WO2023241118A1 - Procédé de criblage de médicament anti-sénescence - Google Patents
Procédé de criblage de médicament anti-sénescence Download PDFInfo
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- WO2023241118A1 WO2023241118A1 PCT/CN2023/080293 CN2023080293W WO2023241118A1 WO 2023241118 A1 WO2023241118 A1 WO 2023241118A1 CN 2023080293 W CN2023080293 W CN 2023080293W WO 2023241118 A1 WO2023241118 A1 WO 2023241118A1
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- drug
- gfp
- progerin
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- cells
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
- G01N33/5026—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on cell morphology
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
- G01N33/5035—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on sub-cellular localization
Definitions
- the invention relates to the technical field of genetic engineering, and in particular to a screening method for anti-aging drugs.
- Senescent cells exhibit a variety of typical characteristics, including increased DNA damage, increased p16, increased ⁇ -galactosidase activity, and increased senescence-related secretory phenotypes.
- the idea of developing traditional anti-aging drugs is to kill senescent cells, and the specific strategy is to develop drugs based on the typical characteristics of senescent cells. For example, specifically eliminate cells with high p16 expression, design lead drugs and use the activity of ⁇ -galactosidase to kill cells, inhibit the expression of aging-related secreted factors, etc.
- the anti-aging drugs selected by these methods can inhibit cellular aging and adult aging to a certain extent.
- senescent cells Typical characteristics of senescent cells also appear in normal cells. For example, senescence-related secreted factors can promote embryonic structure recognition, tissue remodeling and repair, etc. The inhibition of their expression will disrupt the normal functions of the body. ⁇ -Galactosidase is also expressed in non-senescent tissue cells, such as bone marrow. Therefore, anti-aging drug screening based on the characteristics of senescent cells has major side effects and affects the functions of normal tissue cells.
- the present invention provides a screening method for anti-aging drugs based on the principle that the positioning of progerin protein on the nuclear membrane in cells overexpressing GFP-progerin protein will change based on the anti-aging effect of the drug. , drugs with anti-aging effects can be screened accurately and quickly.
- the present invention provides a method for screening anti-aging drugs, including:
- the cells overexpressing the GFP-progerin protein are treated with the drug to be screened and compared with the cells overexpressing the GFP-progerin protein that are not treated with the drug to be screened.
- the resistance of the drug to be screened is judged based on the changes in cell morphology. Aging effect.
- the cells overexpressing GFP-progerin protein are primary cells overexpressing GFP-progerin protein.
- progerin protein includes the amino acid sequence shown in SEQ ID NO.1.
- the cells overexpressing the GFP-progerin protein are prepared by constructing the gene encoding the progerin protein into a lentiviral vector and then transfecting HK293T cells, collecting the viral fluid and then infecting primary cells.
- the gene encoding the progerin protein includes the nucleotide sequence shown in SEQ ID NO. 2.
- the primary cells are human primary skin fibroblasts.
- the lentiviral vector includes one or more of pCDH, pQCXIP, pLVX or pLenti6/TR.
- the positioning changes from positioning on the cell nuclear membrane to positioning within the cell nucleus.
- the present invention provides an anti-aging drug screening method based on the GFP-progerin senescent cell model, which can achieve high-throughput and high-precision anti-aging drug screening.
- the present invention provides an efficient, stable and accurate drug screening platform, which can realize the screening of up to 1536 small molecule compounds at a time, achieving high-throughput and high-precision drug screening.
- the present invention has successfully screened a variety of candidate drugs with anti-aging functions, and it has been verified that they also have the effect of inhibiting aging on patient cells, which affects progeria, aging, vascular sclerosis, tissue and organ fibrosis, The treatment of aging inflammation and other diseases provides new possibilities.
- Figure 1 is a diagram showing the results of cell immunofluorescence detection of abnormal cell nuclei caused by GFP-progerin provided in Example 1 of the present invention.
- Figure 2 is a graph showing the proportional statistical results of nuclear membrane budding caused by GFP-progerin provided in Example 1 of the present invention.
- Figure 3 is a schematic diagram of the impact of progerin protein localization on cells in the GFP-progerin senescent cell model provided in Example 1 of the present invention.
- Figure 4 is an overall flow chart of anti-aging drug screening provided in Embodiment 1 of the present invention.
- Figure 5 is a schematic flow chart of high-throughput screening of anti-aging drugs provided in Embodiment 1 of the present invention.
- Figure 6 is a schematic diagram of the effect of drug candidate 1 provided in Example 2 of the present invention on progerin localization.
- Figure 7 is a schematic diagram of the effects of candidate drugs 2 and 3 provided in Example 2 of the present invention on progerin localization.
- Figure 8 is a schematic diagram of the effects of candidate drugs 1, 2 and 3 on nuclear membrane budding provided in Example 2 of the present invention.
- Figure 9 is a schematic diagram of the effects of candidate drugs 1, 2 and 3 provided in Example 2 of the present invention on the localization of progerin in cells of patients with progeria.
- Figure 10 shows the effect of candidate drugs 1, 2 and 3 on progeria patient cells provided in Example 2 of the present invention. Schematic representation of the effects of nuclear membrane budding.
- This embodiment provides a method for screening anti-aging drugs.
- the process is as follows:
- Senescent cell model GFP-progerin senescent cell model
- DMEM modified Eagle medium
- fetal calf serum 100 U/mL penicillin + 100 ⁇ g/mL streptomycin
- the GFP-progerin senescent cell model was prepared by the following method:
- the cell suspension to a 35 mm culture dish, add 4 mL of DMED medium containing 5-20% fetal bovine serum, 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin, and place it in a cell culture incubator at 5% CO2 , culture at 37°C for 4-6 days. As the culture progresses, the culture medium can be added appropriately according to the amount of culture medium in the petri dish.
- the isolated cells are primary human dermal fibroblasts (HDF).
- HDF primary human dermal fibroblasts
- the donor skin sample is cut into small pieces with ophthalmic scissors, digested with trypsin and cultured in an incubator.
- the freed cells are skin fibroblasts.
- Isolated primary human skin fibroblasts (passage 3) were used in this example.
- the coding sequence of GFP was cloned from the pEGFP-C1 vector by PCR, and then the pCDH-CMV-MCS-EF1 vector was cut with XbaI and NotI double enzyme digestion, and the coding sequences of GFP and progerin were inserted respectively. Among them, GFP is located at the N-terminus of progerin. The vector was used for subsequent experiments after successful sequencing.
- the PCR primer sequence of progerin is as follows:
- progerin R 5’-CAGGCGGCCGCTTACATGATGCTGCAGTTCT-3’.
- GFP-positive cells are sorted out by a sorting instrument and inoculated for amplification.
- the cells obtained are GFP-progerin senescent cells.
- GFP-progerin senescent cells were observed on a high-content fluorescence microscope and a large-field fluorescence image was captured.
- GFP-progerin senescent cells were seeded into a 96-well plate, treated with small molecule compounds for 24 hours, and then screened by high-content fluorescence microscopy. The screening criterion was that GFP-progerin was localized in the nucleus. Finally, the single wells in the 96-well plate that change the positioning of GFP-progerin are screened, and the corresponding small molecule compounds are candidate drugs.
- a small molecule that is effective against GFP-progerin senescent cells and progeria patient cells The compound is the final candidate drug screened.
- the anti-aging drug screening process includes: inoculation of GFP-progerin senescent cells, drug treatment, high-content fluorescence microscopy screening, and progeria patient cell verification.
- Example 1 the anti-aging drugs screened in Example 1 were verified through cellular immunofluorescence experiments.
- the fixed cells were labeled with antibodies.
- Antibodies for progerin, emerin, lamin A/C, and lamin B1 were added to 3% BSA in PBS buffer at a ratio of 1:200.
- the fixed cells were inverted in primary antibody dilution and incubated overnight at 4°C.
- green fluorescence represents GFP-progerin
- red fluorescence represents nuclear membrane protein emerin
- purple fluorescence represents lamin B1
- blue fluorescence represents chromatin.
- green fluorescence represents GFP-progerin
- red fluorescence represents lamin A/C
- purple fluorescence represents lamin B1
- blue fluorescence represents chromatin.
- green fluorescence represents progerin
- red fluorescence represents lamin B1
- blue fluorescence represents chromatin.
- the invention provides a screening method for anti-aging drugs.
- the cells overexpressing the GFP-progerin protein are treated with the drug to be screened and compared with the cells overexpressing the GFP-progerin protein that are not treated with the drug to be screened.
- the resistance of the drug to be screened is judged based on the changes in cell morphology. Aging effect.
- the present invention provides an anti-aging drug screening method based on the GFP-progerin senescent cell model, which can achieve high-throughput and high-precision anti-aging drug screening. It provides new possibilities for the treatment of diseases such as progeria, aging, vascular sclerosis, tissue and organ fibrosis, aging inflammation, etc., and has good economic value and application prospects.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Chemical & Material Sciences (AREA)
- Urology & Nephrology (AREA)
- Molecular Biology (AREA)
- Cell Biology (AREA)
- Microbiology (AREA)
- Medicinal Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Toxicology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pathology (AREA)
- Food Science & Technology (AREA)
- Biotechnology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
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- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
La présente invention concerne le domaine technique de l'ingénierie génétique, et en particulier un procédé de criblage de médicament anti-sénescence. Le procédé de criblage comprend : le traitement d'une cellule surexprimant la protéine GFP-progérine à l'aide d'un médicament à cribler ; la comparaison de la cellule surexprimant la protéine GFP-progérine traitée avec une cellule surexprimant la protéine GFP-progérine qui n'est pas traitée par le médicament à cribler ; et la détermination, en fonction d'un changement de morphologie cellulaire, d'une fonction anti-sénescence du médicament à cribler. Selon la présente invention, une protéine progérine située sur une membrane nucléaire peut amener une cellule à présenter des caractéristiques évidentes de sénescence, notamment le rétrécissement de la membrane nucléaire et le bourgeonnement de la membrane nucléaire. Cependant, une protéine progérine située dans le noyau d'une cellule n'entraînerait pas l'apparition de caractéristiques évidentes de sénescence dans la cellule. Si un médicament présente un effet anti-sénescence, une protéine progérine située sur une membrane nucléaire serait transférée dans le noyau d'une cellule. Ainsi, la présente invention concerne un procédé de criblage de médicaments anti-sénescence, capable de cribler avec précision et efficacité un médicament anti-sénescence.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210664879.4 | 2022-06-13 | ||
| CN202210664879.4A CN115044639A (zh) | 2022-06-13 | 2022-06-13 | 一种抗衰老药物的筛选方法 |
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| Publication Number | Publication Date |
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| WO2023241118A1 true WO2023241118A1 (fr) | 2023-12-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/CN2023/080293 WO2023241118A1 (fr) | 2022-06-13 | 2023-03-08 | Procédé de criblage de médicament anti-sénescence |
Country Status (2)
| Country | Link |
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| CN (1) | CN115044639A (fr) |
| WO (1) | WO2023241118A1 (fr) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115044639A (zh) * | 2022-06-13 | 2022-09-13 | 北京大学 | 一种抗衰老药物的筛选方法 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140039010A1 (en) * | 2011-03-18 | 2014-02-06 | Pusan National University Industry-University Cooperation Foundation | Pharmaceutical composition for treating aging-associated diseases, containing progerin expression inhibitor as active ingredient, and screening method of said progerin expression inhibitor |
| WO2020061497A1 (fr) * | 2018-09-20 | 2020-03-26 | Ionis Pharmaceuticals, Inc. | Compositions et procédés de modulation de l'expression de lmna |
| CN114958766A (zh) * | 2022-05-31 | 2022-08-30 | 北京大学 | 一种衰老细胞模型的构建方法 |
| CN115044639A (zh) * | 2022-06-13 | 2022-09-13 | 北京大学 | 一种抗衰老药物的筛选方法 |
-
2022
- 2022-06-13 CN CN202210664879.4A patent/CN115044639A/zh active Pending
-
2023
- 2023-03-08 WO PCT/CN2023/080293 patent/WO2023241118A1/fr unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140039010A1 (en) * | 2011-03-18 | 2014-02-06 | Pusan National University Industry-University Cooperation Foundation | Pharmaceutical composition for treating aging-associated diseases, containing progerin expression inhibitor as active ingredient, and screening method of said progerin expression inhibitor |
| WO2020061497A1 (fr) * | 2018-09-20 | 2020-03-26 | Ionis Pharmaceuticals, Inc. | Compositions et procédés de modulation de l'expression de lmna |
| CN114958766A (zh) * | 2022-05-31 | 2022-08-30 | 北京大学 | 一种衰老细胞模型的构建方法 |
| CN115044639A (zh) * | 2022-06-13 | 2022-09-13 | 北京大学 | 一种抗衰老药物的筛选方法 |
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