Application of SIRT4-IN-1 in preparation of medicine for treating autoimmune diseases

Abstract

The invention belongs to the field of new application of medicines, and particularly relates to application of SIRT4-IN-1 in preparation of medicines for treating autoimmune diseases. It is found for the first time that SIRT4-IN-1 reduces the activation degree of immune response induced by HSV-1 virus infection by up-regulating acetylation modification of cGAS, inhibits abnormal activation of immune response in Trex1 deficient mouse cells and peripheral blood mononuclear cells of systemic lupus erythematosus patients, and improves abnormal activation of autoimmune response. The invention provides a new candidate drug for clinical treatment of systemic lupus erythematosus.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of new use of drugs, more particularly, to the application of SIRT4-IN-1 in the preparation of drugs for treating autoimmune diseases. BACKGROUND

[0002] The presence of cytosolic DNA is a potential danger signal, usually indicating the occurrence or presence of tissue damage caused by infection triggered by pathogenic microorganisms, which can quickly trigger the body's innate immune response. In most cells, cyclic guanosine-adenosine synthase (cGAS) is the most common DNA recognition receptor. cGAS functions as the main DNA recognition receptor in the process of transfection of exogenous DNA, bacterial infection, DNA virus or retrovirus infection, and leakage of mitochondrial DNA, chromosomal DNA and other self DNA.

[0003] Abnormal activation of cGAS by self DNA is an important cause of many serious autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Aicardi-Goutieres syndrome (AGS). SLE is a chronic autoimmune disease, accompanied by high concentration of autoantibodies and multiple organ damage, and its pathogenesis is not completely clear. There is no good treatment method. The typical serological feature of SLE is autoantibody against self nucleic acid (especially self dsDNA) and nucleic acid binding protein, which accumulates in tissues, leading to inflammation and production of type I IFN. In recent years, more and more evidence shows that cGAS is related to the pathological process of SLE. The expression of cGAS and cGAMP is up-regulated in the peripheral blood mononuclear cells (PBMCs) of SLE patients, and the expression level of cGAS and cGAMP is highly related to the activity of disease. About 1~2% of SLE patients have TREX1 (a kind of exonuclease that degrades cytosolic DNA) mutation, and TREX1 deficiency in mice leads to accumulation of cytosolic DNA, spontaneous production of type I interferon dependent autoimmune disease, and defects in cGAS or STING can eliminate all detectable pathological and molecular phenotypes of the defective mice.

[0004] Recent studies have shown that various post-translational modifications, including phosphorylation, glutamylation, ubiquitination, sumoylation (SUMOylation) and acetylation, play an important regulatory function in the function of cGAS. The research on cGAS acetylation started late. Mass spectrometry results show that cGAS has acetylation modification at K7, K50, K384, K392, K394 and K414 sites, among which acetylation at K384, K394 and K414 sites can inhibit the function of cGAS, and after DNA stimulation, cGAS can be deacetylated and activated.

[0005] The nicotinamide adenine dinucleotide (NAD+) dependent Sirtuin (Sirt) family contains seven family members (Sirt1-7), which can perform deacetylation modification on various histones or non-histones to participate in the regulation of important biological processes such as transcription, DNA repair, genome stability, cell metabolism, antioxidant and aging.

[0006] SIRT4-IN-1 is a small molecule inhibitor selectively targeting mitochondrial deacetylase SIRT4, which has high selectivity: no obvious inhibitory activity on other sirtuin family members such as SIRT1 / 2 / 3 / 5 / 6 / 7, is a rare SIRT4 specific tool compound, and the current research on SIRT4-IN-1 mainly focuses on metabolic diseases, liver protection and cancer mechanism research, in order to further expand the application range of SIRT4-IN-1, further research on other pharmaceutical uses of SIRT4-IN-1 is still needed. SUMMARY

[0007] The purpose of the present application is to provide the application of SIRT4-IN-1 in the preparation of drugs for treating autoimmune diseases.

[0008] The present application provides the application of SIRT4-IN-1 in the preparation of drugs for treating autoimmune response reaction abnormal activation diseases.

[0009] SIRT4-IN-1 is a selective Sirtuin 4 (SIRT4) inhibitor, and its chemical formula is C 19 H 13 N5O6S3, and its molecular weight is 503.53 g / mol. The compound has no obvious effect on other sirtuin subtypes such as SIRT1, SIRT2 and SIRT3, and shows high selectivity. It is found for the first time that SIRT4-IN-1 can reduce the activation degree of immune response reaction induced by HSV-1 virus infection by up-regulating the acetylation modification of cGAS, and inhibit Trex1 The abnormal activation of immune response reaction in defective mouse cells and peripheral blood mononuclear cells of systemic lupus erythematosus patients is improved, and the abnormal activation of autoimmune response reaction is improved, which provides a new candidate drug for clinical treatment of abnormal activation of autoimmune response reaction.

[0010] Further, the autoimmune response reaction abnormal activation disease includes systemic lupus erythematosus.

[0011] Further, the drug has SIRT4-IN-1 as the only effective component.

[0012] Further, the drug further comprises pharmaceutically acceptable excipients.

[0013] Further, the excipients comprise any one or more of non-toxic fillers, stabilizers, diluents, adjuvants.

[0014] Further, the diluents are any one of water and normal saline.

[0015] Further, the drug is prepared by mixing SIRT4-IN-1 and excipients as described in claim 1, and the content of SIRT4-IN-1 in the drug is 0.1wt% to 99wt%.

[0016] Further, the solid dosage forms comprise granules, tablets, capsules, pills, dripping pills, and the solution dosage forms comprise oral liquid preparations, intragastric administration preparations, and injection administration preparations.

[0017] Further, the solution dosage forms are solutions of water and SIRT4-IN-1, or solutions of normal saline and SIRT4-IN-1.

[0018] The present application has the following beneficial effects: The present application first finds that SIRT4-IN-1 can weaken the immune response induced by HSV60 in PMA-THP1 cells, and SIRT4-IN-1 can inhibit the abnormal immune activation in Trex1-deficient mice. Animal experiment results show that SIRT4-IN-1 can reduce the activation of the immune response induced by HSV-1 virus infection in mice. From the level of PBMCs of SLE patients, SIRT4-IN-1 significantly inhibits the expression of type I interferon and chronic inflammation-related cytokines and proteins in PBMCs of SLE patients, which provides a new idea for the treatment of SLE disease. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 Figure 4 is a result diagram of up-regulation of acetylation modification of cGAS by SIRT4-IN-1, wherein A is a result diagram of protein expression in HeLa cells transfected with HA-tagged cGAS by immunoblotting, B is a result diagram of protein expression in HeLa cells after SIRT4-IN-1 treatment, and C is a result diagram of protein expression in PMA-THP1 cells after SIRT4-IN-1 treatment.

[0020] Figure 2Figure for SIRT4-IN-1 inhibits immune response in PMA-THP1 cells, wherein A is a statistical diagram of mRNA relative expression amount of IFNB, B is a statistical diagram of mRNA relative expression amount of IFIT1, C is a statistical diagram of mRNA relative expression amount of CXCL10, D is a statistical diagram of mRNA relative expression amount of CCL5, E is a statistical diagram of mRNA relative expression amount of TNF, and F is a statistical diagram of mRNA relative expression amount of IL6.

[0021] Figure 3 Figure for SIRT4-IN-1 can inhibit immune response in mice, wherein A is a statistical diagram of IFN-β content in mouse serum, B is a statistical diagram of IL6 content in mouse serum, C is a statistical diagram of IFN-β content in mouse bronchoalveolar lavage fluid, and D is a statistical diagram of IL6 content in mouse bronchoalveolar lavage fluid.

[0022] Figure 4 Figure for expression amount of proteins and proinflammatory factors in mouse lung, wherein A is a statistical diagram of mRNA relative expression amount of IFNB, B is a statistical diagram of mRNA relative expression amount of IFIT1, C is a statistical diagram of mRNA relative expression amount of CXCL5, D is a statistical diagram of mRNA relative expression amount of CXCL10, E is a statistical diagram of mRNA relative expression amount of TNF, F is a statistical diagram of mRNA relative expression amount of IL6, and G is a statistical diagram of mRNA relative expression amount of UL30.

[0023] Figure 5 Figure for expression amount of proteins and proinflammatory factors in mouse liver, wherein A is a statistical diagram of mRNA relative expression amount of IFNB, B is a statistical diagram of mRNA relative expression amount of IFIT1, C is a statistical diagram of mRNA relative expression amount of CXCL5, D is a statistical diagram of mRNA relative expression amount of CXCL10, E is a statistical diagram of mRNA relative expression amount of TNF, F is a statistical diagram of mRNA relative expression amount of IL6, and G is a statistical diagram of mRNA relative expression amount of UL30.

[0024] Figure 6 Figure for expression amount of proteins and proinflammatory factors in mouse spleen, wherein A is a statistical diagram of mRNA relative expression amount of IFNB, B is a statistical diagram of mRNA relative expression amount of IFIT1, C is a statistical diagram of mRNA relative expression amount of CXCL5, D is a statistical diagram of mRNA relative expression amount of CXCL10, E is a statistical diagram of mRNA relative expression amount of TNF, F is a statistical diagram of mRNA relative expression amount of IL6, and G is a statistical diagram of mRNA relative expression amount of UL30.

[0025] Figure 7Figure 9. SIRT4-IN-1 inhibits abnormal activation of immune response in peritoneal macrophages of Trexl-deficient mice. A, B, C, D, E, F, G, H, I, and J are the relative mRNA expression of IFNA, IFNB, CXCL10, IRF7, IFI15, IFIT1, MX1, CCL5, TNF, and IFNG, respectively.

[0026] Figure 8 Figure 10. SIRT4-IN-1 inhibits abnormal activation of immune response in BMDCs of Trexl-deficient mice. A, B, C, D, E, F, G, and H are the relative mRNA expression of IFNA, IFNB, CXCL10, IFIT1, CCL5, TNF, and IL6, respectively.

[0027] Figure 9 Figure 11. SIRT4-IN-1 inhibits abnormal activation of immune response in BMDCs of Trexl-deficient mice. A, B, C, D, E, F, G, and H are the relative mRNA expression of IFNA, IFNB, CXCL10, IFIT1, CCL5, TNF, and IL6, respectively.

[0028] Figure 10 Figure 12. Analysis of SIRT4 expression in SLE patient database.

[0029] Figure 11 Figure 13. SIRT4 expression in PBMCs of SLE patients. A, B, and C are the relative mRNA expression of IFNB, TNF, and SIRT4, respectively.

[0030] Figure 12 Figure 14. SIRT4 inhibitor SIRT4-IN-1 inhibits autoimmune response in PBMCs of SLE patients. A, B, C, D, E, and F are the relative mRNA expression of IFNB, CXCL10, IFIT1, CCL5, TNF, and IL6, respectively. DETAILED DESCRIPTION

[0031] The application will be described in detail below with reference to the accompanying drawings and specific examples, but should not be understood as limiting the application. If not specifically stated, the technical means used in the following examples are conventional means known to those skilled in the art, and the materials, reagents, etc. used in the following examples, if not specifically stated, can be obtained from commercial channels.

[0032] Example 1 I. Experimental materials

[0033] 1. SIRT4-IN-1 (Cat. No. HY-163316) was purchased from MedChemExpress. HA-tagged cGAS was purchased from Molling Biotech. HSV60 was purchased from Suzhou Jw Biosciences. Trex1 gene-deficient mice were purchased from Cyagen Biosciences, which has a C57BL / 6 genetic background. THP1 cells were cultured in RPMI 1640 medium. PMA-THP1 cell line refers to THP1 cells pretreated with 100 ng / ml phorbol myristate acetate (PMA) for 24 hours. All cells were cultured at 37°C, 5% CO2, with the addition of 10% fetal bovine serum (Gibco), 4 mM L-glutamine, 100 μg / mL penicillin and 100 μg / mL streptomycin.

[0034] HSV-1 virus has been disclosed in the article "Yang B, Pei J, Lu C, Wang Y, Shen M, Qin X, Huang Y, Yang X, Zhao X, Ma S, Song Z, Liang Y, Wang H, Wang J. RNF144A promotes antiviral responses by modulating STING ubiquitination. EMBO Rep. 2023 Dec 6;24(12):e57528. doi: 10.15252 / embr.202357528".

[0035] HSV-1 virus amplification: in Vero cells, wash the bottom of the cell culture flask twice with 3 mL of phosphate buffered saline, then add HSV-1 virus with an infection mol of 1 and 12 mL of fresh DMEM medium, mix well, incubate for 2 h, then discard the mixture and replace it with DMEM medium containing 3% fetal bovine serum and incubate for 48 h. When the cells are confluent and large pieces of cells are shed, centrifuge the cell suspension at 2000 rpm / min for 20 min, collect the supernatant for use.

[0036] Virus infection: Discard the original cell culture medium in the culture plate, then add sterile PBS, 300 μL / well (24-well plate), wash the cell culture plate 2 times. After washing, add the supernatant containing HSV-1 virus, so that the infection mol is 1, and put it in the incubator. After 1.5 h in the incubator, discard the original virus liquid in the culture plate, wash the culture plate carefully 2 times with PBS, add complete culture medium in the 24-well cell culture plate according to 500 μL / well, and then put it in the cell culture incubator for culture. In the mouse model, the experimental group matched in age and gender was inoculated with HSV-1 by nasal instillation. 100 μL of HSV-1 virus (titer 10 5 PFU / μL) was used to drop into the mouse nostrils around the nostrils, and enter the nasal cavity with the mouse breathing.

[0037] ELISA mouse serum or lung lavage fluid was collected for detection of the following indicators: IFN-β (purchased from R&D company), IL-6 (item number 88-7064-88, Thermo Fisher Scientific company) II. Experimental method 1. Western blot: separate proteins by SDS-PAGE (polyacrylamide gel electrophoresis) according to molecular weight. Transfer the proteins in the gel to PVDF membrane, block at room temperature for 1 h. Then use the specific antibody to bind to the target protein, and then add the labeled secondary antibody to amplify the signal. The target protein band is detected by chemiluminescence method. Finally, the band intensity is quantified by Image J software, and normalized to the band intensity of β-actin.

[0038] Primary antibodies include Acetylated-Lysine Antibody (Cell Signaling Technology), anti-HA (901515, Biolend), anti-cGAS (26416-1-AP, Proteintech), anti-p-TBK1 (5483T, Cell Signaling Technology), anti-TBK1 (CSB-PA024154LA01HU, Flarbio), anti-p-IRF3 (4947, Cell Signaling Technology), anti-IRF3 (11312-1-AP, Proteintech), anti-p-p65 (3033, Cell Signaling Technology), anti-p65 (10745-1-AP, Proteintech), anti-β-actin (60008-1, Proteintech).

[0039] The secondary antibodies included HRP-conjugated Goat Anti-Rabbit IgG (H+L) and HRP-conjugated Goat Anti-Mouse IgG (H+L), both purchased from Proteintech.

[0040] 2. RNA extraction and real-time quantitative polymerase chain reaction: THP1 cells treated with different doses of SIRT4-IN-1 were lysed with Trizol. RNA precipitates were obtained through phase separation and washing. The RNA was then reverse transcribed into cDNA. The reaction system was prepared using the SYBR Green method, and PCR amplification was performed. Finally, factors such as IFNB, IFIT1, and CXCL10 were quantified using CT value and ΔΔCt method.

[0041] IV. Experimental Results.

[0042] 1. The SIRT4 inhibitor SIRT4-IN-1 can upregulate the acetylation modification of cGAS. First, the regulation of acetylation modification of exogenously transfected cGAS by the SIRT4 inhibitor SIRT4-IN-1 was examined. For example... Figure 1 As shown in Figure A, HA-tagged cGAS was transfected into HeLa cells, followed by treatment with the SIRT4 inhibitor SIRT4-IN-1 (0, 10, 25 μM). Twenty-four hours after transfection, cells were transfected with HSV60 (1 μg / ml) for 8 hours. A mock cell line contained untransfected cells. Cell lysis was followed by immunoprecipitation and Western blotting analysis. The results showed that, regardless of HSV60 transfection, the SIRT4 inhibitor SIRT4-IN-1 upregulated cGAS acetylation. Figure 1 As shown in Figures B and C, HeLa and PMA-THP1 cells were treated with the SIRT4 inhibitor SIRT4-IN-1 (0, 10, 25 μM) for 12 hours, followed by transfection with HSV60 (1 μg / ml) for 8 hours. Mock cells were untransfected. Cell lysis was followed by immunoprecipitation and Western blotting analysis. The effect of the SIRT4 inhibitor SIRT4-IN-1 on the acetylation modification of endogenous cGAS was examined. It was found that SIRT4-IN-1 upregulated cGAS acetylation modification in both HeLa and PMA-THP1 cells.

[0043] 2. The SIRT4 inhibitor SIRT4-IN-1 can suppress the immune response in PMA-THP1 cells. The immune response induced by viral DNA dependent on cGAS activation was detected. PMA-THP1 cells were treated with SIRT4 inhibitor SIRT4-IN-1 (0, 5, 10, 25 mM) for 12 hours, then transfected with HSV60 (1 pg / ml) for 8 hours, and the Mock was the cells without transfection. Then the cells were lysed for real-time PCR analysis. The experimental results are shown in Figure 2 Fig. 2A and Fig. 2B: The expression of type I interferon and its induced proteins and proinflammatory factors induced by HSV60 were significantly reduced in a dose-dependent manner.

[0044] 3. SIRT4 inhibitor SIRT4-IN-1 can inhibit the immune response in mice Figure 3 In A and B of Fig. 3, 8-week-old wild-type (WT) mice (n=4) were treated with SIRT4 inhibitor SIRT4-IN-1 (0, 10, 25 mg / kg body weight) by gavage, then intranasally inoculated with HSV-1 virus (1 x 10 7 PFU) for 24 hours. The serum was collected and detected by ELISA.

[0045] Figure 3 In C and D of Fig. 3, wild-type (WT) mice (n=4, 8 weeks old) were treated with SIRT4 inhibitor SIRT4-IN-1 (0, 10 mg / kg), then intranasally inoculated with HSV-1 virus (1 x 10 7 PFU) for 24 hours. The bronchoalveolar lavage fluid was collected and detected by ELISA.

[0046] 8-week-old wild-type (WT) mice (n=3) were treated with SIRT4 inhibitor SIRT4-IN-1 (0, 10 mg / kg), then intranasally inoculated with HSV-1 virus (1 x 10 7 PFU) for 24 hours. The tissues of the mice were taken for real-time PCR analysis.

[0047] The experimental results are shown in Figure 3 , Figure 4 , Figure 5 and Figure 6 In mice, the immune response induced by HSV-1 virus infection was significantly inhibited after treatment with SIRT4 inhibitor SIRT4-IN-1, including the expression of IFN-β and IL-6 in serum and lung lavage fluid, and the expression of type I interferon and its induced proteins and proinflammatory factors in liver, spleen and lung tissues.

[0048] 4. SIRT4 inhibitor SIRT4-IN-1 can inhibit the abnormal activation of immune response in PM cells of Trex1 deficient mice The effect of SIRT4 inhibitor SIRT4-IN-1 on spontaneous abnormal autoimmune response in Trex1 deficient mice was detected.

[0049] The preparation method of peritoneal macrophages is as follows: 2.5 ml of 4% mass / volume percentage Brewersthioglycollate (TG) solution is injected into the abdominal cavity of mice, and after 4 days, the mice are sacrificed, the abdominal cavity is exposed under sterile conditions, the peritoneum is kept intact, 5 ml of pre-cooled PBS is injected into the abdominal cavity with a syringe, the needle is not pulled out, the abdominal cavity is gently massaged with fingers, and fresh pre-cooled PBS is repeatedly washed once. Centrifuge at 1000 rpm for about 5 min, remove the supernatant. Count the cells. Poured into a 24-well plate, 1×10 6 cells per well, after 6 hours, the unattached suspended cells were washed away, and the remaining cells were peritoneal macrophages (PM).

[0050] The peritoneal macrophages (Trex - / - ) of wild type (WT) and Trex1 deficient mice were treated with SIRT4 inhibitor SIRT4-IN-1 (25 μM) and DMSO (25 μM) for 12 hours, and the cells were lysed for real-time fluorescent quantitative PCR detection.

[0051] The experimental results are shown in Figure 7 , it is found that SIRT4 inhibitor SIRT4-IN-1 can significantly inhibit the spontaneous abnormal autoimmune response in PM cells of Trex1 deficient mice.

[0052] 5. SIRT4 inhibitor SIRT4-IN-1 can inhibit the abnormal activation of immune response in BMDC cells of Trex1 deficient mice Further confirmation was carried out in myeloid-derived dendritic cells of Trex1 deficient mice, and the preparation method of dendritic cells was as follows: the mice were sacrificed, the femur and tibia were taken out aseptically, the bone marrow cavity was flushed with a syringe, the cell suspension was collected, the cell suspension was treated with red blood cell lysis solution, and after centrifugation, it was resuspended in complete culture medium containing GM-CSF (20 ng / mL), inoculated in a culture dish, and cultured to the 3rd day, half of the medium was replaced, and fresh GM-CSF was supplemented, and the culture was continued to the 8th day, and the semi-suspended and suspended cells were collected by gently blowing.

[0053] Figure 8 In the experiment, wild type (WT) and Trex1 deficient bone marrow-derived dendritic cells (Trex - / -) After 12 hours of treatment with SIRT4 inhibitor SIRT4-IN-1 (0 μM, 25 μM), the cells were lysed for immunoblot analysis.

[0054] Figure 9 In the middle, wild type (WT) and Trex1-deficient bone marrow-derived dendritic cells (Trex - / - ) After 12 hours of treatment with SIRT4 inhibitor SIRT4-IN-1 (25 μM) or DMSO (25 μM), the cells were lysed for real-time quantitative PCR detection.

[0055] The experimental results are shown in Figure 8 and Figure 9 SIRT4 inhibitor SIRT4-IN-1 can significantly inhibit the spontaneous abnormal autoimmune response of Trex1-deficient mouse BMDCs cells.

[0056] 6, SIRT4 expression is elevated in SLE patients To further evaluate the role of SIRT4 in systemic lupus erythematosus (SLE), the large-scale gene expression dataset GSE No. GSE45291 (containing gene expression characteristics of peripheral blood mononuclear cells of 302 SLE patients and 27 healthy donors) was analyzed in GEO Datasets. The experimental results are shown in Figure 10 The analysis results show that the expression level of SIRT4 in SLE patients is significantly higher than that in healthy controls.

[0057] Subsequently, peripheral blood mononuclear cells (PBMCs) were isolated from SLE patients. As shown in Figure 11 Compared with healthy individuals (HC), the expression level of SIRT4 in SLE patient PBMCs is significantly higher, which is consistent with the expected result.

[0058] PBMCs were isolated from SLE patient blood samples, and after 12 hours of treatment with SIRT4 inhibitor SIRT4-IN-1 (0 μM, 25 μM), the cells were lysed for real-time quantitative PCR detection. The experimental results are shown in Figure 12 SIRT4-IN-1 treatment can significantly inhibit the expression of type I interferon and chronic inflammation-related cytokines and proteins in SLE patient PBMCs. It is suggested that SIRT4 inhibitors can become a potential treatment strategy for cGAS-related autoimmune diseases.

[0059] It should be noted that when the present application claims involving numerical ranges, it should be understood that each numerical range of two endpoints and any number between the two endpoints can be selected. In order to prevent repetition, the present application describes the preferred embodiments.

[0060] While the preferred embodiments of the application have been described, additional variations and modifications can be made to these embodiments by those skilled in the art once they have the benefit of the present disclosure without departing from the spirit and scope of the application. Accordingly, it is intended that the appended claims include all such modifications and variations as fall within the scope of the present application.

[0061] It is apparent that those skilled in the art can make various changes and modifications to the application without departing from the spirit and scope of the application. It is therefore intended that the present application cover all such changes and modifications that are within its scope.

Claims

1. Use of SIRT4-IN-1 in the preparation of a medicament for treating a disease of abnormal activation of autoimmune response.

2. Use according to claim 1, characterized in that, The disease of abnormal activation of autoimmune response includes systemic lupus erythematosus.

3. Use of SIRT4-IN-1 according to claim 1 for the preparation of a medicament for the treatment of a disease in which the autoimmune response is abnormally activated, characterized in that, The SIRT4-IN-1 is the only effective component in the medicament.

4. Use of SIRT4-IN-1 according to claim 1 for the preparation of a medicament for the treatment of a disease in which the autoimmune response is abnormally activated, characterized in that, The medicament further comprises a pharmaceutically acceptable adjuvant.

5. Use of SIRT4-IN-1 according to claim 4 for the preparation of a medicament for the treatment of a disease in which the autoimmune response is abnormally activated, characterized in that, The adjuvant comprises any one or more of a filler, a stabilizer, a diluent, an adjuvant.

6. Use of SIRT4-IN-1 according to claim 5 for the preparation of a medicament for the treatment of a disease with an abnormal activation of the autoimmune response, characterized in that, The diluent is any one of water and normal saline.

7. A medicament for treating a disease in which an autoimmune response is abnormally activated, characterized by comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof. The medicament is prepared by mixing the SIRT4-IN-1 and the adjuvant, and the content of the SIRT4-IN-1 in the medicament is 0.1wt% to 99wt%.

8. The medicament according to claim 7, characterized in that, The medicament is in a solid dosage form or a solution dosage form, the solid dosage form comprises granules, tablets, capsules, pills, dripping pills, and the solution dosage form comprises oral liquid preparation, intragastric administration, and injection administration.

9. The medicament according to claim 8, characterized in that, The solution dosage form is a solution of water and the SIRT4-IN-1, or a solution of normal saline and the SIRT4-IN-1.

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