CN116473957A - Application of STING inhibitor C176 in preparation of medicine for preventing and treating age-related macular degeneration - Google Patents
Application of STING inhibitor C176 in preparation of medicine for preventing and treating age-related macular degeneration Download PDFInfo
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- CN116473957A CN116473957A CN202210973977.6A CN202210973977A CN116473957A CN 116473957 A CN116473957 A CN 116473957A CN 202210973977 A CN202210973977 A CN 202210973977A CN 116473957 A CN116473957 A CN 116473957A
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- A—HUMAN NECESSITIES
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention provides an application of STING inhibitor C176 in preparing a medicament for preventing and treating age-related macular degeneration, belonging to the technical field of chemical medicaments. According to the invention, the STING inhibitor C176 is used for dosing age-related macular degeneration model mice, and the C176 is found to be capable of effectively inhibiting activation of a cGAS-STING signal path and inhibiting expression of inflammatory factors and aggregation of immune cells in retina, so that the activity of photoreceptor cells of retina is improved, and a guiding effect is provided for intervention and treatment of map-type wilting type age-related macular degeneration.
Description
Technical Field
The invention belongs to the technical field of chemical medicaments, and particularly relates to application of STING inhibitor C176 in preparation of a medicament for preventing and treating age-related macular degeneration.
Background
Geographic atrophy is one of the types of age-related macular degeneration, and no effective treatment is currently available. Map-like age-related macular degeneration results from progressive retinal pigment epithelium degeneration and atrophy, and permanent visual impairment due to death of photoreceptor cells caused by retinal pigment epithelium degeneration. It has been shown that although age-related macular degeneration is a multifactorial disease, the disorder of autoimmune function plays an important role in the disease development of age-related macular degeneration. Thus, immunomodulation is seen as a very promising treatment for age-related macular degeneration.
The cGAS-STING signaling pathway is an important cytoplasmic DNA sensing pathway in vivo, induces the expression of type I interferon (type I Inteferons, IFN 1), affects the immune response of the body, and plays an important role in regulating pathogen infection, tumor immunity and autoimmune diseases. Guanosine monophosphate-adenylate synthetase (cyclic guanosinemonophosphate-adenosine monophosphate synthase, cGAS) is a direct cytoplasmic DNA sensor, when cGAS recognizes DNA accumulated in the cytoplasm, cGAS binds to these DNA, the cGAS active site conformation changes, catalyzing ATP and GTP synthesis of cyclic dinucleotides (cyclic guanosine monophos-phase-adenosine monophosphate, cGAMP). cGAMP acts as a second messenger and binds to the interferon gene stimulatory factor (stimulator of interferon gene, STING) protein on the membrane of the endoplasmic reticulum (endoplasmic reticulum, ER), rapid dimerization of STING is activated, activated STING is transferred from ER to golgi apparatus, and kinases such as TANK-binding kinase 1 (tbk 1) and ikb kinase (IKK) are recruited in golgi apparatus, which phosphorylate interferon regulatory factor 3 (interferon regulatory factor, irf 3) and nuclear factor- κb (nuclear factor kappa-B, NF- κb) inhibitors ikbα, respectively. Phosphorylated IRF3 dimerizes and migrates into the nucleus, activating transcription of genes encoding type I interferons. Whereas iκbα phosphorylation results in NF- κb transfer to the nucleus and activates transcription of the pro-inflammatory cytokines interleukin-6 (il-6), tumor necrosis factor (tumor necrosis factor, TNF) and type I interferon genes, exerting an immunomodulatory effect affecting viral defense, inflammation and tumor therapy in the body. The functional enhancement mutation of STING gene can lead to serious autoimmune diseases, and in various inflammatory diseases such as cerebral apoplexy, liver and kidney injury, the inhibition of cGAS-STING signal pathway is beneficial to the alleviation and treatment of diseases. Recently, it has been found that there is a phenomenon in which the level of cGAS is increased in retinal pigment epithelium of patients with age-related macular degeneration in the form of map-like wilting reduction mouse disease model established by over-expression of a non-coding RNA (Alu RNA), cGAS causes activation of atypical inflammatory corpuscles by recognizing mitochondrial DNA in cytoplasm, whereas inhibition of cGAS-STING signaling pathway significantly down regulates inflammatory response in retinal pigment epithelium of map-like wilting reduction mouse disease model in cGAS knockout mice. Therefore, finding or developing a small molecule compound can effectively inhibit the cGAS-STING signal pathway in a map-type wilt-reducing mouse disease model, and has important practical significance.
Disclosure of Invention
Accordingly, the invention aims to provide an application of STING inhibitor C176 in preparing medicines for preventing and treating age-related macular degeneration.
The invention provides an application of C176 in preparation of STING inhibitors, wherein the structural formula of the C176 is shown as a formula I;
preferably, the STING inhibitor has the effect of inhibiting palmitoylation of STING protein and thereby inhibiting STING function.
The invention provides an application of a compound for inhibiting STING activity in preparing a medicament for preventing and/or treating age-related macular degeneration, wherein the compound for inhibiting STING is C176.
Preferably, the age-related macular degeneration comprises map-like, withered age-related macular degeneration.
Preferably, the medicament has one or more of the following effects: protecting retinopathy, inhibiting activation of cGAS-STING signaling pathway proteins in retina, inhibiting expression of inflammatory factor genes in retina, and reducing immune cell aggregation.
Preferably, the protein of the cGAS-STING signaling pathway includes cGAS, STING, P-STING and P-nfκbp65.
Preferably, the inflammatory factors include interleukin-1 beta, interleukin-6 and type I interferon B.
Preferably, the map-like withered age-related macular degeneration is caused by sodium iodate.
The invention provides an application of a compound for inhibiting STING activity in preparing a medicament for inhibiting inflammatory response in age-related macular degeneration, wherein the compound for inhibiting STING is C176.
Preferably, the medicament has the effect of inhibiting expression of inflammatory factor genes in the retina and reducing aggregation of immune cells.
The invention provides an application of C176 in preparation of STING inhibitors, wherein the structural formula of the C176 is shown as a formula I. Experiments show that in a mouse disease model of age-related macular degeneration constructed by sodium iodate injection, a cGAS-STING signal channel in eyeball retina is activated, the expression level of STING protein is increased, and after administration of C176, the activation of the cGAS-STING signal channel protein can be inhibited, and the expression of STING protein is obviously reduced.
The invention provides an application of a compound for inhibiting STING in preparing a medicament for preventing and/or treating age-related macular degeneration, wherein the compound for inhibiting STING is C176. Experiments prove that the sodium iodate-induced age-related macular degeneration mouse disease model is taken as a study object, a model control group shows typical retinopathy through physiological and biochemical detection and molecular level detection, and the administration of C176 can effectively inhibit and protect retinopathy, inhibit activation of protein of a cGAS-STING signal path in retina, can also effectively inhibit inflammatory reaction in retina, particularly inhibit expression of inflammatory factor genes in retina and reduce aggregation of immune cells, and provides a new idea for preventing and/or treating age-related macular degeneration.
The invention provides an application of a compound for inhibiting STING in preparing a medicament for inhibiting inflammatory response in age-related macular degeneration, wherein the compound for inhibiting STING is C176. The invention reports for the first time that the small molecule drug STING inhibitor C176 can inhibit the expression of inflammatory factors in eyes of mice and the immune cells gather, thereby improving the activity of retina photoreceptor cells and providing guiding effect for the intervention and treatment of map-type withered age-related macular degeneration.
Drawings
FIG. 1 is a schematic diagram showing activation of the cGAS-STING signaling pathway in retinas of sodium iodate-induced age-related macular degeneration mice disease model, FIG. 1A is a fundus image and fluorescein fundus angiography image of a control group and sodium iodate-treated group; fig. 1B shows the change in cGAS-STING signaling pathway-related protein levels in the retinas of control and sodium iodate-treated mice, with the lower half of the plot showing the results of gray scale analysis, n=5; p-value was calculated from independent sample t-test: p <0.05,: p <0.01,: p is less than 0.0001, and the error line is standard deviation; fig. 1C shows changes in expression levels of IL1 β, IL6, IFNB1 and other genes mRNA in retinas of control and sodium iodate treated mice, n=5; p-value was calculated from independent sample t-test: p <0.05,: p <0.01,: p is less than 0.0001, and the error line is standard deviation;
FIG. 2 is a graph of C176 inhibiting activation of the cGAS-STING signaling pathway in the retina of a mouse model of age-related macular degeneration induced by sodium iodate; the left panel shows western immunoblots of sodium iodate treatment and sodium iodate plus C176 dosing treatment, where 60, 40kDa, 40, 75, 60 and 35 represent molecular weights (kDa) of the respective proteins, respectively; 1 to 5 respectively represent the number of mice; the right graph is the result of gray level analysis; sodium iodate treatment group n=4, sodium iodate plus C176 group n=5; p-value was calculated from independent sample t-test: p <0.05,: p <0.01,: p is less than 0.0001, and the error line is standard deviation;
FIG. 3 shows changes in IL1 beta, IL6, IFNB1 isogenic mRNA expression levels in retinas from sodium iodate treatment groups, n=4, sodium iodate plus JQ1 dosing groups, n=5; p-value was calculated from independent sample t-test: p <0.05,: p is less than 0.01, and the error line is standard deviation;
fig. 4a. He staining indicates that C176 protects the mouse retina, inhibits sodium iodate-induced retinal structural disorders and pigment epithelial cell swelling and detachment;
FIG. 4B shows that immunofluorescent staining of frozen sections of retina indicates a decrease in IBA1 positive immune cells after C176 treatment;
FIG. 4℃ Immunofluorescent staining of retinal patches further demonstrates that IAB1 positive cells are reduced in the retina after C176 treatment; the right graph shows the statistical result after IBA1 positive cell technology; p values were calculated from independent sample t-test: p <0.01, error line is standard deviation.
Detailed Description
The invention provides an application of C176 in preparation of STING inhibitors, wherein the structural formula of the C176 is shown as a formula I;
in the present invention, the chemical name of the C176 is N- (4-iodophenyl) -5-nitrofuran-2-carboxamide, the molecular weight is 358.09, and the molecular formula is C 11 H 7 IN 2 O 4 . The source of the C176 is not particularly limited in the present invention, and sources well known in the art may be used. In the present example, the C176 is purchased from Selleck corporation as # S6575. The STING inhibitor preferably has an effect of inhibiting palmitoylation of STING protein and thus inhibiting STING function.
The invention provides an application of a compound for inhibiting STING activity in preparing a medicament for preventing and/or treating age-related macular degeneration, wherein the compound for inhibiting STING is C176.
In the present invention, the age-related macular degeneration preferably includes map-type age-related macular degeneration. The geographic-like, wilted age-related macular degeneration is preferably caused by sodium iodate. In the embodiment of the invention, healthy mice are treated with sodium iodate to obtain a map-like wilted age-related macular degeneration mouse model, which is characterized in that compared with a control group, the retina of the sodium iodate-treated mice is obviously damaged after three days of sodium iodate injection, and cGAS-STING signal channels in the retina of the mice are activated, inflammatory factor expression is increased, inflammatory cells are aggregated and the like. The map-type withered age-related macular degeneration mouse model is taken as a study object, and C176 injection can effectively protect retina injury, inhibit activation of protein of a cGAS-STING signal path in retina, inhibit expression of inflammatory factor genes in retina and reduce aggregation of immune cells. The proteins of the cGAS-STING signal pathway preferably include cGAS, STING, P-STING and P-nfκbp65. The inflammatory factors preferably include interleukin-1 beta, interleukin-6 and type I interferon B. Thus, the C176 can achieve the aim of protecting the retina injury by inhibiting the cGAS-STING signal path in the retina and inhibiting inflammatory reaction in the retina, thereby being beneficial to improving the activity of the retina photoreceptor cells and providing guiding effect for the intervention and treatment of the map-type withered age-related macular degeneration.
In the present invention, the effective dose of C176 is preferably 8 to 12 mg/kg of mice, more preferably 10mg/kg of mice. The effective concentration of C176 in the medicament is preferably 0.9-1.1 mg/ml, more preferably 1mg/ml. The dosage form of the medicament is preferably injection. The method for preparing the injection is not particularly limited, and can be any method known in the art.
The invention provides an application of a compound for inhibiting STING activity in preparing a medicament for inhibiting inflammatory response in age-related macular degeneration, wherein the compound for inhibiting STING is C176.
In the present invention, the drug preferably has effects of inhibiting the expression of inflammatory factor genes in the retina and reducing the aggregation of immune cells. The medicines are the same as those described above, and are not described in detail here.
The following examples are presented to illustrate the use of STING inhibitor C176 according to the present invention in the manufacture of a medicament for the prevention and treatment of age-related macular degeneration, but are not to be construed as limiting the scope of the invention.
Example 1
Construction of age-related macular degeneration mouse disease model and C176 administration therapy
1. The age-related macular degeneration mice disease model was established by intraperitoneal injection of sodium iodate (0.5%, PBS) at a dose of 35 mg/kg. Two hours after sodium iodate injection, C176 (1 mg/ml) was injected intraperitoneally into the C176-dosed treatment group at a dose of 10mg/kg, and the sodium iodate-treated group was intraperitoneally injected with the same volume of the drug solvent (2%DMSO,30%Polyoxy ethylene300,5%Tween80), both C176 and the drug solvent were injected for 3 days, once daily. Mice in the placebo group were injected with an equal volume of sterile Phosphate Buffer (PBS).
2 mouse retina dissection and material sampling
Three days after sodium iodate injection, all groups of mice were sacrificed by cervical removal, the eyelids of the mice were opened with one hand to protrude their eyes, and the other hand-held forceps were inserted into the eye sockets, forced upward from below the eyes, and the eyes were removed along with the optic nerve. This was placed in a 10cm cell culture dish containing PBS and dissected under a split microscope as follows: extraocular muscles and connective tissue attached to the eyeball floating in PBS were removed with an ophthalmic scissors. A small incision is made on the corner consolidating edge, the left hand-held forceps extend from the incision to clamp the cornea, the right hand-held ophthalmic scissors cut the eyeball along the corner consolidating edge, and the eyeball is divided into two parts, namely an anterior pole part (cornea, iris, lens) and a posterior optic cup (sclera, choroid and retina). The retina is peeled off from the rearview cup by forceps, the retina is filled into a centrifuge tube with the information of the name of the sample, the date of drawing the materials and the like marked in advance, the centrifuge tube is placed into liquid nitrogen for quick freezing, and the subsequent operation is carried out after the same batch of materials are taken out.
3 extraction of mouse retina protein and Western blotting experiment
200 μl of RIPA lysate containing protease inhibitor is added into a centrifuge tube containing mouse retina sample, and the tissue protein is placed into a fresh ganoderma lucidum ultrasonic instrument, and is connected with ice water circulation, and ultrasonic energy is set at 60%, total time is 1min,2 seconds is on, and 2 seconds is off. After sufficient lysis of the tissue cells, the protein supernatant was separated from other material pellet by centrifugation at 12000rpm for 10min at 4℃and the supernatant fraction was added to a centrifuge tube with the information on standard. Protein supernatant is subjected to concentration measurement by using a BCA protein concentration measurement kit, and 20-50 mug protein samples are taken for carrying out a protein immunoblotting experiment, so that the expression of cGAS-STING signal pathway related proteins (including cGAS, STING, phosphorylated STING (P-STING), phosphorylated NFKB P65 (P-NFKB P65), IL1 beta precursor (Pro-IL 1 beta) and active cutter (clear IL1 beta) proteins) in the retina of a mouse are respectively detected.
4 mouse retina RNA extraction and real-time fluorescence quantitative PCR experiment
1ml of Trizol reagent was added to a centrifuge tube containing a mouse retina sample, and the mixture was ground with an RNase-free grinding rod to obtain tissue cells, and RNA was extracted according to the Trizol reagent protocol after the tissue cells were sufficiently lysed.
1. Mu.g of RNA was taken and cDNA was synthesized using a reverse transcription kit. Real-time fluorescent quantitative PCR experiments were performed using SuperReal PreMix Plus (SYBR Green) and a fluorescent quantitative PCR instrument, and the specific procedure was as follows:
(1) RNA reverse transcription: reverse transcription of RNA was performed using HiScript II qRT SuperMix II (novzan) kit:
1) Removal of genomic DNA: the reaction solution was prepared in RNase-free PCR tubes:
template RNA 1. Mu.g, 4 XgDNA wind Mix 4. Mu.l, RNase free ddH 2 O was supplemented to 16. Mu.l.
Placing the prepared reaction solution into a PCR instrument at 42 ℃ for 2min;
2) Reverse transcription reaction: to the reaction mixture in 1), 4. Mu.l of 5X HiScript II qRT SuperMix II was added, and the mixture was blown and mixed, and then placed in a PCR apparatus, and the PCR program was set at 55℃for 15min and 85℃for 5sec.
(2) Real-time fluorescent quantitative PCR: fluorescent real-time quantitative PCR was performed using a 2X ChamQTM SYBR Color qPCR Master Mix (Norflu) kit, and the specific steps are as follows:
1) Preparing a PCR reaction solution:
4.5. Mu.l of cDNA template, 2X SYBR qPCR Master Mix. Mu.l of 10. Mu. M F +R primer (specific sequence as follows) and 0.5. Mu.l of each.
The primers of the detected target genes are as follows:
mouse IL-1β F TGCAGACTCAAACTCC (SEQ ID NO: 1);
mouse IL-1β R TGAAAGACGGCACACC (SEQ ID NO: 2);
mouse IL-6F GTTCTCTGGGAAATCGTGG (SEQ ID NO: 3);
mouse IL-6R CTGCAAGTGCATCATCGTT (SEQ ID NO: 4);
mouse IFNB F CTCCAGCTCCAAGAAAGGAC (SEQ ID NO: 5);
mouse IFNB R TGGCAAAGGCAGTGTAACTC (SEQ ID NO: 6);
the internal reference gene is Beta ACTIN, and specific primers are as follows:
mouse BetaACTIN F CCTAAGGCCAACCGTGAAAA (SEQ ID NO: 7);
mouse Beta ACTIN R CAGAGGCATACAGGGACAGC (SEQ ID NO: 8).
The prepared PCR reaction solution is added into a 384-well plate, 3 multiple wells are repeated for each sample, and after the sample application is finished, the 384-well plate is placed into a centrifuge for centrifugation at 2500rpm for 5min. Real-time fluorescent quantitative PCR reactions were performed using the rosen LightCycler 480 II, with the program set to: pre-denaturation at 94℃for 5min, denaturation at 94℃for 10s, annealing at 58℃for 20s, extension at 72℃for 20s, and single fluorescence signals were collected by the machine during the extension phase. Analyzing the data after the instrument is operated, using ACTB (beta actin) as an internal reference gene, and applying 2 -ΔΔCt The ratio of the mRNA expression quantity of the target gene to the mRNA expression quantity of the reference gene is calculated by the method, and the relative quantification is carried out.
5. HE staining, immunohistochemistry and immunofluorescence staining of mouse eye tissues. Taking eyeballs, putting the eyeballs into PBS for washing for one time, and puncturing a small opening at the cornice edge by using a syringe, so that the entrance of a fixing solution is facilitated; placing the eyeball in a 2ml EP tube, adding 1ml of FAS eyeball fixing solution, and fixing at room temperature overnight; dehydrating: sequentially placing the fixed eyeball into 50%, 60%, 70%, 80%, 90%, 95% ethanol for 1 time each for 30min, and anhydrous ethanol for two times each for 30min; and (3) transparency: sequentially placing dehydrated eyeballs in an absolute ethyl alcohol-xylene=1:1 solution for 15min, and performing xylene twice for 15min each time; wax dipping: sequentially placing eyeball tissues in low-melting-point wax I at 55deg.C for 30min, low-melting-point wax II at 55deg.C for 90min, and high-melting-point wax at 60deg.C for 90min; embedding: according to the longitudinal cutting direction of the eyeball, horizontally placing the eyeball along the direction of the cornea optic nerve axis, firstly adding a thin layer of wax to hold the eyeball, slowly adding the rest wax after the lower layer of wax is solidified to uniformly fill the embedding frame, and slicing after the wax is completely solidified and is frozen overnight in a refrigerator at minus 20 ℃; slicing: slicing by using a paraffin slicer, wherein each slice has a thickness of 8 mu m, and placing the paraffin slices into a water bath kettle at 40 ℃ for spreading; selecting cut slices, placing the slices in a slide clamp, and drying the slices in an oven at 60 ℃ for 2 hours; the dried slide was stored at minus 20 ℃.
6. Experimental results
6.1 activation of the cGAS-STING signaling pathway in retinas of sodium iodate-induced age-related macular degeneration mouse disease models
The disease model of age-related macular degeneration mice was successfully established by intraperitoneal injection of sodium iodate (dosage of 35 mg/kg) into mice. As shown in fig. 1A, three days after sodium iodate injection, the retinas of sodium iodate-treated mice appeared to be significantly damaged compared to the control group. And we found through western blotting experiments and real-time fluorescent quantitative PCR experiments that cGAS-STING signaling pathway was activated in the retinas of mice in the sodium iodate treatment group, and that the inflammatory factors interleukin-1β (interleukin-1β, IL-1β), interleukin-6 (interleukin 6, IL-6), and type I interferon B (type I Inteferons, IFNB 1) were up-regulated, as compared to the control group, as shown in fig. 1B and 1C.
6.2 C176 may inhibit activation of the cGAS-STING signaling pathway protein in the retina of a mouse model of age-related macular degeneration induced by sodium iodate.
Mice with age-related macular degeneration induced by sodium iodate were intraperitoneally injected with the small molecule drug C176 at a dose of 10mg/kg. Western immunoblotting experiments show that the C176 treatment can significantly reduce the expression of cGAS-STING signal pathway related proteins (phosphorylated STING (P-STING), phosphorylated NFKB (P-NFKB) and phosphorylated TBK1 (P-TBK 1)) in the retina of the mouse.
6.3 C176 can inhibit the expression of the inflammatory factors interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and Interferon (Interferon beta, IFNB 1) genes in the retina of a mouse model of age-related macular degeneration induced by sodium iodate.
Mice with age-related macular degeneration induced by sodium iodate were intraperitoneally injected with the small molecule drug C176 at a dose of 10mg/kg. Real-time quantitative PCR experiments show that the C176 treatment can significantly reduce the expression of inflammatory factor related genes in the retina of mice.
6.4 C176 can inhibit retinal degeneration and immune cell aggregation in a mouse disease model of age-related macular degeneration induced by sodium iodate.
Mice with age-related macular degeneration induced by sodium iodate were intraperitoneally injected with the small molecule drug C176 at a dose of 10mg/kg. As shown in fig. 4A to 4C, C176 protected the retina of the mouse, and inhibited retinal structural disturbance and pigment epithelial cell swelling and detachment caused by sodium iodate. Immunofluorescent staining of frozen sections of retina showed that IBA 1-positive immune cells were reduced after C176 treatment. Immunofluorescent staining of retinal patches further showed that IAB1 positive cells were reduced in the retina after C176 treatment.
From the results of the above examples, it is known that the small molecular compound C176 has a protective effect on retinal damage caused by sodium iodate injection, and the invention proves for the first time that the small molecular compound C176 achieves the effect of preventing and treating age-related macular degeneration diseases by inhibiting cGAS-STING signaling pathway and downstream inflammatory reaction.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The application of C176 in preparing STING inhibitor, wherein the structural formula of C176 is shown in formula I;
2. the use according to claim 1, wherein said STING inhibitor has the effect of inhibiting palmitoylation of STING proteins and thereby inhibiting STING function.
3. Use of a compound that inhibits STING activity, wherein the compound that inhibits STING is C176, in the manufacture of a medicament for the prevention and/or treatment of age-related macular degeneration.
4. The use according to claim 3, wherein the age-related macular degeneration comprises map-like, withered age-related macular degeneration.
5. The use according to claim 4, wherein the medicament has one or more of the following effects: protecting retinopathy, inhibiting activation of cGAS-STING signaling pathway proteins in retina, inhibiting expression of inflammatory factor genes in retina, and reducing immune cell aggregation.
6. The use according to claim 5, wherein the cGAS-STING signaling pathway proteins include cGAS, STING, P-STING and P-nfκ B P65.
7. The use according to claim 5, wherein the inflammatory factors include interleukin-1 beta, interleukin-6 and type I interferon B.
8. The use according to any one of claims 4 to 7, wherein the map-like age-related macular degeneration is caused by sodium iodate.
9. Use of a compound that inhibits STING activity, wherein the compound that inhibits STING is C176, in the manufacture of a medicament for inhibiting inflammatory responses in age-related macular degeneration.
10. The use according to claim 9, wherein the medicament has the effect of inhibiting the expression of inflammatory factor genes in the retina and reducing the aggregation of immune cells.
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