CN117924226A - Sting agonist and application thereof - Google Patents
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- CN117924226A CN117924226A CN202410043858.XA CN202410043858A CN117924226A CN 117924226 A CN117924226 A CN 117924226A CN 202410043858 A CN202410043858 A CN 202410043858A CN 117924226 A CN117924226 A CN 117924226A
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Abstract
The invention provides a sting agonist and application thereof, and belongs to the technical field of biology and new medicines. The invention explores the action mechanism of salvianolic acid B as a STING agonist, discovers that the salvianolic acid B can induce the activation of a cGAS-STING-TBK1 signal path, promotes the high expression of p-STING, p-IRF3 and p-TBK1/NAK in 4T1 cells, and improves the survival rate of breast cancer mice. Therefore, the salvianolic acid B has the potential of serving as a STING agonist in tumor immunotherapy, and provides a new thought for the application of the salvianolic acid B in resisting tumors.
Description
Technical Field
The invention belongs to the technical field of biology and new medicines, and particularly relates to a sting agonist and application thereof.
Background
With advances in immunology, molecular biology and genetic engineering, tumor immunotherapy has become the fourth modality of tumor therapy, following surgery, radiation therapy and chemotherapy. Among them, the cGAS-STING pathway has attracted a great deal of attention, and the cGAS-STING-TBK1 axis is the main signaling pathway of the innate immune response in different species. Drug development aiming at cGAS-STING-TBK1 signal pathway has wide prospect in tumor immunotherapy, wherein STING agonists have become hot spots of current research, and unlike most macromolecular immune checkpoint inhibitors, STING agonists are small-molecule innate immune agonists with pioneering significance. On the one hand, it has a small molecular weight and can achieve higher concentrations within the tumor by systemic administration. On the other hand, STING agonists can make up for the shortfall of immune checkpoint inhibitors, and also have good anti-tumor effects on "cold tumors" by activating and recruiting intratumoral tumor-specific cd8+ T cells. Therefore, the development of a novel STING agonist, the excavation of an anti-tumor action mechanism thereof, and the development of the novel STING agonist has very important significance.
GSK in 2018 reported a class of aminobenzimidazole compound dimers (dinerized amidobenzimidazole, diABZI), which realized the efficacy of systemic administration and opened a new chapter for non-nucleotide STING agonists. Although STING agonists have promise in cancer immunotherapy, none of the drugs has yet entered the medical market. Thus, the use of repositioning clinically approved small molecule drugs is an attractive option.
Salvianolic acid B (salvianolic acid B, salB) is an effective bioactive component extracted from dried root of Saviae Miltiorrhizae radix, and is one of main active components of Saviae Miltiorrhizae radix, and a large number of researches report that it has antiinflammatory, antioxidant, neuroprotection, cardioprotection, and anti-tumor effects, but the research about SalB as STING agonist applied in tumor immunotherapy has not been reported yet.
Disclosure of Invention
In view of this, the present invention aims to provide a STING agonist and its application, the present invention discusses SalB inhibition of 4T1 cell proliferation, and SalB acts as tumor immunotherapy by activating cGAS-STING-TBK1 signaling pathway to stimulate the innate immune system and enhance tumor immunogenicity.
In order to achieve the above purpose, the invention provides a sting agonist, wherein the sting agonist is salvianolic acid B.
Preferably, the molecular formula of the salvianolic acid B is C 36H30O16, and the structural formula is as follows:
Preferably, the sting agonist can also be a salt or a derivative of salvianolic acid B which is pharmaceutically acceptable. Wherein the pharmaceutically acceptable salt or derivative of salvianolic acid B can be used for improving the solubility, stability, bioavailability or targeting of salvianolic acid B, and can optimize the pharmacokinetics and pharmacodynamics of the salvianolic acid B while maintaining or even enhancing the activity of the original medicine.
The invention also provides application of the STING agonist in inducing a cGAS-STING-TBK1 signal path. Activating cGAS-STING-TBK1 signaling pathway to stimulate the innate immune system and enhance tumor immunogenicity, thereby acting as an immune therapy for tumors.
The invention also provides application of the sting agonist in tumor treatment.
The invention also provides application of the STING agonist in preparing medicines for preventing or treating tumors related to the cGAS-STING-TBK1 signal path.
Preferably, the tumor includes, but is not limited to, any of leukemia, lymphoma, myeloma, lung cancer, prostate cancer, pancreatic cancer, colon cancer, breast cancer, liver cancer, or stomach cancer.
Compared with the prior art, the invention has the following beneficial effects:
According to the invention, firstly, the salvianolic acid B can be initially discovered to be used as a STING agonist through molecular docking, then, a Western blot and fluorescent quantitative PCR technology are utilized to determine the channel acting on the cGAS-STING, the activation of the cGAS-STING-TBK1 signal channel is induced, and the high expression of p-STING, p-IRF3 and p-TBK1/NAK in 4T1 cells is promoted. Finally, in a breast cancer mouse model, salB was used to demonstrate that mice survival was prolonged using in vivo pharmacodynamic studies. From the in-vivo and in-vitro point of view, the invention reveals that SalB old medicines are used newly, and the salvianolic acid B can be used as STING agonist and has better effect in anti-tumor treatment and prevention.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic diagram of the structures of salvianolic acid B and diABZI compounds
FIG. 2 is a schematic diagram showing molecular docking of salvianolic acid B and diABZI with STING protein
FIG. 3 is a graph showing Western blot results of salvianolic acid B and diABZI treated with the same
FIG. 4 is a schematic diagram showing the results of real-time fluorescent quantitative PCR after treatment with salvianolic acid B and diABZI at different concentrations
FIG. 5 is a schematic diagram of in vivo pharmacodynamic studies in SalB compound mice versus survival curves in mice
Detailed Description
The present invention will be described in detail with reference to specific examples. These embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. The technical means used in the examples are conventional means well known to those skilled in the art unless otherwise indicated. The test methods in the following examples are conventional methods unless otherwise specified. The reagents and materials employed, unless otherwise indicated, are commercially available.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Examples
1. The experimental method comprises the following steps:
1. the experimental materials and sources are as follows:
roswell Park Memorial Institute (RPMI) 1640 medium, penicillin/streptomycin mix, 0.25% trypsin was purchased from Gibco, china.
Salvianolic acid B (salvianolic acid B) was purchased from Vickers, diABZI was purchased from MCE.
P-STING, p-IRF3, p-TBK1/NAK, STING, TBK1/NAK, beta-actin are available from CELL SIGNALING, USA.
The 4T1 cell line was purchased from the national center for cell culture identification. 4T1 cells were grown in RPMI 1640 medium supplemented with 5% FBS, 1% penicillin/streptomycin, 1mM sodium pyruvate and 0.4mM glutamine at 37℃under 5% CO 2.
Balb/c mice 7-8 weeks old were purchased from beijing vitelli laboratory animal farming limited (beijing, china). All animal studies have passed the examination and approval of the animal ethics committee of the university of Tianjin traditional Chinese medicine and followed the guidelines for animal care of the laboratory animal administration committee.
2. Molecular docking method
Preparation of the receptor the desired protein crystal structure PDB (ID: 6 DXL) was downloaded from the PDB protein database, and the protein was subjected to pretreatment such as hydrogenation and charge by using AutoDouck1.5.7 software to remove water molecules and ligand structures in the protein, and used for the next docking study. And introducing the protein and the compound into AutoDockTools-1.5.7 together for molecular docking to obtain a 3D docking diagram of the protein and the compound. And scoring the docking capability based on a self-contained scoring system by the docking program, and finally obtaining the optimal combination mode combination energy value of the docking of each compound.
3. Western blotting
The compounds were diluted to appropriate concentrations (SalB. Mu. M, salB. Mu.10. Mu. M, salB. Mu. M, diABZI. Mu.M), 4T1 cells were selected, 4T1 cells were treated with salvianolic acid B at the above concentrations for 24 hours, and the effect of each compound on activation of STING signaling pathway and upstream and downstream related protein expression levels was investigated by WB analysis. The conventional WB experimental analysis and detection of the related protein level are completed through a series of operations including protein quantification, denaturation, gel preparation, sample addition, electrophoresis, membrane transfer, blocking, antibody incubation, exposure and development and the like.
4. Real-time fluorescent quantitative PCR
After treating 4T1 cells with SalB. Mu. M, salB 10, 10. Mu. M, salB 20, 20. Mu. M, diABZI. Mu.M for 24h, the cells were collected, total RNA was extracted using Trizol reagent, and RNA concentration was determined using NanoDropTM One (Thermo Scientific). qPCR amplification was performed using SuperScriptTMII RT (Invitrogen) synthetic cDNA and using ABITaqMan gene expression assays in the ABI QuantStudio system, GAPDH levels were analyzed and used to normalize specific gene mRNA expression levels.
5. SalB in vivo pharmacodynamics study of Compound mice
4T1 cells in the logarithmic growth phase were selected and subcutaneously inoculated at 1X 10 5 into the fourth mammary gland on the right side of BALB/c female mice to prepare a metastatic breast cancer tumor-bearing mouse model. When the tumor grows to 500mm 3, the tumor-bearing mice are divided into a control group and a SalB group, the administration dose is 15mg/kg, and the number of the mice in each group is 10. The administration is carried out twice a week, the administration mode is nasal inhalation administration, the state of tumor-bearing mice is monitored, and finally, a survival curve graph is drawn.
6. Data analysis
Statistical analysis was performed using SPSS17.0 and GRAPH PAD PRISM software. Statistical differences between the model group and the dosing group were determined using either T-test or one-way anova test. Data are expressed as mean ± standard deviation SD. Error bars represent standard deviations. P <0.05 was considered statistically significant.
2. Experimental results
1. Regarding molecular docking
The structure of 6DXL, salB and diABZI is obtained through protein structure modeling, salB is initially verified through molecular docking based on the thought of new use of old drugs (figure 2), and the novel use of SalB is discovered by finding that the STING agonist diABZI can be stably combined with 6DXL and SalB can be stably combined with 6DXL at the same time, and the combination energy values of the two are basically the same.
2. Western blotting
Western blot detection results show (FIG. 3), compared with a blank group (Ctrl) and a positive control group (diABZI), salB groups (5, 10, 20 mu M concentration) have an effect on the expression level of the cGAS-STING classical signal pathway related protein, wherein SalB different concentrations have obvious enhancement on the expression levels of p-STING, p-IRF3 and p-TBK 1/NAK. The invention is based on preliminary speculation of molecular docking, and salvianolic acid B can induce the activation of STING signal pathway, further discovers that salvianolic acid B activates cGAS-STING signal pathway through WB, and speculates that salvianolic acid B plays an anti-tumor role by activating cGAS-STING signal pathway.
3. Real-time fluorescent quantitative PCR
The results of real-time fluorescent quantitative PCR showed a different increase in the expression levels of the cGAS-STING signaling pathway-associated immune chemokines CCL5, CXCL9, CXCL10 at concentrations of 5, 10, 20. Mu.M in diABZI, salB groups compared to the control group (FIG. 4).
4. In vivo pharmacodynamic studies on SalB Compound mice
The in vivo pharmacodynamic results showed (fig. 5) that SalB mice survived longer by P <0.05 compared to the model group.
The above description is only of the preferred embodiments of the present application and is not intended to limit the present application, but various modifications and variations can be made to the present application by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (7)
1. A sting agonist, which is characterized by being salvianolic acid B.
2. The sting agonist of claim 1, wherein the salvianolic acid B has the formula C 36H30O16 and has the following structural formula:
3. the sting agonist of claim 1, wherein the sting agonist is further a pharmaceutically acceptable salt or derivative of salvianolic acid B.
4. Use of a STING agonist according to any one of claims 1 to 3 for inducing cGAS-STING-TBK1 signalling pathway.
5. Use of a sting agonist as claimed in any one of claims 1 to 3 in the treatment of a tumour.
6. Use of a STING agonist according to any one of claims 1 to 3 in the manufacture of a medicament for the prophylaxis or treatment of a tumour associated with the cGAS-STING-TBK1 signalling pathway.
7. The use according to claim 6, wherein the neoplasm includes, but is not limited to, any of leukemia, lymphoma, myeloma, lung cancer, prostate cancer, pancreatic cancer, colon cancer, breast cancer, liver cancer or stomach cancer.
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