CN112546049A - Application of small molecule medicine (+) -JQ1 in preparation of medicine for treating pattern-collapse-type age-related macular degeneration - Google Patents
Application of small molecule medicine (+) -JQ1 in preparation of medicine for treating pattern-collapse-type age-related macular degeneration Download PDFInfo
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- CN112546049A CN112546049A CN202011530342.6A CN202011530342A CN112546049A CN 112546049 A CN112546049 A CN 112546049A CN 202011530342 A CN202011530342 A CN 202011530342A CN 112546049 A CN112546049 A CN 112546049A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Abstract
The invention discloses an application of a small molecule drug (+) -JQ1 in a medicine for treating pattern-collapse-type age-related macular degeneration, and particularly discloses a small molecule drug (+) -JQ1 with a cGAS-STING signal channel inhibition function, and an autoimmune regulation function and an anti-inflammatory function of the small molecule drug (+) -JQ 1. The invention firstly provides that in a mouse disease model of map-like atrophic age-related macular degeneration induced by sodium iodate injection, (+) -JQ1 can inhibit the expression of cGAS and STING genes, and plays roles of immunoregulation and anti-inflammation by inhibiting the function of a cGAS-STING signal pathway. The inhibition of (+) -JQ1 on the cGAS-STING signal channel and the anti-inflammatory action in a disease model of geographic collapsed age-related macular degeneration are promising new-use clinical strategies of old drugs, and provide references for the research of small molecule compounds for resisting autoimmune response and treating age-related macular degeneration diseases.
Description
Technical Field
The invention relates to the technical field of macular degeneration, in particular to application of a small molecule drug (+) -JQ1 in a therapeutic pattern-collapsed age-related macular degeneration drug.
Background
Macular degeneration is a relatively common eye disease, which is classified into age-related macular degeneration and juvenile macular degeneration. Geographic atrophy is one of the types of age-related macular degeneration that affects the normal life of about five million patients worldwide, and there is currently no effective treatment. The pattern-collapsed age-related macular degeneration results from progressive retinal pigment epithelium degeneration and atrophy, and death of photoreceptor cells due to retinal pigment epithelium degeneration causes permanent visual impairment.
It has been shown that although age-related macular degeneration is a multifactorial disease, the disturbance of autoimmune function plays an important role in the pathogenesis of age-related macular degeneration. Thus, immunomodulation is considered as a very promising therapeutic approach to age-related macular degeneration.
The cGAS-STING signaling pathway is an important cytoplasmic DNA sensing pathway in vivo, induces the expression of type I interferons (IFN 1), influences the immune response of the body, and plays an important role in regulating pathogen infection, tumor immunity and autoimmune diseases. Cyclic guanosine monophosphate-adenosine synthetase (cGAS) is a direct cytosolic DNA sensor when cGAS recognizes DNA accumulated in the cytoplasm, cGAS binds to these DNAs, changes in the cGAS active site conformation, and catalyzes synthesis of cyclic dinucleotide from ATP and GTP (cGAMP). cGAMP acts as a second messenger, binds to interferon gene stimulating factor (STING) proteins on the membrane of the Endoplasmic Reticulum (ER), which undergo rapid dimerization to be activated, and the activated STING is transferred from the ER to the golgi apparatus, where kinases such as TANK-binding kinase 1 (TBK 1) and I κ B kinase (IKK) are recruited, which phosphorylate interferon regulatory factor 3 (IRF 3) and nuclear factor- κ B (nuclear factor kappa-B, NF- κ B) inhibitors I κ B α, respectively. Phosphorylated IRF3 dimerizes and transfers into the nucleus, activating transcription of genes encoding type I interferons. And phosphorylation of IkB alpha causes NF-kB to transfer to cell nucleus, activates the transcription of proinflammatory cytokine interleukin-6 (IL-6), Tumor Necrosis Factor (TNF) and type I interferon genes, plays a role in immune regulation, and influences body virus defense, inflammation and tumor treatment. The function-enhancing mutation of STING gene can cause serious autoimmune diseases, and in various inflammatory diseases such as cerebral apoplexy and liver and kidney injury, the inhibition of the cGAS-STING signaling pathway is beneficial to the alleviation and treatment of diseases. It has recently been discovered that cGAS levels are elevated in the retinal pigment epithelium of patients with geographic collapsed age-related macular degeneration, and that cGAS leads to activation of atypical inflammatory bodies by recognizing mitochondrial DNA in the cytoplasm in retinal pigment epithelium cells of a geographic atrophic mouse disease model established by overexpression of a non-coding rna (alu rna), whereas inhibition of the cGAS-STING signaling pathway significantly down-regulates the inflammatory response in retinal pigment epithelium cells of a geographic atrophic mouse disease model in cGAS knockout mice. Therefore, the search or development of a small molecular compound can effectively inhibit the cGAS-STING signal pathway in a geographic atrophy mouse disease model, and has important practical significance.
JQ1 has the chemical name (±) -2- [4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepan-6-yl ] tert-butyl acetate, wherein (+) -JQ1 is a Bromodomain (BRDs) inhibitor developed by the American Cold spring harbor laboratory and has the structure:
bromodomains are a group of 110 amino acid protein molecules that by their special structure can recognize the acetylated lysine sites at the ends of histones. There are 61 bromodomain proteins reported so far, and classified into 8 large BRD protein families according to structural and functional characteristics, and the bromodomain and extra terminal structure (BET) family, which is a member of the BRD family, includes BRD2, BRD3, BRD4, and BRDT proteins. The brominated structural protein 4 (BRD 4) can promote related proteins such as chromatin remodeling factors and transcription factors to be enriched at a specific gene transcription site by combining with histone terminal acetylated lysine, change the activity of RNA polymerase II, regulate the expression of genes, and participate in a series of important biological activity processes such as cell growth, cell cycle, inflammation and the like. To date, a variety of BET protein family small molecule inhibitors have been reported, including (+) -JQ1 and I-BET 762. As with all BET inhibitors, (+) -JQ1 competitively binds to the BRD4 bromodomain, displacing the BRD4 protein from the acetylated lysine in chromatin, thereby interfering with the biological role of BRD4 in the body. However, no report that (+) -JQ1 can inhibit the cGAS-STING signaling pathway and has an immunoregulatory effect on geographic collapsed age-related macular degeneration exists at present.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides application of a small molecule drug (+) -JQ1 in preparation of a drug for treating pattern-collapse type age-related macular degeneration.
In order to achieve the purpose, the invention is realized by the following scheme:
the small molecular compound (+) -JQ1 is used for carrying out intraperitoneal injection on a mouse model with geographic atrophy and age-related macular degeneration, the injection dose is 50 mg/kg/day, and the injection is carried out for 3 days. The (+) -JQ1 is found to inhibit the cGAS-STING signaling pathway in mouse retina, is an inhibitor of the cGAS-STING signaling pathway, and provides guiding effect for the immune regulation and treatment of geographic collapsing age-related macular degeneration.
Therefore, the invention claims the application of a small molecular drug (+) -JQ1 in the preparation of a drug for preventing and treating macular degeneration.
Preferably, the macular degeneration is age-related macular degeneration.
Preferably, the macular degeneration is age-related macular degeneration of the geographic collapsed type.
Preferably, (+) -JQ1 inhibits the cGAS-STING signaling pathway.
Preferably, (+) -JQ1 down-regulates expression of cGAS-STING signaling pathway related proteins in the retina.
Preferably, (+) -JQ1 down-regulates the expression of the inflammatory factor interleukin-1 β gene.
Preferably, (+) -JQ1 down-regulates the expression of the inflammatory factor interleukin-6 gene.
Compared with the prior art, the invention has the following beneficial effects:
the invention discloses a micromolecule drug (+) -JQ1 with a cGAS-STING signal channel inhibition function, and a regulating effect and an anti-inflammatory effect on autoimmunity of the micromolecule drug (+) -JQ 1. The invention firstly provides that in a mouse disease model of map-like atrophic age-related macular degeneration induced by sodium iodate injection, (+) -JQ1 can inhibit the expression of cGAS and STING genes, and plays roles of immunoregulation and anti-inflammation by inhibiting the function of a cGAS-STING signal pathway. The inhibition of (+) -JQ1 on the cGAS-STING signal channel and the anti-inflammatory action in a disease model of age-related macular degeneration are a promising new-use clinical strategy of the old drugs, and provide reference for the research of anti-autoimmune reaction and small molecule compounds for treating age-related macular degeneration diseases.
Drawings
FIG. 1 is a graph of cGAS-STING signaling pathway activation in the retina of a sodium iodate-induced mouse model of geographic atrophy of age-related macular degeneration; FIG. 1A is a fundus image and fluorescein fundus angiographic image of the control and sodium iodate treated groups; fig. 1B shows the change in the cGAS-STING signaling pathway-related protein level in the retinas of the control and sodium iodate-treated mice, with the lower half of the results of gray scale analysis, where n is 5. P values were calculated from independent sample t-tests: p <0.05, x: p <0.01, x: p <0.0001, error bars are standard deviations. Fig. 1C shows the change in the expression level of mRNA of genes such as IL1 β, IL6, IFNB1, and n is 5 in the retinas of the control and sodium iodate-treated mice. P values were calculated from independent sample t-tests: p <0.05, x: p <0.01, x: p <0.0001, error bars are standard deviations.
FIG. 2 shows that (+) -JQ1 can inhibit activation of cGAS-STING signaling pathway and downstream inflammatory response in retina of sodium iodate-induced geographic atrophy age-related macular degeneration mouse disease model, and has protective effect on retinal damage. Fig. 2A is a fundus image and fluorescein fundus angiographic image of the sodium iodate-treated group and the sodium iodate plus (+) -JQ 1-dosed group. Fig. 2B shows the change in the cGAS-STING signaling pathway-related protein levels in the retinas of mice treated with sodium iodate plus (+) -JQ1, and the results of gray scale analysis on the right side, where n is 5. P values were calculated from independent sample t-tests: p <0.05, x: p <0.01, x: p <0.0001, error bars are standard deviations. Fig. 2C shows the change in the expression level of mRNA of genes such as IL1 β and IL6 in retinas of mice treated with sodium iodate plus JQ1, where n is 5. P values were calculated from independent sample t-tests: p <0.05, x: p <0.01, x: p <0.0001, error bars are standard deviations.
Detailed Description
The present invention will be described in further detail with reference to the drawings and specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
1. Reagents and materials
Sodium iodate (Sodium iodide, SI) (Sigma-Aldrich, S4007); 1ml syringe (KDL); 30 total C57BL/6 mice at 5-8 weeks (Experimental animals center of university of Zhongshan); sterile Phosphate Buffered Saline (PBS), (+) -JQ1 (select, S7110), DMSO (MP Biomedicals, 196055), Polyoxy ethylene300 (select, S6704), Tween80(BioFrox, 1716ML100), fluorescein sodium (Alcon laboratories, TX, USA), BCA protein concentration determination Reagent (Biyunshi, P0012), reverse transcription kit (Novezak, R223-01), SuperReal Premix Plus (SYBR Green) (Tiangen, FP205), Invitrogen TRIzol Reagent (Thermo Fisher, 15596026), protein antibodies and real-time fluorescent quantitative PCR primers.
2. Instrument for measuring the position of a moving object
The electrophoresis apparatus (Bio-Rad,
tetra), gel imaging system (Tanon, Tanon 5200), bulk microscope (ZEISS, SteREO Discovery), PCR instrument (ABI, VERITI PCR) fluorescent quantitative PCR instrument (Roche, LC480), Micron IV retinal imaging system (Phoenix Research Laboratories, Pleasanton, CA, USA), New Ganoderma ultrasound instrument (SCIENTZ-IID), centrifuge (Eppendorf, 5424R).
3. Animal experiment grouping
30C 57BL/6 mice (Experimental animal center of Zhongshan university) at 5-8 weeks were divided into 10 groups each of a control group, a sodium iodate-treated group, and a sodium iodate plus (+) -JQ 1-administered group.
Example 1 activation of the cGAS-STING Signaling pathway in the retina of a mouse sodium iodate-induced age-related macular degeneration disease model
1. Experimental methods
(1) Construction of models
The mouse is injected with sodium iodate (0.5 percent, prepared by PBS) in the abdominal cavity, and the age-related macular degeneration mouse disease model is established by a method with the dosage of 35 mg/kg.
(2) Mouse fundus photography and fluorescein fundus angiography
The mouse fundus photography and fluorescein fundus angiography are performed before and three days after the sodium iodate injection, and the specific operations are as follows:
before the fundus photography of the mice, the mice were anesthetized with 4% chloral hydrate (100. mu.l/10 g), 1-2 drops of compound tropicamide eye drops dilate the pupils, and hypromellose gel lubricates the cornea. Thereafter, photographing of fundus images was performed using a Micron IV retinal imaging system. For fluorescein fundus angiography experiments, mice were injected intraperitoneally with 2% sodium fluorescein (5 μ l/g) after anesthesia and mydriatic procedures and immediately subjected to fluorescein fundus angiography imaging using a Micron IV retinal imaging system.
(3) Mouse retina dissection and material selection
Three days after the sodium iodate injection, all mice were sacrificed by decapitation, the eyelids of the mice were opened with one hand to protrude the eyeball, and the other hand-held forceps were inserted into the orbit, and the eyeball was taken out together with the optic nerve with force applied upward from under the eyeball. The cells were placed in a 10cm cell culture dish containing PBS and dissected under a stereomicroscope in the following general procedure: the extraocular muscles and connective tissue attached to the eyeball floating in PBS were removed with ophthalmic scissors. A small incision is made at the scleral edge, left hand forceps are inserted through the incision to clamp the cornea, and right hand ophthalmic scissors are used to cut the eyeball along the scleral edge and divide the eyeball into two parts, namely, the anterior pole of the eyeball (cornea, iris, crystalline lens) and the posterior cup (sclera, choroid, retina). And (3) peeling the retina from the rearview cup by using tweezers, putting the retina into a centrifuge tube with the information of the sample name, the material taking date and the like marked in advance, putting the centrifuge tube into liquid nitrogen for quick freezing, and performing subsequent operation after the same batch of materials are taken out.
(4) Mouse retina protein extraction and protein immunoblotting experiment
Adding 200 μ l RIPA lysate containing protease inhibitor into centrifuge tube containing mouse retina sample, placing histon into Xinzhi ultrasonic instrument, connecting with ice water circulation, setting ultrasonic energy at 60%, total time 1min, 2 s on, 2 s off. After fully cracking the tissue cells, centrifuging the tissue cells for 10min at 12000rpm by a 4 ℃ centrifuge, separating protein supernatant from other substance precipitates, taking the supernatant part, and adding the supernatant part into a centrifuge tube with marked information. Protein supernatant was subjected to concentration measurement using BCA protein concentration measurement kit, and 20-50. mu.g of protein sample was taken for Western blotting experiment.
The antibodies used are as in table 1.
Table 1:
(5) mouse retina RNA extraction and real-time fluorescent quantitative PCR experiment
1ml of Trizol reagent was added to the centrifuge tube containing the mouse retina sample and ground with a RNAse-free grind bar to allow sufficient lysis of the tissue cells and RNA extraction according to Trizol reagent instructions.
Mu.g of RNA was taken and cDNA was synthesized using a reverse transcription kit. The SuperReal Premix Plus (SYBR Green) and a fluorescent quantitative PCR instrument are used for carrying out real-time fluorescent quantitative PCR experiments, and the program is set as follows: pre-denaturation at 94 ℃ for 5min, denaturation at 94 ℃ for 10sec, annealing at 58 ℃ for 20sec, extension at 72 ℃ for 20sec, and single fluorescence signal acquisition during the extension phase. Uses ACTB (beta actin) as an internal reference gene and uses 2-ΔΔAnd calculating the ratio of the target gene mRNA expression quantity to the reference gene mRNA expression quantity by the Ct method, and carrying out relative quantification.
The primers used are shown in Table 2.
Table 2:
2. results of the experiment
An age-related macular degeneration mouse disease model is successfully established by carrying out intraperitoneal injection (the dose is 35mg/kg) on mice with sodium iodate. As shown in fig. 1A, three days after the sodium iodate injection, significant damage occurred to the retinas of mice in the sodium iodate-treated group compared to the control group.
Through western blotting experiments and real-time fluorescent quantitative PCR experiments, it was found that the cGAS-STING signal pathway was activated in retinas of mice in the sodium iodate-treated group and that the expression of the genes for inflammatory factors interleukin-1 β (interleukin 1 β, IL-1 β), interleukin-6 (interleukin 6, IL-6), and type I interferon B (type I Inteferons, IFNB1) was up-regulated, as compared with the control group, and the results are shown in FIGS. 1B and 1C.
Example 2(+) -JQ1 inhibits activation of cGAS-STING signaling pathway and downstream inflammatory responses in retinas from sodium iodate-induced mouse disease model of geographic atrophy age-related macular degeneration and protects against retinal damage
1. Experimental methods
The mouse is injected with sodium iodate (0.5 percent, prepared by PBS) in the abdominal cavity, and the age-related macular degeneration mouse disease model is established by a method with the dosage of 35 mg/kg.
Two hours after the sodium iodate injection, (+) -JQ1 was intraperitoneally injected into (+) -JQ1(5mg/ml) at a dose of 50mg/kg in the treatment group, and an equal volume of drug solvent (2% DMSO, 30% Polyoxy ethylene300, 5% Tween80) was intraperitoneally injected into the sodium iodate treatment group, and (+) -JQ1 and the drug solvent were injected for 3 days, once a day. Control mice were injected with an equal volume of sterile Phosphate Buffered Saline (PBS).
The subsequent experiment was the same as in example 1
2. Results of the experiment
The small molecule medicine (+) -JQ1 is used for carrying out intraperitoneal injection on the mouse with geographic atrophy age-related macular degeneration induced by sodium iodate, and the dosage is 50 mg/kg. The results of fundus photography and fluorescein fundus angiography are shown in fig. 2A, which shows that the damage degree of retina and fluorescence leakage of the small molecule drug (+) -JQ1 treated group are reduced compared with the sodium iodate treated group. And the (+) -JQ1 treatment can obviously reduce the expression of cGAS-STING signal pathway related protein in mouse retina and the expression of downstream inflammatory factors interleukin-1 beta (interleukin 1 beta, IL-1 beta) and interleukin-6 (interleukin 6, IL-6) genes, and the results are shown in FIGS. 2B and 2C. The result shows that the small molecule medicine (+) -JQ1 has protective effect on the damage of retina.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (7)
1. An application of a small molecular drug (+) -JQ1 in preparing a drug for preventing and treating macular degeneration.
2. The use of claim 1, wherein the macular degeneration is age-related macular degeneration.
3. The use of claim 1, wherein the macular degeneration is age-related macular degeneration of the geographic collapsed type.
4. The use of claim 1, wherein (+) -JQ1 inhibits the cGAS-STING signaling pathway.
5. The use of claim 1, wherein (+) -JQ1 down-regulates expression of cGAS-STING signaling pathway-related proteins in the retina.
6. The use of claim 1, wherein (+) -JQ1 down-regulates the expression of the interleukin-1 β gene of the inflammatory factor.
7. The use of claim 1, wherein (+) -JQ1 down-regulates the expression of the inflammatory factor interleukin-6 gene.
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Cited By (1)
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| CN116473957A (en) * | 2022-08-15 | 2023-07-25 | 中山大学中山眼科中心 | Application of STING inhibitor C176 in preparation of medicine for preventing and treating age-related macular degeneration |
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