CN109513005B - Drug action target for treating AGS - Google Patents

Drug action target for treating AGS Download PDF

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CN109513005B
CN109513005B CN201811363770.7A CN201811363770A CN109513005B CN 109513005 B CN109513005 B CN 109513005B CN 201811363770 A CN201811363770 A CN 201811363770A CN 109513005 B CN109513005 B CN 109513005B
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廖亚金
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Nanjing Angkeli Medicine Technology Innovation Research Institute Co ltd
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    • A—HUMAN NECESSITIES
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Abstract

The invention discloses application of a medicament taking histone deacetylase as a medicament action target in preparing a medicament for treating AGS. The medicine taking histone deacetylase as the medicine action target is an inhibitor of expression and function of the histone deacetylase. Inhibitors of histone deacetylase expression and function include RGFP966 and RGFP 109. The aim of treating Aicardi-Gouti res syndrome is achieved by inhibiting cGAS expression and STING-TBK1-IRF3 pathway activity.

Description

Drug action target for treating AGS
Technical Field
The invention relates to a drug action target for treating AGS, belonging to the field of biological medicine.
Background
Aicardi-Gouti res syndrome (AGS) is a rare genetic disease mainly involved in nervous system and skin, and has major clinical features including intracranial multiple calcifications, leukoencephalopathy, chronic lymphocytosis of cerebrospinal fluid (CSF) and chilblain-like skin lesions, to date 7 AGS pathogenic genes including TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR1 and IFIH1 genes have been found, which are defective, lead to reduction or loss of nuclease activity, intracellular nucleic acid accumulation, are recognized by STING, RIG1, MDA5 or DAI, lead to pathological overactivation of STING-TBK1-IRFs, IPS1-TRAF3-TBK1-IRFs/NF- к B or TRIF-TRAF3-IRFs, and lead to increase of IFN receptor transcriptional activity of IFN receptor, IFN receptor tyrosine kinase, IFN receptor, protein
The important role of STING-TBK1-IRFs signaling pathway in Aicardi-goutres syndrome suggests it as a potential therapeutic target. Knocking out intracellular DNA recognition receptor cGAS can effectively inhibit autoimmune inflammation caused by TREX1 deletion, remarkably improve disease symptoms of Aicardi-Gouti res syndrome model mice and prolong the life span of the mice.
Currently, there are mainly the following treatment modalities:
1) intravenous gamma globulin (IVIG) and (or) glucocorticoids: IVIG and glucocorticoids are common drugs for empirical therapy, and can improve nervous system symptoms, relieve autoinflammation or autoimmune manifestations to different degrees by single use or combined use, but the exact curative effect is not clear.
2) Homozygous mutation of anti-Interleukin (IL) -6 receptor (toslizumab) SAMHD1 may also lead to intracranial aortic multifocal stenosis-aneurysm-cerebral basolateral abnormal vascular network-chronic ischemia and early-onset stroke syndrome. Tozhuzumab can effectively relieve cerebrovascular diseases, improve laboratory abnormal indexes, and reduce hormone dosage. But are currently limited to SAMS clinical case reports.
3) The anti-IFN- α antibody AGS causes over-activation of type I IFN signaling pathway due to gene defect, in vitro tests show that the anti-IFN- α antibody can prevent over-expression of type I IFN related genes, and the current anti-IFN- α monoclonal antibody used for treating systemic lupus erythematosus is in the phase II clinical test stage.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a drug action target for treating AGS.
In order to solve the technical problems, the invention provides the following technical scheme:
histone Deacetylases (HDACs) are a class of enzymes that play an important role in epigenetic regulation by removing the acetyl group at the site of acetylation modification of histones and other proteins. RGFP966 (formula 1) and RGFP109 (formula 2) are specific inhibitors of HDAC3 and HDAC1/3, respectively, highly selectively inhibiting the deacetylase activity of HDAC3, HDAC1 and HDAC3, respectively.
Figure BDA0001867955390000021
The medicine using histone deacetylase as the medicine action target can be used for preparing AGS medicines, and the cGAS expression and the STING-TBK1-IRF3 pathway activity are inhibited by histone deacetylase expression and function inhibitors such as RGFP966 and RGFP109, so as to achieve the purpose of treating Aicardi-Gouti res syndrome.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention. In the drawings:
FIG. 1 is a graph showing the results of measuring the regulatory effects of RGFP966 on cGAS expression and cGAS-STING-TBK1-IRF3 pathway activity;
FIG. 2 is the results of the measurement of the regulatory effect of RGFP109 on cGAS expression and cGAS-STING-TBK1-IRF3 pathway activity;
FIG. 3 shows the results of the measurement of the therapeutic effect of RGFP966 and RGFP109 in a mouse model of Aicardi-Gouti syndrome.
Detailed Description
The preferred embodiments of the present invention will be described in conjunction with the accompanying drawings, and it will be understood that they are described herein for the purpose of illustration and explanation and not limitation.
Example 1 assay of the modulating effects of RGFP966 on cGAS expression and cGAS-STING-TBK1-IRF3 pathway activity.
A cell stimulation step:
① cells BV2 microglia cells were seeded in 6 wells of 12-well cell culture plates at a density of 3X 105Per well;
② pretreatment, after seeding cells for 12h, RGFP966 was added to final concentrations of 0, 10 and 20 μ M, two wells each, for 6 h;
③ poly (dA: dT) stimulation, namely, transfecting poly (dA: dT) to cells by lipofection2000, wherein the transfection process comprises the steps of taking 1.5 mu g poly (dA: dT) and 3 mu L lipofection2000, respectively, incubating with 75 mu L Opti-MEM for 5min at room temperature, combining the two, blowing and uniformly mixing, incubating for 20min at room temperature, replacing the cells with fresh culture medium, finally, dropwise dispersing and dripping the incubated transfection compound into the cell culture medium, wherein each hole has 50 mu L, only one hole is added at each RGFP966 concentration, the other is a control, slightly shaking for 2-3 times, returning to an incubator for culture, adding poly (dA: dT) for 6h, cracking the cells, and detecting the expression amount of p-IRF3 and cGAS by Western blotting.
Western blotting procedure:
① tissue/cell protein extraction
Firstly, preparing cell lysate, wherein the cell lysate formula is as follows: 50mM HEPES (pH 7.4), 1% NP-40, 0.05% SDS, 150mM NaCl, 100mM NaF, 1mM EGTA, stored at 4 ℃. The protease inhibitor cocktail and phosphatase inhibitor phosSTOP are added before use. After cell collection, the cells were washed once with pre-cooled PBS to remove serum and media components (tissue was perfused with normal saline when material was taken), and then added with a suitable volume of cell lysate and incubated at 4 ℃ for 20min with rotation (tissue was homogenized with a tissue homogenizer and then incubated at 5000rpm for 15 s). Finally, centrifugation was carried out at 12000 Xg for 15min at 4 ℃ to collect the supernatant, and protein concentration was measured. According to the protein concentration determination result, the same amount of total protein is taken, cell lysate is added for leveling, a proper volume of 6 Xloading buffer is added, and heating is carried out for 10min at 95 ℃.
② determination of protein concentration
The protein concentration determination of the research adopts a BCA method, and the main steps are as follows: 1. mixing the reagent A with the reagent B with the volume of 50 times and the reagent B with the volume of 1 time, and adding the mixture into a 96-well plate, wherein each well is 100 mu L; 2. adding a BSA standard substance which is diluted in advance and has a corresponding volume according to a set standard curve value to make a concentration gradient-absorbance curve; 3. simultaneously, 1 mu L of cell (tissue) lysate is correspondingly added into each well to centrifuge the supernatant (or the supernatant is diluted properly by deionized water); incubating for 30min at 4.37 ℃, and reading the light absorption value at 462nm wavelength by using a multifunctional microplate reader; 5. calculating a standard curve according to the light absorption value of the standard substance; 6. calculating the total protein concentration of the cell (tissue) lysate centrifugal supernatant according to a standard curve; 7. all cell/tissue lysates were diluted to the same concentration and total protein concentration was controlled as much as possible between 2-10. mu.g/. mu.L.
③ Western immunoblot (western blot)
The main steps are that ① polyacrylamide gel with 15% separation gel concentration is prepared to carry out SDS-PAGE electrophoresis, ② wet-transfer method is used for membrane transfer, 250mA constant-transfer membrane is used for 90min, ③ 5% skim milk/TBST is used for sealing for 1h at room temperature, ④ p-IRF3, cGAAS and GAPDH antibodies are respectively diluted by 2% BSA/TBS containing 0.1% sodium azide and then incubated with the membrane at 4 ℃ overnight, ⑤ TBST is used for membrane washing for 3 times, each time for 5min, ⑥ the membrane is incubated with appropriate HRP-labeled secondary antibodies of corresponding species (the p-IRF3 and the cGAAS antibodies belong to rabbits, and the GAPDH light sheet antibody species belong to mice), ⑦ chemiluminescence method is combined with X development technology for imaging, and ⑧ scanner scanning development results are obtained.
The results are shown in FIG. 1, RGFP966 significantly inhibited the expression of cGAS and the expression level of p-IRF3 activated by poly (dA: dT) and exhibited significant dose effects.
Example 2: detection of the effects of RGFP109 on the modulation of cGAS expression and cGAS-STING-TBK1-IRF3 pathway Activity
A cell stimulation step:
① cells BV2 microglia cells were seeded in 6 wells of 12-well cell culture plates at a density of 3X 105Per well;
② pretreatment, after seeding the cells for 12h, RGFP109 was added to final concentrations of 0, 6 and 12. mu.M, in each of two wells for 6 h;
③ poly (dA: dT) stimulation, namely, transfecting poly (dA: dT) to cells by lipofection2000, wherein the transfection process comprises the steps of taking 1.5 mu g poly (dA: dT) and 3 mu L lipofection2000, respectively, incubating with 75 mu L Opti-MEM for 5min at room temperature, combining the two, blowing and uniformly mixing, incubating for 20min at room temperature, replacing the cells with fresh culture medium, finally, dropwise and dispersedly adding the incubated transfection compound into the cell culture medium, wherein each hole has 50 mu L, only one hole is added at each RGFP109 concentration, the other is a control, slightly shaking for 2-3 times, returning to an incubator for culture, cracking the cells when the poly (dA: dT) is added for 6h, and detecting the expression amount of p-IRF3 and cGAS by western blotting.
Western blotting procedure:
① tissue/cell protein extraction
Firstly, preparing cell lysate, wherein the cell lysate formula is as follows: 50mM HEPES (pH 7.4), 1% NP-40, 0.05% SDS, 150mM NaCl, 100mM NaF, 1mM EGTA, stored at 4 ℃. The protease inhibitor cocktail and phosphatase inhibitor phosSTOP are added before use. After cell collection, the cells were washed once with pre-cooled PBS to remove serum and media components (tissue was perfused with normal saline when material was taken), and then added with a suitable volume of cell lysate and incubated at 4 ℃ for 20min with rotation (tissue was homogenized with a tissue homogenizer and then incubated at 5000rpm for 15 s). Finally, centrifugation was carried out at 12000 Xg for 15min at 4 ℃ to collect the supernatant, and protein concentration was measured. According to the protein concentration determination result, the same amount of total protein is taken, cell lysate is added for leveling, a proper volume of 6 Xloading buffer is added, and heating is carried out for 10min at 95 ℃.
② determination of protein concentration
The protein concentration determination of the research adopts a BCA method, and the main steps are as follows: 1. mixing the reagent A with the reagent B with the volume of 50 times and the reagent B with the volume of 1 time, and adding the mixture into a 96-well plate, wherein each well is 100 mu L; 2, adding a BSA standard substance which is diluted in advance and has a corresponding volume according to a set standard curve value to make a concentration gradient-absorbance curve; 3. simultaneously, 1 mu L of cell (tissue) lysate is correspondingly added into each well to centrifuge the supernatant (or the supernatant is diluted properly by deionized water); incubating for 30min at 4.37 ℃, and reading the light absorption value at 462nm wavelength by using a multifunctional microplate reader; 5. calculating a standard curve according to the light absorption value of the standard substance; 6. calculating the total protein concentration of the cell (tissue) lysate centrifugal supernatant according to a standard curve; 7. all cell/tissue lysates were diluted to the same concentration and total protein concentration was controlled as much as possible between 2-10. mu.g/. mu.L.
③ Western immunoblot (western blot)
The main steps are that ① polyacrylamide gel with 15% separation gel concentration is prepared to carry out SDS-PAGE electrophoresis, ② wet-transfer method is used for membrane transfer, 250mA constant-transfer membrane is used for 90min, ③ 5% skim milk/TBST is used for sealing for 1h at room temperature, ④ p-IRF3, cGAAS and GAPDH antibodies are respectively diluted by 2% BSA/TBS containing 0.1% sodium azide and then incubated with the membrane at 4 ℃ overnight, ⑤ TBST is used for membrane washing for 3 times, each time for 5min, ⑥ the membrane is incubated with appropriate HRP-labeled secondary antibodies of corresponding species (the p-IRF3 and the cGAAS antibodies belong to rabbits, and the GAPDH light sheet antibody species belong to mice), ⑦ chemiluminescence method is combined with X development technology for imaging, and ⑧ scanner scanning development results are obtained.
As a result, as shown in FIG. 2, RGFP109 significantly inhibited the expression of cGAS and the expression level of p-IRF3 activated by poly (dA: dT), and the inhibition effect was more significant as the concentration increased.
Example 3: RGFP966 and RGFP109 were tested for therapeutic efficacy in a model mouse of Aicardi-Gouti res syndrome.
Experimental animals: 60 trex1 knockout mice, 3 weeks old, were randomly divided into 3 groups of 20 mice, one group being the solvent control group, one group being the RGFP966 dosing group, and one group being the RGFP109 dosing group.
The preparation method of the medicine comprises the steps of dissolving RGFP966 and RGFP109 in DMSO to obtain stock solutions with the concentration of 30mg/ml, dissolving 3g of cosolvent hydroxypropyl- β -cyclodextrin in 5ml of 100mM sodium acetate (pH is 5.4), adding sterile water to reach a constant volume of 10ml to obtain 30% hydroxypropyl- β -cyclodextrin, mixing the stock solutions and 30% hydroxypropyl- β -cyclodextrin uniformly according to the ratio of 1:9, and injecting the mixture into the abdominal cavity, wherein the dose is 30mg/kg of body weight, and the experimental end point is set when the survival rate of a control group is lower than 50%.
As shown in FIG. 3, the survival rate of the control group was reduced to 50% or less at 18 weeks of age, whereas that of the RGFP966 and RGFP109 administration groups was about 90%, indicating that RGFP966 and RGFP109 could significantly prolong the life of mice of the Aicardi-Gouti res syndrome model.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (1)

1. The application of inhibitors RGFP966 and RGFP109 of histone deacetylase expression and function in preparing a medicament for treating Aicardi-Goutieres syndrome is provided, wherein the RGFP966 has a structural formula as follows:
Figure FDA0002448381510000011
the structural formula of RGFP109 is
Figure FDA0002448381510000012
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WO2012016081A2 (en) * 2010-07-30 2012-02-02 The Regents Of The University Of California Method and therapeutic for the treatment and regulation of memory formation

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