CN118001370B - Compositions and methods for treating neurodegenerative diseases - Google Patents
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- CN118001370B CN118001370B CN202410424222.XA CN202410424222A CN118001370B CN 118001370 B CN118001370 B CN 118001370B CN 202410424222 A CN202410424222 A CN 202410424222A CN 118001370 B CN118001370 B CN 118001370B
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
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- 230000000415 inactivating effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- -1 potassium ferricyanide Chemical compound 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
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- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The application provides a composition for treating neurodegenerative diseases, wherein the composition takes a polypeptide which is derived from an M2 type microglial exosome and has an amino acid sequence of SEQ ID NO.1, SEQ ID NO.3 or SEQ ID NO.5 as an active ingredient. The composition of the application has better safety; the method has the advantages that the method shows more remarkable effects on Morris water maze test and serum GSH, SOD, A beta 1–42 level in a D-galactose mouse model. Provides a new potential drug choice for treating such diseases.
Description
Technical Field
The application belongs to the fields of cell biology, protein and neurodegenerative disease treatment, in particular to a composition and a method for treating neurodegenerative diseases.
Background
Neurodegenerative diseases, such as Alzheimer's disease, are frequently found in elderly patients. It is currently believed that the main causes of alzheimer's disease are amyloid β deposition and neurofibrillary tangles. In the absence of effective therapeutic drugs, alzheimer's disease places a heavy burden on both the home and society.
It is thought that microglial dysregulation may be one of the causes of Alzheimer's disease, and that selective M2 activation has the effects of secreting anti-inflammatory factors, neurotrophic factors and the like to protect nerves, while M1 classical activation M1 destroys neurons in a detrimental inflammatory response.
Therefore, starting from M2 microglial cells and secretion/exosome thereof, the preparation method is a feasible way for researching the medicines for treating the neurodegenerative diseases.
Disclosure of Invention
The application identifies peptides with therapeutic effect/auxiliary therapeutic effect on neurodegenerative diseases such as Alzheimer's disease in enzymolysis products of M2 microglial exosomes, and 3 polypeptides with therapeutic potential on Alzheimer's disease are obtained through practical D-galactose mouse model verification of oxidation resistance screening, toxicity screening and digestion screening.
In one aspect, the application provides a composition for treating a neurodegenerative disease, the composition comprising a polypeptide derived from an M2 microglial exosome, the polypeptide having the amino acid sequence of SEQ ID No.1, SEQ ID No.3 or SEQ ID No.5.
Further, the neurodegenerative disease is Alzheimer's disease.
Further, the polypeptide is the only active ingredient in the so-called composition.
Further, the composition is in liquid form.
Further, the composition also comprises one or more auxiliary materials selected from solvents, cosolvents, pH regulators and osmotic pressure regulators.
Depending on the digestive and bioavailable properties of the polypeptide, the composition may be in liquid form, such as an injection or an oral liquid; can be in the form of oral preparation such as tablet, capsule, etc.
In another aspect, the application provides a polypeptide derived from an M2 microglial exosome, the amino acid sequence of which is SEQ ID No.1, SEQ ID No.3 or SEQ ID No.5.
In another aspect, the application provides the use of a polypeptide derived from an M2 microglial exosome, the amino acid sequence of which is SEQ ID No.1, SEQ ID No.3 or SEQ ID No.5, in the manufacture of a medicament for the treatment of a neurodegenerative disease.
Further, the neurodegenerative disease is Alzheimer's disease.
In another aspect, the present application provides a method for preparing the above polypeptide, which is a solid phase synthesis method.
In another aspect, the application provides a method of treating a neurodegenerative disease, such as Alzheimer's disease, comprising administering to a subject suffering from a neurodegenerative disease a polypeptide as described above.
The subject may be a human or an animal.
Due to the differences in regulations, no method of treatment of the disease is claimed in the present application, but applicants reserve the right to apply for a method of treatment based on the above description.
The polypeptide is obtained by enzymolysis and separation from human M2 microglial exosomes, and has better safety; the method has the advantages that the method shows more remarkable effects on Morris water maze test and serum GSH, SOD, A beta 1–42 level in a D-galactose mouse model. Provides a new potential drug choice for treating such diseases.
Drawings
FIG. 1 shows DPPH radical scavenging performance of 6 polypeptides;
FIG. 2 is a graph of the reducing power performance of 6 polypeptides;
FIG. 3 is a Morris water maze test result; part a is latency; the part B is the total distance;
FIG. 4 shows the results of the concentration detection of Abeta 1–42;
FIG. 5 shows the results of GSH and SOD activity assays.
Detailed Description
EXAMPLE 1 M2 preparation and enzymatic treatment of microglial exosomes
HMC3 microglial cell line was purchased from Abiowell; the cells were induced to culture M2 microglial cells (marked by increased Arg-1/Ym1 expression as observed under a microscope) using DMEM containing 20ng/mL of IL-4 according to the prior art.
Collecting exosomes of M2 microglial cells by an ultracentrifugation method; performing ultrasonic treatment and cracking; preparing into 1M (urea concentration meter) solution; adding trypsin (2%) and papain (2%) for enzymolysis, and performing enzymolysis at 37 ℃ for 1 hour; inactivating enzyme in boiling water bath, and collecting supernatant.
Example 2 identification and screening of peptides
Intercepting a fraction below 3.0kDa by using an ultrafiltration membrane; separation using semi-preparative HPLC (Ultimate 3000,3000, zemoeimeric); selecting a part with better activity by taking antioxidant activity as a basic index; analysis using LC-MS/MS (Ab Sciex Triple Quad 4500, match ACCLAIM PEPMAP C18); maxQuant the analytical peptide data was retrieved from Uniport database.
Docking and free energy analysis (peptide docking) of the obtained peptide data using BDNF as target; predicting toxicity of the peptide using admetSAR; PEPTIDERANKER predict biological activity; BIOPEP-UWM predicts gastrointestinal tract digestions (pepsin, trypsin).
The following peptides were selected by combining the above factors:
TABLE 1 preliminary screening of peptides
| Sequence and numbering | Molecular weight | Toxicity of | Gastrointestinal digestibility |
| PEVQQAC（SEQ ID NO.1） | 773.3 | Nontoxic | Indigestion is prevented |
| FMLHIKL（SEQ ID NO.2） | 900.5 | Nontoxic | Digestion |
| EICAEGS（SEQ ID NO.3） | 707.2 | Nontoxic | Indigestion is prevented |
| RNQMVW（SEQ ID NO.4） | 832.4 | Nontoxic | Indigestion is prevented |
| SSCFNY（SEQ ID NO.5） | 719.2 | Nontoxic | Digestion |
| LVPSE（SEQ ID NO.6） | 543.2 | Nontoxic | Indigestion is prevented |
EXAMPLE 3 detection of antioxidant Properties of peptides
The 6 polypeptides were subjected to solid-phase synthesis by the client gold, and DPPH radical scavenging rate and reducing power were measured:
DPPH radical scavenging Rate determination:
Preparing a polypeptide solution sample according to the concentration of 0.05 mg/mL; taking 2mL of a sample, mixing with 2mL of a DPPH absolute ethanol solution (sample) with the concentration of 0.1mM or 2mL of absolute ethanol (control), and carrying out light-shielding reaction for 30min at the temperature of 25 ℃; measuring absorbance at 517nm of the sample reaction solution, the control reaction solution and a reference (2 mL of absolute ethyl alcohol plus 2mL of 0.1mM DPPH absolute ethyl alcohol solution) by using a spectrophotometer; DPPH radical clearance% = (1- (a Sample of -A Control ）/A Reference(s) ) x 100%.
Reducing force measurement:
Preparing a polypeptide solution sample according to the concentration of 0.05 mg/mL; taking 2mL of a sample, and mixing with 2mL of 1% potassium ferricyanide aqueous solution and 3mL of PBS with pH of 6.5; reacting at 45 ℃ for half an hour; 2mL of a 10% by mass trichloroacetic acid solution was added; centrifuging for 10min; 2mL of the supernatant was mixed with 2mL of distilled water and 0.1% by mass of an aqueous solution of ferric chloride, and the reducing power was directly expressed as absorbance A 700 at 700 nm.
The results are shown in figures 1 and 2, and SEQ ID NO.1, SEQ ID NO.3, SEQ ID NO.5 and SEQ ID NO.6 with good selection effect are used for further animal model tests.
EXAMPLE 4 Effect in D-galactose Alzheimer's disease mouse model
22 G.+ -.2 g of healthy Kunming mice 60 were divided equally into 6 groups:
positive control group: d-gal 8mg was subcutaneously injected daily for 6 weeks;
A negative control group, daily subcutaneous saline, for 6 weeks;
Sequence 1 group, daily subcutaneous injection of D-gal 8mg, for 6 weeks; from day 8 (day 1 when D-gal injection was started), 20mg of the SEQ ID NO.1 polypeptide was infused daily;
sequence 3 groups, daily subcutaneous injections of D-gal 8mg, for 6 weeks; from day 8 (day 1 when D-gal injection was started), 20mg of the polypeptide SEQ ID NO.3 was infused daily;
sequence 5 groups, daily subcutaneous injections of D-gal 8mg, for 6 weeks; from day 8 (day 1 when D-gal injection was started), 20mg of the SEQ ID NO.5 polypeptide was infused daily;
Sequence 6 groups, daily subcutaneous injections of D-gal 8mg, for 6 weeks; from day 8 (day 1 when D-gal injection was started), 20mg of the SEQ ID NO.6 polypeptide was infused daily.
After the injection period, mice were subjected to Morris water maze test to detect GSH, SOD level, abeta 1–42 (Van-state biological mouse GSH ELISA kit, pullulan SOD activity kit, kang Lang biological mouse Abeta 1–42 ELISA kit) in serum.
As with the computer predicted results, the mice did not die or have obvious toxic symptoms (body weight, degree celsius, activity, skin and basic blood biochemical indicators were all substantially normal) during the test.
The experimental results are shown in fig. 3-5, compared with the negative control group, the latency time and the total distance after the positive control group induces aging are obviously longer, abeta 1–42 has an enrichment trend, GSH and SOD levels are reduced, and the model successfully simulates the neural aging symptoms of the Alzheimer disease. The polypeptides of SEQ ID No.1, SEQ ID No.3 and SEQ ID No.5 effectively reduce the symptoms, and SEQ ID No.6 has no obvious effect in most indexes.
Claims (7)
1. A composition for treating alzheimer's disease, comprising a polypeptide derived from M2 microglial exosomes, the polypeptide having the amino acid sequence SEQ ID No.1, SEQ ID No.3 or SEQ ID No.5.
2. The composition of claim 1, wherein the polypeptide is the only active ingredient in the composition.
3. The composition of claim 2, wherein the composition is in liquid form.
4. A composition according to claim 3, wherein the composition further comprises an adjunct ingredient selected from one or more of solvents, co-solvents, pH adjusting agents and osmolality adjusting agents.
5. A polypeptide derived from M2 microglial exosomes, characterized in that the amino acid sequence of the polypeptide is SEQ ID No.1, SEQ ID No.3 or SEQ ID No.5.
6. Use of a polypeptide derived from M2 microglial exosomes for the preparation of a medicament for the treatment of alzheimer's disease, characterized in that the amino acid sequence of the polypeptide is SEQ ID No.1, SEQ ID No.3 or SEQ ID No.5.
7. A method of preparing a polypeptide according to claim 6, wherein the method is a solid phase synthesis method.
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| CN112194730A (en) * | 2020-10-28 | 2021-01-08 | 中国医科大学 | Polypeptide TI-16 and application thereof |
| CN113057963A (en) * | 2021-03-31 | 2021-07-02 | 华中科技大学 | Specific capture carrier for eliminating beta-amyloid and application thereof |
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| WO2016198627A1 (en) * | 2015-06-12 | 2016-12-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical composition for the treatment of alzheimer's disease |
| CN117126243B (en) * | 2023-10-26 | 2024-01-26 | 中国海洋大学 | Small molecular peptide PYPDW and application thereof |
| CN117683843A (en) * | 2023-12-13 | 2024-03-12 | 浙江省农业科学院 | Hickory nut polypeptide for relieving or improving Alzheimer's disease and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112194730A (en) * | 2020-10-28 | 2021-01-08 | 中国医科大学 | Polypeptide TI-16 and application thereof |
| CN113057963A (en) * | 2021-03-31 | 2021-07-02 | 华中科技大学 | Specific capture carrier for eliminating beta-amyloid and application thereof |
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