CN112898382A - Polypeptide compound and application thereof in preventing or treating nonalcoholic steatohepatitis - Google Patents
Polypeptide compound and application thereof in preventing or treating nonalcoholic steatohepatitis Download PDFInfo
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- CN112898382A CN112898382A CN202110092784.5A CN202110092784A CN112898382A CN 112898382 A CN112898382 A CN 112898382A CN 202110092784 A CN202110092784 A CN 202110092784A CN 112898382 A CN112898382 A CN 112898382A
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- C07—ORGANIC CHEMISTRY
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- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a polypeptide compound and application thereof in preventing or treating nonalcoholic steatohepatitis, wherein the polypeptide compound comprises the following amino acid sequences: Cys-Xaa2-Lys-Asn-Xaa5-Xaa6-Thr-Xaa8-Cys-COR1(ii) a Wherein R is1＝‑NH2or-OH; xaa2 ═ Lys or Ser; xaa5 ═ Ser or Tyr; xaa6 ═ Pro or Lys; xaa8 ═ Leu or Ala. The polypeptide compound is targeted to GPR55, and a large number of experimental studies prove that the polypeptide compound can obviously improve the nonalcoholic steatohepatitis and can be applied to preparation of medicines for preventing or treating the nonalcoholic steatohepatitis.
Description
Technical Field
The invention belongs to the technical field of biochemistry, and particularly relates to a polypeptide compound which can be used for preventing or treating nonalcoholic steatohepatitis.
Background
Nonalcoholic fatty liver disease is a major cause of chronic liver disease, usually accompanied by simple accumulation of lipids, inflammation, increased reactive oxygen species, death of hepatocytes and the appearance of fibrotic symptoms (Younossi ZM, Rinella ME, Sanyal A, Harrison SA, Brunt E, Goodman Z, Cohen DE, et al. from NAFLD to MAFLD: indications of a preservation change in medicine. hepatology 2020). Non-alcoholic fatty liver disease is widespread worldwide and is considered the second major indication for liver transplantation (Nobili V, Alisi A, Valenti L, Miele L, Feldstein AE, Alkhouri N.NAFLD in children: new genes, new diagnostic models and new drugs. Nat Rev Gastroenterol Heapatol 2019; 16: 517-. However, there is no approved drug for non-alcoholic fatty liver disease, and drug development for the disease still has very serious challenges. In recent years, the polypeptide with biological activity is considered as the most promising drug for treating nonalcoholic fatty liver diseases mainly due to the characteristics of predictable metabolism, high selectivity, good curative effect and safety (Fosgerau K, Hoffmann T. peptide therapeutics: current status and future directives. drug Discov Today 2015; 20: 122) and the like. Therefore, we believe that polypeptide drugs will become the main force for drug discovery and development.
GPR55 is a cannabinoid receptor expressed primarily in the pancreas, adipose tissue, gastrointestinal tract, liver and brain. Lysophosphatidylinositol is an endogenous ligand of GPR55, which binds to GPR55 and activates its downstream pathways, such as the RhoA-ROCK pathway and calcium ion release (Tuduri E, Imbernon M, Hernandez-Bautista RJ, Tojo M, Ferno J, Dieguez C, nogueras r.gpr55: a new formulating target for metablism J Mol Endocrinol 2017; 58: R191-R202). In recent years, it has been reported that the LPI/GPR55 system plays a crucial role in the development of nonalcoholic fatty liver diseases (Fondervia MF, FernandeZ U, Gonzalez-Rellan MJ, Da Silva Lima N, Buque X, Gonzalez-Rodriguez A, Alonso C, et al. the L-alpha-lysophosphatdylisinosite/GPR 55system indexes of the grade of non-alcoholic steatosides and steatopathies. hepatology 2020). Therefore, GPR55 may be a potential therapeutic target for alleviating chronic liver disease.
Disclosure of Invention
The invention aims to provide a polypeptide compound and application thereof in preventing or treating nonalcoholic steatohepatitis. The polypeptide compound is targeted to GPR55, and a large number of experimental studies prove that the polypeptide compound can obviously improve the nonalcoholic steatohepatitis and can be applied to preparation of a medicine for preventing or treating the nonalcoholic steatohepatitis.
To achieve the above object, the present invention provides a polypeptide compound comprising an amino acid sequence shown below:
Cys-Xaa2-Lys-Asn-Xaa5-Xaa6-Thr-Xaa8-Cys-COR1
wherein R is1＝-NH2or-OH;
xaa2 ═ Lys or Ser;
xaa5 ═ Ser or Tyr;
xaa6 ═ Pro or Lys;
xaa8 ═ Leu or Ala.
The polypeptide compound of the present invention, preferably Xaa6 ═ Pro.
The polypeptide compound of the present invention is preferably Xaa2 ═ Lys.
The polypeptide compound of the present invention is any one of the following compounds 1 to 8:
compound 1(SEQ ID NO. 1):
Cys-Lys-Lys-Asn-Ser-Pro-Thr-Ala-Cys
CKKNSPTAC
compound 2(SEQ ID NO. 2):
Cys-Lys-Lys-Asn-Tyr-Pro-Thr-Leu-Cys
CKKNYPTLC
compound 3(SEQ ID NO. 3):
Cys-Lys-Lys-Asn-Tyr-Pro-Thr-Ala-Cys
CKKNYPTAC
compound 4(SEQ ID NO. 4):
Cys-Lys-Lys-Asn-Ser-Pro-Thr-Leu-Cys
CKKNSPTLC
compound 5(SEQ ID NO. 5):
Cys-Ser-Lys-Asn-Tyr-Pro-Thr-Leu-Cys
CSKNYPTLC
compound 6(SEQ ID NO. 6):
Cys-Ser-Lys-Asn-Ser-Pro-Thr-Leu-Cys
CSKNSPTLC
compound 7(SEQ ID NO. 7):
Cys-Ser-Lys-Asn-Ser-Pro-Thr-Ala-Cys
CSKNSPTAC
compound 8(SEQ ID NO. 8):
Cys-Ser-Lys-Asn-Tyr-Pro-Thr-Ala-Cys
CSKNYPTAC。
another aspect of the present invention is to provide a composition comprising the above polypeptide compound.
The composition is a pharmaceutical composition, and the polypeptide compound is used as an active ingredient and is added with a pharmaceutically acceptable carrier and/or an auxiliary material to prepare the pharmaceutical composition.
Still another aspect of the present invention is to provide a pharmaceutical use of the polypeptide compound of the present invention. Cell and animal experiments show that the polypeptide compound has no adverse reaction and can be used for preventing or treating nonalcoholic steatohepatitis.
It will be appreciated by those skilled in the art that the pharmaceutical compositions of the present invention are suitable for various modes of administration, such as oral, transdermal, intravenous, intramuscular, topical, nasal, and the like. Depending on the mode of administration employed, the pharmaceutical compositions of the polypeptide compounds of the present invention may be formulated into various suitable dosage forms comprising at least one effective dose of the polypeptide compound of the present invention and at least one pharmaceutically acceptable carrier. Examples of suitable dosage forms are tablets, capsules, sugar-coated tablets, granules, oral solutions and syrups, ointments and patches for the skin surface, aerosols, nasal sprays, and sterile solutions for injection.
Pharmaceutical compositions containing the polypeptide compounds of the present invention may be formulated as solutions or lyophilized powders for parenteral administration, which powders may be reconstituted with a suitable solvent or other pharmaceutically acceptable carrier prior to use, and liquid formulations are typically buffers, isotonic and aqueous solutions.
The amount of the pharmaceutical composition of the present invention may vary over a wide range and can be readily determined by one skilled in the art based on objective factors such as the type of disease, the severity of the condition, the weight of the patient, the dosage form, and the route of administration.
The invention has the advantages that:
1) the polypeptide compound of the invention has good biological activity;
2) the polypeptide compound has good treatment effect on the nonalcoholic steatohepatitis;
3) the polypeptide compound of the invention shows significant pharmaceutical activity in the drug-induced experiments;
4) the polypeptide compound of the invention shows good safety and stability in the pharmaceutical experiment;
5) the polypeptide compound has high synthesis yield, good stability, easy scale-up production and low cost.
Abbreviations used in the present invention have the following specific meanings:
fmoc is fluorenylmethyloxycarbonyl, resin is resin, mPEG is monomethoxy polyethylene glycol, Cys is cysteine, Lys is lysine, Ser is serine, Asn is asparagine, Tyr is tyrosine, Thr is threonine, Ala is alanine, Leu is leucine, and Pro is proline.
Drawings
FIG. 1 is a graph of H & E stained pathological sections of mouse livers after administration of 150. mu.g/kg of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6, respectively, in a MCD (methionine Choline deficiency) feed-induced mouse hepatic nonalcoholic steatohepatitis model.
FIG. 2 is a bar graph of mouse liver lipid accumulation after administration of 80. mu.g/kg of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6, respectively, in a MCD feed-induced mouse model of hepatic nonalcoholic steatohepatitis; wherein: representing a confidence of > 95%, the difference being statistically significant (P < 0.05); **: the confidence degree is greater than 99%, and the difference between the two is very significant (P < 0.01); ***: the confidence coefficient is greater than 99.9%, and the difference between the two is extremely significant (P < 0.001); # ##: indicating that the model group has a very significant difference (P <0.001) compared with the control group.
FIG. 3 is a pathological section of mouse liver stained with oil Red O after administration of 80. mu.g/kg of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6, respectively, in a MCD feed-induced mouse liver nonalcoholic steatohepatitis model.
FIG. 4 is a bar graph of mouse liver lipid accumulation after administration of 80. mu.g/kg of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6, respectively, in a MCD feed-induced mouse model of hepatic nonalcoholic steatohepatitis; wherein: representing a confidence of > 95%, the difference being statistically significant (P < 0.05); **: the confidence degree is greater than 99%, and the difference between the two is very significant (P < 0.01); ***: the confidence coefficient is greater than 99.9%, and the difference between the two is extremely significant (P < 0.001); # ##: indicating that the model group has a very significant difference (P <0.001) compared with the control group.
FIG. 5 is a photograph of pathological sections stained with sirius red of mouse livers after administration of 80. mu.g/kg of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6, respectively, in a MCD feed-induced mouse liver nonalcoholic steatohepatitis model.
FIG. 6 is a bar graph of mouse liver lipid accumulation after administration of 80. mu.g/kg of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6, respectively, in a MCD feed-induced mouse model of hepatic nonalcoholic steatohepatitis; wherein: representing a confidence of > 95%, the difference being statistically significant (P < 0.05); **: the confidence degree is greater than 99%, and the difference between the two is very significant (P < 0.01); ***: the confidence coefficient is greater than 99.9%, and the difference between the two is extremely significant (P < 0.001); # ##: indicating that the model group has a very significant difference (P <0.001) compared with the control group.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1Synthesis of polypeptide Compounds
Materials:
all amino acids were purchased from gill biochemical (shanghai) ltd. All other reagents were analytical grade, Sigma brand reagents, unless otherwise specified. Protein Technologies PRELUDE 6 channel polypeptide synthesizer was used. Phenomenex Luna C18 preparative columns (46 mm. times.250 mm) were used to purify the polypeptides. The high performance liquid chromatograph is a product of Waters company. Mass spectrometry was performed using an Agilent mass spectrometer.
The experimental method comprises the following steps:
the compound is synthesized from a carboxyl terminal to an amino terminal by adopting an Fmoc solid-phase polypeptide synthesis method and is sequentially connected according to the sequence of the amino acid sequence. The method comprises the following specific steps: firstly, MBHAR (Amide-MBHA-Resin Amide protected MBHA Resin) or Wang Resin is adopted to remove Fmoc protecting group for synthesis. And (3) detecting by using an indene detection reagent, wherein the use amount of the indene detection reagent is that the reagent 1: reagent 2: reagent 3 ═ l: 2: l (dropping), heating in boiling water for 3-10 min. Treating resin, weighing a certain amount of MBHA resin in a synthesizer, adding DCM, stirring for 30min, draining, washing with DMF for 4 times, each time for 2min, picking out a small amount of resin, performing indene detection, and if the resin color is not changed, indicating normal, using. Removing Fmoc protection: the 20% piperidine was washed 4 times, and after the 3 rd wash, it was indenylated, indicating that the next amino acid was accessible if the indenylated color appeared bluish-purple. Repeating the operation until the peptide synthesis is completed. Finally, washing the polypeptide after precipitation and cutting by utilizing ethyl acetate, and then purifying by high performance liquid chromatography.
Based on the above synthetic procedures, the following polypeptide compounds of the present invention were synthesized (table 1):
table 1. structure of the polypeptide compound synthesized in the examples of the present invention:
| compound (I) | Numbering | Sequence of |
| 1 | SEQ ID NO.1 | Cys-Lys-Lys-Asn-Ser-Pro-Thr-Ala- |
| 2 | SEQ ID NO.2 | Cys-Lys-Lys-Asn-Tyr-Pro-Thr-Leu- |
| 3 | SEQ ID NO.3 | Cys-Lys-Lys-Asn-Tyr-Pro-Thr-Ala- |
| 4 | SEQ ID NO.4 | Cys-Lys-Lys-Asn-Ser-Pro-Thr-Leu- |
| 5 | SEQ ID NO.5 | Cys-Ser-Lys-Asn-Tyr-Pro-Thr-Leu- |
| 6 | SEQ ID NO.6 | Cys-Ser-Lys-Asn-Ser-Pro-Thr-Leu-Cys |
| 7 | SEQ ID NO.7 | Cys-Ser-Lys-Asn-Ser-Pro-Thr-Ala-Cys |
| 8 | SEQ ID NO.8 | Cys-Ser-Lys-Asn-Tyr-Pro-Thr-Ala-Cys |
Example 2Effect of the polypeptide Compound of the present invention on the treatment of MCD-induced non-Alcoholic steatohepatitis in mice
In this example, polypeptide compound 1, polypeptide compound 2, polypeptide compound 3, polypeptide compound 4, polypeptide compound 5, and polypeptide compound 6 were selected as examples to study the effect of the polypeptide compound of the present invention on the improvement and treatment of non-alcoholic steatitis in mice, and the specific method is as follows.
Establishing a model:
the tested drugs are: polypeptide compound 1, polypeptide compound 2, polypeptide compound 3, polypeptide compound 4, polypeptide compound 5 and polypeptide compound 6, and the storage condition is-20 ℃.
The molding method comprises the following steps: 48 male C57BL/6J mice, week-old 8 weeks (purchased from Peking Wittingle laboratory animal technology Co., Ltd.), were randomly divided into 8 groups, each: 1) control (MCS) + saline, i.e., i.p., n-6; 2) model group (MCD) + saline, i.p., n ═ 6; 3) model group (MCD) +150 μ g/kg compound 1, n ═ 6; 4) model group (MCD) +150 μ g/kg compound 2, n ═ 6; 5) model group (MCD) +150 μ g/kg compound 3, n ═ 6; 6) model group (MCD) +150 μ g/kg compound 4, n ═ 6; 7) model group (MCD) +150 μ g/kg compound 5, n ═ 6; 8) model group (MCD) +150 μ g/kg compound 6, n-6.
After feeding methionine-choline deficient feed (MCD) (purchased from Jiangsumeidison biomedical Co., Ltd.) for 4 weeks, mice were administered with drug or treated with physiological saline, and the materials were taken 3 weeks after the drug administration for pathological observation.
The experimental method comprises the following steps:
h & E staining: baking and dewaxing; staining with hematoxylin for 7 min, washing with tap water, differentiating with 1% hydrochloric acid ethanol for 1s, washing with tap water, staining with eosin, washing with tap water, dehydrating, air drying, and sealing with gum.
Dyeing with oil red O: drying frozen slices (thickness of 4-8 μm) at room temperature for 15-20 min; incubate with 100% isopropanol for 5 minutes (avoid bringing water into oil red O); incubation with 0.5% oil red O solution for 7-8 minutes (oven at 60 ℃); washing with 85% isopropanol solution for 3 min; double dehydration washing; hematoxylin staining for 1-1.5 min; double dehydration washing; the sealing agent seals the sheet.
Dyeing with sirius red: baking and dewaxing; standing in double distilled water for 5.0 minutes; dyeing with sirius red for 60-80 minutes in a dark room; rinsing with 0.5% glacial acetic acid for 5 s; dehydrating and transparentizing, sealing and taking a picture.
In the MCD-induced mouse nonalcoholic steatohepatitis model, the mouse performance characteristics are: abnormal lipid metabolism, and accumulation of large amounts of Triglycerides (TG) in the liver, and the like. After 3 weeks of treatment with the polypeptide compounds of the present invention, mice were treated and material was taken, and liver tissues were taken for pathological analysis.
The results of H & E staining and lipid accumulation analysis of mouse liver after 150 μ g/kg of each of polypeptide compound 1, polypeptide compound 2, polypeptide compound 3, polypeptide compound 4, polypeptide compound 5 and polypeptide compound 6 was administered to the MCD-induced mouse liver nonalcoholic steatohepatitis model are shown in fig. 1 to 2; the results of oil red O staining and lipid accumulation analysis of mouse liver are shown in fig. 3 to 4; results of sirius red staining and lipid accumulation analysis of mouse liver are shown in fig. 5 to 6.
As can be seen from the results of FIGS. 1 to 6, the accumulation of triglycerides in the liver of mice was significantly increased after the mice were administered with MCD feed, and the accumulation of triglycerides in the liver of mice was significantly improved after the treatment with the polypeptide compound of the present invention. Therefore, the polypeptide compound has a good treatment effect on the nonalcoholic steatohepatitis.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof, and it is therefore intended that all such changes and modifications as fall within the true spirit and scope of the invention as defined by the appended claims be interpreted in accordance with the breadth to which they are fairly, if not explicitly recited herein.
Sequence listing
<110> Qing Yuan City chart microampere scientific and technological development Co., Ltd
<120> polypeptide compound and use thereof for preventing or treating nonalcoholic steatohepatitis
<130> GD2390-21P125281
<160> 8
<170> PatentIn version 3.5
<210> 1
<211> 9
<212> PRT
<213> Artificial sequence
<400> 1
Cys Lys Lys Asn Ser Pro Thr Ala Cys
1 5
<210> 2
<211> 9
<212> PRT
<213> Artificial sequence
<400> 2
Cys Lys Lys Asn Tyr Pro Thr Leu Cys
1 5
<210> 3
<211> 9
<212> PRT
<213> Artificial sequence
<400> 3
Cys Lys Lys Asn Tyr Pro Thr Ala Cys
1 5
<210> 4
<211> 9
<212> PRT
<213> Artificial sequence
<400> 4
Cys Lys Lys Asn Ser Pro Thr Leu Cys
1 5
<210> 5
<211> 9
<212> PRT
<213> Artificial sequence
<400> 5
Cys Ser Lys Asn Tyr Pro Thr Leu Cys
1 5
<210> 6
<211> 9
<212> PRT
<213> Artificial sequence
<400> 6
Cys Ser Lys Asn Ser Pro Thr Leu Cys
1 5
<210> 7
<211> 9
<212> PRT
<213> Artificial sequence
<400> 7
Cys Ser Lys Asn Ser Pro Thr Ala Cys
1 5
<210> 8
<211> 9
<212> PRT
<213> Artificial sequence
<400> 8
Cys Ser Lys Asn Tyr Pro Thr Ala Cys
1 5
Claims (7)
1. A polypeptide compound comprising an amino acid sequence set forth in seq id no:
Cys-Xaa2-Lys-Asn-Xaa5-Xaa6-Thr-Xaa8-Cys-COR1
wherein R is1＝-NH2or-OH;
xaa2 ═ Lys or Ser;
xaa5 ═ Ser or Tyr;
xaa6 ═ Pro or Lys;
xaa8 ═ Leu or Ala.
2. The polypeptide compound of claim 1 wherein Xaa6 is Pro.
3. The polypeptide compound of claim 2 wherein Xaa2 ═ Lys.
4. The polypeptide compound of claim 1, wherein the polypeptide compound is any one of the following compounds 1-8:
compound 1(SEQ ID NO. 1):
Cys-Lys-Lys-Asn-Ser-Pro-Thr-Ala-Cys
compound 2(SEQ ID NO. 2):
Cys-Lys-Lys-Asn-Tyr-Pro-Thr-Leu-Cys
compound 3(SEQ ID NO. 3):
Cys-Lys-Lys-Asn-Tyr-Pro-Thr-Ala-Cys
compound 4(SEQ ID NO. 4):
Cys-Lys-Lys-Asn-Ser-Pro-Thr-Leu-Cys
compound 5(SEQ ID NO. 5):
Cys-Ser-Lys-Asn-Tyr-Pro-Thr-Leu-Cys
compound 6(SEQ ID NO. 6):
Cys-Ser-Lys-Asn-Ser-Pro-Thr-Leu-Cys
compound 7(SEQ ID NO. 7):
Cys-Ser-Lys-Asn-Ser-Pro-Thr-Ala-Cys
compound 8(SEQ ID NO. 8):
Cys-Ser-Lys-Asn-Tyr-Pro-Thr-Ala-Cys。
5. a composition comprising the polypeptide compound of any one of claims 1 to 4.
6. The composition of claim 5, wherein the composition is a pharmaceutical composition, optionally further comprising a pharmaceutically acceptable carrier or adjuvant.
7. Use of the polypeptide compound according to any one of claims 1 to 4 for the preparation of a medicament for the prophylaxis or treatment of nonalcoholic steatohepatitis.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110092784.5A CN112898382A (en) | 2021-01-22 | 2021-01-22 | Polypeptide compound and application thereof in preventing or treating nonalcoholic steatohepatitis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110092784.5A CN112898382A (en) | 2021-01-22 | 2021-01-22 | Polypeptide compound and application thereof in preventing or treating nonalcoholic steatohepatitis |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113499426A (en) * | 2021-07-13 | 2021-10-15 | 南京市妇幼保健院 | Application of milk-derived polypeptide in preparation of medicine, health-care product or food additive for preventing and treating alcoholic fatty liver |
-
2021
- 2021-01-22 CN CN202110092784.5A patent/CN112898382A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113499426A (en) * | 2021-07-13 | 2021-10-15 | 南京市妇幼保健院 | Application of milk-derived polypeptide in preparation of medicine, health-care product or food additive for preventing and treating alcoholic fatty liver |
| CN113499426B (en) * | 2021-07-13 | 2023-09-19 | 南京市妇幼保健院 | Application of milk-derived polypeptide in preparation of medicines, health products or food additives for preventing and treating alcoholic fatty liver disease |
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