. 201810234152.6.
3、FGF1 ΔHBS -FGF19 C-tail 、FGF1 ΔHBS -FGF21 C-tail Effects on db/db mice
Diabetes model (db/db) mice (C57 BLKS/J-lepr db/lepr db) and their control normal phenotype mice (db/m) were purchased from the university of Nanj model animal research center.
1. Effects on blood sugar
Diabetes model (db/db) mice were equally divided into four groups, one of which served as a control group of PBS, and the other three db/db mice were subcutaneously injected with FGF21, respectively WT 、FGF1 ΔHBS -FGF19 C-tail And FGF1 ΔHBS -FGF21 C-tail (0.5 mg/kg body weight), and the change in blood glucose level within 24 hours after a single injection was detected. The administration was then continued for 24 days, and the chronic hypoglycemic effect was observed daily.
As shown in fig. 2, it can be seen that the first FGF chimeric protein and the second FGF chimeric protein have better acute hypoglycemic activity in db/db diabetic mice than wild-type FGF21, and that the FGF1-FGF19 chimeric protein has the strongest acute hypoglycemic activity.
Chronic administration of FGF1-FGF19 chimeric protein reduced blood glucose to normal mouse levels in db/db mice without causing hypoglycemia as shown in figure 3, and long term administration did not affect ingestion of the mice as shown in figure 4, wherein both figures 3 and 4 increased normal mice as control (db/m).
As shown in FIG. 5, both the FGF1-FGF21 chimeric protein and the FGF1-FGF19 chimeric protein significantly improved glucose tolerance (IPGTT) in db/db mice.
4、FGF1 ΔHBS -FGF19 C-tail 、FGF1 ΔHBS -FGF21 C-tail Effects on db/db mouse liver
Five groups of mice, including normal group db/m, diabetes group db/db, FGF1 ΔHBS -FGF19 C-tail Group, FGF1 ΔHBS -FGF21 C-tail Group and FGF21 group, FGF1 ΔHBS -FGF19 C-tail Group, FGF1 ΔHBS -FGF21 C-tail Subcutaneous injection of FGF1 into group and FGF21 group respectively ΔHBS -FGF19 C-tail 、FGF1 ΔHBS -FGF21 C-tail And FGF21 WT (0.5 mg/kg body weight) five groups of mice were dissected, observed for tissue morphology, and HE stained, as shown in fig. 6 and 7, and both the tissue morphology and HE staining indicated that FGF1-FGF21 chimeric protein and FGF1-FGF19 chimeric protein significantly improved lipid accumulation in liver tissue of db/db mice, thereby producing anti-nonalcoholic fatty liver effects. The results of oil red staining and PAS staining of the tissues of the five groups of mice are shown in fig. 8, and further prove that the FGF1-FGF21 chimeric protein and the FGF1-FGF19 chimeric protein can remarkably improve lipid droplet accumulation in the liver tissues of db/db mice, thereby generating the anti-nonalcoholic fatty liver effect.
Although embodiments of the present invention have been disclosed above, it is not limited to the details and embodiments shown and described, it is well suited to various fields of use for which the invention would be readily apparent to those skilled in the art, and accordingly, the invention is not limited to the specific details and illustrations shown and described herein, without departing from the general concepts defined in the claims and their equivalents.
Claims (9)
- FGF chimeric protein characterized in that it comprises a first FGF chimeric protein or a second FGF chimeric protein, said first FGF chimeric protein having an amino acid sequence as set forth in SEQ ID NO:1 or SEQ ID NO:2, the amino acid sequence of the second FGF chimeric protein is shown as SEQ ID NO:3 or SEQ ID NO: 4.
- 2. The FGF chimeric protein of claim 1, wherein said first FGF chimeric protein consists of an FGF1 mutant and the C-tail of FGF 19.
- 3. The FGF chimeric protein according to claim 2, characterized in that said second FGF chimeric protein consists of a FGF1 mutant and the C-tail of FGF 21.
- 4. The FGF chimeric protein according to claim 3, characterized in that said FGF1 mutant has any one or a combination of any plurality of Lys127Asp, lys128 gin, lys133Val mutations compared to the wild type FGF 1.
- 5. The FGF chimeric protein according to claim 2, characterized in that the C-tail of FGF19 comprises positions 169-216 of the amino acid sequence of FGF 19.
- 6. The FGF chimeric protein according to claim 3, characterized in that the C-tail of FGF21 comprises positions 169-209 of the amino acid sequence of FGF 21.
- 7. A pharmaceutical composition comprising the FGF chimeric protein of any one of claims 1-6 and a pharmaceutically acceptable carrier.
- Application of FGF chimeric protein in preparing medicament for treating diabetes.
- Application of FGF chimeric protein in preparing medicines for treating non-alcoholic fatty liver disease.
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