Therapeutic application of polyphyllin 1 in activation of STING-mediated immune response

Abstract

The invention provides a therapeutic application of polyphyllin 1 in activation of STING-mediated immune response. The main active ingredient of the STING agonist is steroidal saponin, the steroidal saponin is selected from paris polyphylla saponin I, and preferably, the paris polyphylla saponin I is extracted from paris polyphylla. The polyphyllin I can be used for directly activating STING protein, effectively activating an STING signal channel and improving immune response. The STING agonist provided by the invention has relatively good chemical stability and bioavailability, can improve the effectiveness and durability of the medicine, does not cause excessive inflammatory response and tissue damage while effectively activating immune response, reduces side effects, and has relatively high safety.

Description

Technical Field

[0001] The present application relates to the field of biomedicine, and specifically to the therapeutic application of Paris saponin 1 in activating STING-mediated immune responses. Background Art

[0002] The stimulator of interferon genes (STING) is an endoplasmic reticulum membrane protein that is mainly expressed on the outer membranes of the rough endoplasmic reticulum, mitochondria, and microsomes of human macrophages, T lymphocytes, dendritic cells, endothelial cells, epithelial cells, and fibroblasts. The STING pathway is a key regulator of the immune response to viruses and bacteria and a key component of the innate immune system. Activation of STING-dependent signaling pathways can promote the secretion of type I interferons and the expression of proteins related to antiviral and anti-tumor immunity, thereby blocking viral replication and promoting immune responses to cancer cells. When studying the mechanism of action of agonists, it was found that some agonists can bind to STING, which can be called direct STING agonists, such as cyclic dinucleotides and aminobenzimidazole compounds; while other agonists do not bind to STING, which can be called indirect STING agonists.

[0003] At present, the commonly used pathway in regulating immune response is the cGAS (cyclic guanosine monophosphate-adenylate synthase)-STING pathway. When DNA virus or bacterial DNA is detected in the cell, cGAS synthesizes cGAMP (cyclic guanosine monophosphate-adenylate monophosphate), which then activates STING, initiates the phosphorylation of TBK1 and IRF3, and ultimately induces the expression of type I interferon and other antiviral genes. In addition, the cGAS-STING cascade can play a role in breaking tumor immune tolerance by accelerating the cancer immunity cycle, but as clinical trials are conducted, its effect is not ideal.

[0004] Most of the existing STING agonists face problems such as poor stability (such as cGAMP and its analogs), low bioavailability and obvious side effects. Many STING agonists may induce excessive inflammatory responses while enhancing immune responses, leading to tissue damage or autoimmune diseases. In addition, many existing STING agonists are difficult to effectively deliver to target tissues or cells, limiting their clinical application. Summary of the invention

[0005] Based on the above problems, the present application discloses a STING agonist, wherein the main active ingredient is a steroidal saponin, wherein the steroidal saponin is selected from Paris polyphylla saponin I, and preferably, the Paris polyphylla saponin I is extracted from Paris polyphylla. The steroidal saponin binds to STING and is a direct STING agonist.

[0006] Preferably, the steroidal saponin is extracted from Paris polyphylla, and the preparation method comprises: drying the Paris polyphylla, crushing it, sieving it, extracting it by heating and refluxing it with a solvent, filtering and concentrating it, and separating and purifying it to obtain Paris polyphylla saponin I.

[0007] Preferably, the solvent is ethanol or methanol, the heating temperature is 50° C.-70° C., and the extraction time is 2-4 h.

[0008] Preferably, the separation process is chromatography separation, gradient elution, and the purification process is purification by recrystallization.

[0009] Furthermore, the agonist is delivered via a drug delivery system; the drug delivery system mainly includes one of an oral sustained-release system, a transdermal drug delivery system and a targeted drug delivery system;

[0010] Preferably, the drug delivery system of the agonist is a targeted drug delivery system.

[0011] Preferably, the targeted drug delivery system comprises administration of nanoparticles using liposomes as carriers.

[0012] Furthermore, the dosage is 2-100 mg / kg.

[0013] The second aspect of the present application discloses the use of a STING agonist as described above in the preparation of a therapeutic drug for activating a STING-mediated immune response.

[0014] The third aspect of the present application discloses the use of the above-mentioned STING agonist in a product that promotes the release of type I interferon.

[0015] Furthermore, the type I interferon is IFN-β, Ifn-α, or Ifn-β.

[0016] The fourth aspect of the present application discloses the use of the above-mentioned STING agonist in combination with a standard antiviral drug in the preparation of an antiviral drug.

[0017] The molar concentration ratio of the STING agonist to the standard antiviral drug is in the range of (10-100):1; preferably, the antiviral drug includes at least one of 2',3'-cGAMP, 3',3'-cGAMP, SR717, and diABZI.

[0018] The fifth aspect of the present application discloses the use of the above-mentioned STING agonist and chemotherapy drugs in combination for the preparation of anti-tumor drugs.

[0019] The fifth aspect of the present application discloses a drug comprising the above-mentioned agonist and auxiliary materials, excipients, stabilizers, solvents, and solubilizers.

[0020] Preferably, the excipient comprises at least one of starch and microcrystalline cellulose; the stabilizer comprises vitamin E; the solvent comprises at least one of water and ethanol; and the solubilizer comprises polysorbate 80.

[0021] The beneficial effects of this application are as follows:

[0022] 1. The Paris polyphylla saponin I of the present application can directly activate the STING protein, effectively activate the STING signaling pathway, and enhance the immune response. The STING agonist of the present application has good chemical stability and bioavailability, can improve the effectiveness and durability of the drug, and the STING agonist of the present application will not cause excessive inflammatory response and tissue damage while effectively activating the immune response, reduce side effects, and have high safety. The STING agonist of the present application is applied to cancer immunotherapy and antiviral therapy. The experimental results demonstrate the significant role of Paris polyphylla saponin I (PPI) in enhancing the STING signaling pathway and related immune responses, providing an important strategy for the development of new treatment methods targeting immune-related diseases.

[0023] 2. The STING agonist of this application promotes STING activation, and the activated STING is transferred to the endoplasmic reticulum and binds to TBK1, leading to the phosphorylation and activation of TBK1. The activated TBK1 further phosphorylates interferon regulatory factor 3 (IRF3), and IRF3 dimerizes and translocates to the cell nucleus. In the cell nucleus, IRF3 induces the gene expression of type I interferon and other inflammatory factors. Type I interferon and inflammatory factors activate innate and adaptive immune responses through autocrine and paracrine effects, enhance the body's ability to kill viruses and tumors, and promote immune cells to recognize and eliminate pathogens, tumor cells, etc.

[0024] 3. The present application also provides a drug that optimizes the delivery of STING-related drugs, ensures that the drug can efficiently reach the target tissue or cells, improves the drug delivery efficiency, ensures that the drug can accurately reach the target site and exert the maximum therapeutic effect, which is beneficial to the clinical application of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 :Parifolium saponin I (PPI) significantly activates STING signaling pathway;

[0026] Figure 2 : Paris polyphylla saponin I (PPI) enhances the expression of interferon-stimulated genes (ISGs);

[0027] Figure 3 :Parifolium saponin I (PPI) enhances the expression of antiviral cytokines under HSV-1 infection;

[0028] Figure 4:Parifolium saponin I (PPI) synergistically enhances the activation of STING signaling pathway under HSV-1 infection;

[0029] Figure 5 :Parifolium saponin I (PPI) synergistically reduces the expression of Ul30 mRNA in mouse primary BMDM cells;

[0030] Figure 6 :Parifolium saponin I (PPI) inhibits the growth of B16F10 melanoma. DETAILED DESCRIPTION

[0031] The embodiments of the present application will be described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only used to illustrate the present application and should not be considered to limit the scope of the present application. The terms used herein are only used to illustrate specific embodiments and are not intended to limit the claimed solutions.

[0032] Paris polyphylla saponin I (PPI) was purchased from MCE, product number HY-N0047;

[0033] 2',3'-cGAMP was purchased from MCE, catalog number HY-100564A;

[0034] 3',3'-cGAMP was purchased from MCE, catalog number HY-12512;

[0035] SR717 was purchased from MCE, item number HY-131454;

[0036] diABZI purchased the manufacturer MCE, item number HY-112921A.

[0037] Example 1

[0038] This embodiment provides a STING agonist, wherein the main active ingredient is a steroidal saponin, wherein the steroidal saponin is selected from Paris polyphylla saponin I, and preferably, the Paris polyphylla saponin I is extracted from Paris polyphylla.

[0039] Steroidal saponins bind to STING and are direct STING agonists, which can directly activate STING protein, effectively activate the STING signaling pathway, and enhance the immune response.

[0040] The molecular formula of Polyphyllin I is C 47 H 76 O 17 Paris polyphylla saponin 1 is a steroidal saponin extracted from traditional Chinese medicine.

[0041] The action process of Paris polyphylla saponin I is as follows:

[0042] STING activation: Paris polyphylla saponin 1 can promote STING activation. The activated STING is transferred to the endoplasmic reticulum and binds to TBK1, leading to the phosphorylation and activation of TBK1.

[0043] Signal transduction: Activated TBK1 further phosphorylates IRF3, which dimerizes and translocates to the nucleus. In the nucleus, IRF3 induces gene expression of type I interferons (such as IFN-β) and other inflammatory factors.

[0044] Immune response: Type I interferons and inflammatory factors activate innate and adaptive immune responses through autocrine and paracrine effects, thereby enhancing the body's defense against viruses and tumors.

[0045] As a further embodiment, the drug delivery system of the agonist mainly includes an oral sustained-release system, a transdermal drug delivery system and a targeted drug delivery system; the drug delivery system of the agonist mainly includes an oral sustained-release system, a transdermal drug delivery system and a targeted drug delivery system;

[0046] Preferably, the drug delivery system of the agonist is a targeted drug delivery system.

[0047] Preferably, the targeted drug delivery system comprises administration of nanoparticles using liposomes as carriers;

[0048] Preferably, the oral sustained-release system includes oral administration, buccal administration, sublingual administration, and inhalation administration;

[0049] Preferably, the transdermal administration system includes injection administration and transdermal administration.

[0050] The route of administration can be supplied in bulk or unit dosage form depending on the expected route of administration of the agonist provided herein. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules and caplets can be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions and solutions can be acceptable as liquid dosage forms. For injection, emulsions and suspensions can be acceptable as liquid dosage forms, and powders suitable for reconstitution with suitable solutions can be acceptable as solid dosage forms. For inhalation, solutions, sprays, dry powders and aerosols can be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, emulsifiable pastes, lotions, gels, solutions and patches can be acceptable dosage forms.

[0051] Preferably, the types of pharmaceutical preparations can be divided into:

[0052] 1. Oral preparations: tablets, capsules, oral solutions;

[0053] 2. Injection preparations: water-soluble injection;

[0054] 3. Topical preparations: ointments, gels.

[0055] As a further embodiment, when administered orally, the dosage is 2-100 mg / kg.

[0056] A medicine comprises the above-mentioned agonist and auxiliary materials, excipients, stabilizers, solvents and solubilizers.

[0057] As a further embodiment, the excipient includes at least one of starch and microcrystalline cellulose; the stabilizer includes vitamin E; the solvent includes at least one of water and ethanol; and the solubilizer is polysorbate 80.

[0058] Example 2

[0059] This example provides the use of the STING agonist described in Example 1 in the preparation of a therapeutic drug for activating a STING-mediated immune response.

[0060] This example provides the use of the STING agonist described in Example 1 in a product for promoting the release of type I interferon.

[0061] As a further embodiment, the type I interferon is IFN-β, Ifn-α, or Ifn-β.

[0062] This example provides the use of the STING agonist described in Example 1 in combination with a standard antiviral drug in the preparation of an antiviral drug.

[0063] The molar concentration ratio of the STING agonist to the standard antiviral drug is in the range of (10-100):1; preferably, the antiviral drug includes at least one of 2',3'-cGAMP, 3',3'-cGAMP, SR717, and diABZI.

[0064] This example provides the use of the STING agonist described in Example 1 in combination with a chemotherapeutic drug in the preparation of an anti-tumor drug.

[0065] The present invention relates to the discovery of the compound Paris saponin I (PPI) as a potent STING (stimulator of interferon genes) signaling pathway activator. In the present application, Paris saponin I (PPI) can synergize with current STING agonists to enhance their therapeutic potential; the ability of Paris saponin I (PPI) to regulate STING signals provides a flexible application strategy for the treatment of a variety of immune-related diseases; the present application covers the therapeutic uses of Paris saponin I (PPI), including its role as a STING agonist in the treatment of cancer and viral infections, as well as related pharmaceutical preparations and dosing regimens.

[0066] Cancer immunotherapy: PPIs can enhance the activation of the STING signaling pathway, induce type I interferon and anti-tumor immune responses. When used in combination with existing immunotherapy, it is expected to improve the therapeutic effect.

[0067] Antiviral therapy: By amplifying ISG expression and cytokine production, PPIs may serve as potential drugs for the treatment of DNA viral infections including herpes simplex virus (HSV).

[0068] Example 3 (Mechanism of Action)

[0069] All reagents used in the experiment can be purchased from the market and will not be described in detail here.

[0070] The activation of STING signaling pathway in THP1 cells was detected by immunoblotting (WB). The experiment included the following treatment conditions:

[0071] Group 1: (Mock): The drug sample was in THP1 cell culture medium + 10 μM PPI, and the control sample was in THP1 cell culture medium only.

[0072] Group 2 (2',3'-cGAMP): Its drug examples are in THP1 cell culture medium

[0073] +1μM 2',3'-cGAMP+10μM PPI, in the control example, in THP1 cell culture medium

[0074] +1 μM 2',3'-cGAMP.

[0075] Group 3: The drug example is THP1 cell culture medium + 1 μM 3',3'-cGAMP + 10 μM PPI, and the control example is THP1 cell culture medium + 1 μM 3',3'-cGAMP.

[0076] Group 4: Its drug example is THP1 cell culture medium + 1 μM SR717 + 10 μM PPI, and its control example is THP1 cell culture medium + 1 μM SR717.

[0077] Group 5: The drug sample contained 100 nM diABZI+10 μM PPI in THP1 cell culture medium, and the control sample contained 100 nM diABZI in THP1 cell culture medium.

[0078] The treatment time for the above experimental groups was 2 hours.

[0079] The levels of signaling pathway activation in the presence or absence of PPIs were also compared.

[0080] Immunoblotting (WB) analysis showed the protein expression of phosphorylated TBK1 (p-TBK1), phosphorylated STING (p-STING), and total STING in THP1 cells after treatment with 2',3'-cGAMP, 3',3'-cGAMP, SR717, or diABZI in the presence or absence of PPI.

[0081] Experimental results: In the presence of PPI, the phosphorylation levels of TBK1 (downstream signaling protein) and STING were significantly increased, indicating that PPI can enhance the activation effect of the STING signaling pathway.

[0082] in conclusion

[0083] Paris polyphylla saponin 1 (PPI) is a potent STING activator that significantly enhances STING activation, such as Figure 1 As shown in Figure 2, significantly increased phosphorylation levels of STING and its downstream TBK1 were observed in THP1 cells. This activation effect can be observed under a variety of stimulation conditions, including 2',3'-cGAMP and diABZI, indicating that PPIs can work synergistically with other existing STING agonists.

[0084] Example 4 (Enhancing interferon-stimulated gene expression)

[0085] The effect of PPI on interferon-stimulated gene expression was measured by luciferase activity using THP1-lucia reporter cells. The experiment included the following treatment conditions:

[0086] Group 1 (blank group): THP1-lucia cell culture medium

[0087] Group 2: THP1 cell culture medium + 100 nM diABZI;

[0088] Group 3: THP1 cell culture medium + 100 nM diABZI + 10 μM PPI;

[0089] Group 4: THP1 cell culture medium + 100 nM diABZI + 20 μM PPI;

[0090] All experimental groups were treated for 18 hours, and the activation of the signal pathway was detected using the luciferase reporter system.

[0091] Luciferase activity of ISGs was detected in THP1-lucia reporter cells treated with diABZI and different concentrations of PPIs.

[0092] Experimental results: PPI significantly enhanced the expression level of ISG in a dose-dependent manner (mean ± standard error, n = 3). Statistical analysis was performed using t-test (***p < 0.001). . The group treated with higher concentrations of PPI showed stronger luciferase activity. (mean ± standard error, n = 3). Statistical analysis was performed using t-test (***p < 0.001). The expression level demonstrated its potential in enhancing innate immunity.

[0093] in conclusion

[0094] In THP1-lucia reporter cells, PPI significantly increased the expression level of interferon-stimulated genes (ISGs) in a dose-dependent manner, showing a significant activation of the STING signaling pathway at 10 μM, and a stronger activation of STING at 20 μM (e.g. Figure 2 ). This result suggests that PPIs can amplify innate immune responses and are particularly critical for antiviral defense.

[0095] Example 5 (Antiviral Effect)

[0096] The mRNA expression levels of antiviral cytokines Ifnb and Cxcl10 in HSV-1 infected THP1 cells were analyzed by quantitative RT-PCR. The immune response induced by HSV-1 infection was compared in the presence or absence of PPIs.

[0097] The experiment included the following treatment conditions:

[0098] (A) Ifnb expression group:

[0099] Group 1: THP1 cell culture medium

[0100] Group 2: culture medium of THP1 cells infected with HSV-1;

[0101] Group 3: culture medium of THP1 cells infected with HSV-1 + 20 μM PPI.

[0102] (B) Cxcl10 expression group:

[0103] Group 1: THP1 cell culture medium

[0104] Group 2: culture medium of THP1 cells infected with HSV-1;

[0105] Group 3: culture medium of THP1 cells infected with HSV-1 + 20 μM PPI.

[0106] The experimental results are as follows Figure 3 As shown:

[0107] (A) Ifnb expression: PPI significantly increased the mRNA level of Ifnb in HSV-1 infected cells.

[0108] (B) Cxcl10 expression: PPI also significantly enhanced the expression of Cxcl10.

[0109] in conclusion

[0110] In HSV-1 infected THP1 cells, PPI significantly enhanced the expression of antiviral cytokines Ifnb and Cxcl10 (e.g. Figure 3 , (mean ± standard error, n = 3). Statistical analysis was performed using t-test (***p < 0.001). These results suggest that PPIs can be used as potential drugs for antiviral treatment by enhancing host immune responses. This indicates that PPIs can significantly activate STING to enhance antiviral immune responses, further verifying their potential for application in antiviral treatment.

[0111] Embodiment 6:

[0112] Western blot analysis of TBK1 phosphorylation in mouse primary BMDM cells.

[0113] The experiment included the following treatment conditions: Figure 4 As shown, the first row shows the treatment conditions of HSV-1 and PPI, and the circles indicate the presence or absence of each treatment. The second row (p-TBK1) shows the phosphorylation status of TBK1, and the third row (TBK1) shows the total TBK1 protein level. GAPDH was used as a loading control.

[0114] Experimental groups: Isolation and culture of primary bone marrow-derived macrophages (BMDM) from mice:

[0115] Group 1: macrophage (BMDM) culture medium;

[0116] Group 2: macrophage (BMDM) culture medium + treatment with HSV-1 at a concentration of 10^6 pfu / ml for 6 hours;

[0117] Group 3: Macrophage (BMDM) culture medium + HSV-1 at a concentration of 10^6 pfu / ml + PPI at a concentration of 10 μM.

[0118] After treatment, protein lysates were extracted and subjected to Western blot analysis to detect phosphorylated TBK1 (p-TBK1), total TBK1 levels, and GAPDH was used as a loading control.

[0119] Experimental results: Western blot analysis results showed that Figure 4As shown, HSV-1 infection induced the phosphorylation of TBK1 (p-TBK1), and the phosphorylation (p-TBK1) effect was more significant after the addition of PPI.

[0120] in conclusion

[0121] This shows that PPI can significantly activate STING and enhance antiviral immune response.

[0122] Example 7

[0123] The expression of Ul30 mRNA in primary mouse BMDM cells was analyzed by quantitative RT-PCR. The experiment included the following treatment conditions: Figure 5 The y-axis shows the relative mRNA expression of Ul30, which is a marker of viral replication. The x-axis shows the different treatment groups, as follows:

[0124] Group 1: BMDM cell culture medium + HSV-1 (10^6 pfu / ml, treated for 6 hours),

[0125] Group 2: BMDM cell culture medium + 10 μM PPI;

[0126] Group 3: BMDM cell culture medium + 1 μM cGAMP:

[0127] Group 4: BMDM cell culture medium + 10μM PPI + 1μM cGAMP.

[0128] Statistical significance was determined by t-test, *p<0.05, **p<0.01, ***p<0.001.

[0129] Experimental content: Primary bone marrow-derived macrophages (BMDM) were isolated and cultured from mice and treated with HSV-1 at a concentration of 10^6 pfu / ml for 6 hours. 10μM PPI and 1μM cGAMP were added. After treatment, total cell RNA was extracted and RT-PCR was performed to detect the mRNA expression of Ul30, which was used as a viral gene to evaluate viral replication. The relative mRNA expression was calculated by the ΔΔCt method, and GAPDH was used as an internal reference.

[0130] Experimental results: RT-PCR results showed that HSV-1 infection significantly upregulated the expression of Ul30 mRNA, and the difference was statistically significant compared with the untreated group (p<0.001). PPI treatment alone reduced Ul30 expression. When cGAMP was added to HSV-1 infected cells, Ul30 expression was significantly reduced (p<0.05), and when used in combination, Ul30 expression was significantly reduced, indicating that HSV-1 replication was significantly inhibited.

[0131] in conclusion

[0132] Although HSV-1 infection induces viral replication, the combined use of PPI and cGAMP can exert a significant antiviral effect.

[0133] Example 8 (Antitumor Activity)

[0134] The mouse B16F10 melanoma model was used as the research object to evaluate the anti-tumor effect of PPI.

[0135] The mice were divided into a DMSO control group and a PPI-treated group, and the volume and weight of tumor tissue were compared. Figure 6 As shown:

[0136] (A) Tumor tissues of C57BL / 6 mice treated with DMSO or PPI (at a dose of 2 mg / kg) after subcutaneous injection of B16F10 melanoma cells.

[0137] (B) Statistics of tumor weights of mice excised from different treatment groups. Compared with the DMSO group, the tumor weight of the PPI (2 mg / kg) treatment group was significantly reduced (mean ± standard error, n = 3 or 4). Independent t-test was used for statistical analysis (*p < 0.05).

[0138] Experimental Results

[0139] (A) Representative image of tumor tissue: The tumors of mice in the PPI-treated group were significantly smaller than those in the DMSO group.

[0140] (B) Tumor weight statistics: PPI treatment significantly reduced the weight of mouse tumors (*p<0.05).

[0141] in conclusion:

[0142] PPI effectively inhibited tumor growth in vivo by activating the STING signaling pathway, demonstrating its potential in tumor immunotherapy.

[0143] PPI showed significant anti-tumor effects in the B16F10 melanoma mouse model (e.g. Figure 6 ). Compared with the control group, the tumor growth of mice in the PPI-treated group was significantly inhibited and the tumor weight was significantly reduced. This result suggests that PPI achieves tumor suppression by activating STING-mediated tumor microenvironment immune response.

[0144] From the above examples, it can be seen that:

[0145] At the cellular level: PPI significantly enhanced the activation of the STING signaling pathway, the expression of interferon-stimulated genes, and the secretion of antiviral factors (such as Figure 1-5 ). Animal level: PPIs show potent tumor suppressive effects (such as Figure 6). These data provide a strong experimental basis for the development of PPIs as anti-tumor and antiviral drugs.

[0146] High efficiency: Paris polyphylla saponin 1 can effectively activate the STING pathway and enhance the immune response, thus improving the effectiveness and durability of the drug.

[0147] Safety: Compared with existing STING agonists, Paris saponin 1 has higher safety and fewer side effects.

[0148] Wide application: It can not only be used for anti-virus and anti-tumor, but also can be used as an immunomodulator, with a wide range of applications.

[0149] It should be understood that some features of the disclosed method in the context of reference to different embodiments for clarity may also be provided in combination in a single embodiment. Based on this application, some modifications or improvements may be made thereto, which will be apparent to those skilled in the art.

Claims

1. A STING agonist, characterized in that The active ingredient is steroidal saponin, which is selected from Paris polyphylla saponin I. Preferably, Paris polyphylla saponin I is extracted from Paris polyphylla.

2. The agonist according to claim 1, characterized in that The agonist is delivered via a drug delivery system; the drug delivery system comprises one of an oral sustained-release system, a transdermal drug delivery system and a targeted drug delivery system; preferably, the drug delivery system is a targeted drug delivery system.

3. The agonist according to claim 1, characterized in that The dosage is 2-100 mg / kg.

4. Use of a STING agonist according to any one of claims 1 to 3 in the preparation of a therapeutic drug for activating a STING-mediated immune response.

5. Use of the STING agonist according to any one of claims 1 to 3 in a product for promoting the release of type I interferon.

6. The use according to claim 5, characterized in that: The type I interferon is IFN-β, Ifn-α, Ifn-β.

7. Use of the STING agonist according to any one of claims 1 to 3 in combination with a standard antiviral drug in the preparation of an antiviral drug.

8. The use according to claim 7, characterized in that: The molar concentration ratio of the STING agonist to the standard antiviral drug is in the range of (10-100):1; preferably, the antiviral drug includes at least one of 2',3'-cGAMP, 3',3'-cGAMP, SR717, and diABZI.

9. Use of the STING agonist according to any one of claims 1 to 3 in combination with a chemotherapeutic drug in the preparation of an anti-tumor drug.

10. A drug, characterized in that It comprises the STING agonist described in claims 1-3 and auxiliary materials, excipients, stabilizers, solvents, and solubilizers; preferably, the excipients include at least one of starch and microcrystalline cellulose; the stabilizer includes vitamin E; the solvent includes at least one of water and ethanol; and the solubilizer is polysorbate 80.

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