CN118924890A - Application of trichosanthin agonizing TLR7 in enhancing immunoprotection efficacy of novel coronavirus vaccine - Google Patents
Application of trichosanthin agonizing TLR7 in enhancing immunoprotection efficacy of novel coronavirus vaccine Download PDFInfo
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Abstract
The invention provides application of trichosanthin in preparing a novel coronavirus vaccine immune adjuvant, wherein the trichosanthin and TLR7 molecules have high protein-protein specificity affinity, and the immune protection effect of the novel coronavirus vaccine is obviously enhanced by exciting TLR 7. This is an innovative application of traditional Chinese medicine trichosanthin to the promotion of immunoprotection efficacy of a novel crown vaccine, which enhances the immune response of the body to the vaccine and expands and enhances the protection of individuals with lower immunogens.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of trichosanthin excited TLR7 in preparation of a novel coronavirus vaccine immunoadjuvant.
Background
Toll-like receptors (Toll like receptor, TLR) are highly conserved important components of the innate immune system, and TLR3, 7, 8 and 9 expressed in intracellular membrane structures recognize viral and bacterial nucleic acids and elicit potent antiviral and antitumor immune responses. TLR7 is located on endosomal membranes of immune cells, expressed primarily in pDC and B cells, recognizes single-stranded ribonucleic acid (ssRNA) and signals via MyD 88-dependent pathways. Among natural ligands, guanosine-rich ORN activates TLR7 and TLR 8-dependent signaling. TLR7 plays a very important role in both antiviral innate immune responses and in the induction of adaptive immune production. The TLR7 signaling pathway, CD40 signaling pathway and BCR signaling pathway on B cells can synergistically promote differentiation of Antibody secreting cells (antibodies SECRETING CELLS, ASCs), involved in Antibody subtype conversion. More than 15 novel heterocyclic molecules, such as imidazoquinoline, pterin, pyrimidine, pyridine pyrimidine, pyrrole pyrimidine, and benzimidazole, have now been found to be identified as TLR7 agonists. Wherein imiquimod (R-837) has been approved by the FDA for marketing, there are a number of TLR7 agonists in the clinical development phase, mainly for two classes of indications: antiviral and tumor immunotherapy. R-837 can treat genital warts caused by human papilloma virus by enhancing antigen presentation and promoting antigen specific Th1 cell mediated immune response, and has been widely used as a therapeutic drug for viral dermatosis and superficial skin tumor clinically. Oral TLR7 agonist GS-9620 (Vesatolimod) has been used in a secondary clinical trial for chronic hepatitis B treatment and clinical trials for HIV treatment have been completed in a primary clinical stage. TQ-A3334 and SHR2150 are both currently in clinical stage one, mainly for tumor treatment. Therefore, the development and application of the TLR7 agonist have broad prospects.
However, a common disadvantage of TLR7 agonists is that they are reactive, promote humoral immunity, and at the same time, cause adverse systemic reactions, which have adverse effects on humans. Systemic immune related toxic side effects (such as systemic immune storm) caused by intravenous injection of R-837 greatly limit the further development and application of clinical dosage forms. How to exert the immunomodulatory effects of TLR7 agonists without adverse effects on the body remains a series of challenges. Trichosanthin (Trichosanthin, TCS) is isolated from the root tuber of Chinese medicinal fructus Trichosanthis, single-chain plant basic protein with molecular weight of 24kD, isoelectric point 9.4, composed of 247 amino acids, and protein crystal structure has been elucidated. The TCS has simple preparation and separation, low price and safe clinical application, and has been proved by researches, the trichosanthin has the functions of resisting tumor, early pregnancy, infection and the like, but no related researches disclose the application of the trichosanthin as a TLR7 agonist in enhancing the immunoprotection efficacy of the novel crown vaccine.
For the novel coronavirus vaccine, after normal people vaccinate according to a standard scheme and complete an immunization program, the antibody titer of 5% -10% of vaccinators still cannot reach the protective threshold (i.e. no response or weak response), and the normal people still cannot be immune protected after vaccination, so that the normal people possibly become new coronaries susceptible. At present, the occurrence of non-response and weak response of the novel crown vaccine is influenced by various factors, and the occurrence mechanism is not clear. In the preparation of the vaccine or the use of the vaccine, a proper adjuvant can be selected to help induce a more robust and durable immune response, which is of great significance for the prevention of novel coronaviruses.
Disclosure of Invention
A first object of the present invention is to provide an application of trichosanthin in preparing TLR7 agonists, wherein trichosanthin has a specific protein affinity effect with TLR7 protein and can be used as an effective agonist of TLR 7.
A second object of the present invention is to provide the use of trichosanthin in the preparation of a novel coronavirus vaccine immunoadjuvant.
In order to achieve the above purpose, the invention discloses application of trichosanthin in preparing TLR7 agonists, which is suitable for improving TLR7 in preventive and therapeutic vaccines.
The invention also discloses application of trichosanthin in preparing novel coronavirus vaccine immunoadjuvant. Specific protein affinity exists between trichosanthin and TLR7 protein, and the immunoprotection efficacy of the novel coronavirus vaccine is obviously enhanced by exciting TLR 7.
As a preferred embodiment, the novel coronavirus vaccine includes an oral vaccine, an intravenous vaccine, an arterial vaccine, a mucosal administration vaccine, an intramuscular injection vaccine, a subcutaneous injection vaccine, an organ injection vaccine, or an intraperitoneal injection vaccine.
As a preferred embodiment, the novel coronavirus vaccines include, but are not limited to, a novel coronavirus inactivated vaccine of klliforum and a novel coronavirus inactivated vaccine (Vero cells).
As a preferred technical scheme of the invention, the immune vaccine adjuvant and a novel coronavirus vaccine matched with the immune vaccine adjuvant are applied simultaneously.
As a preferred embodiment, the vaccine immunoadjuvant is used as a constituent component of the novel coronavirus vaccine preparation and is applied simultaneously with the vaccine, and the immunoadjuvant can also be applied at intervals with the novel coronavirus vaccine matched with the vaccine.
In the invention, the trichosanthin can be used simultaneously with the novel coronavirus vaccine or separately. In the process of simultaneous use, the trichosanthin can act as a constituent component of the vaccine; in the process of separate use, the trichosanthin can be used before and after the use of the novel coronavirus vaccine, preferably after the injection of the vaccine, and the use modes include injection, oral administration and the like. The trichosanthin can improve the immune effect of the novel coronavirus vaccine, and especially for the vaccinating personnel who do not respond or respond poorly to the vaccine, the trichosanthin can promote the personnel to obtain better immune effect.
The invention has the advantages that the invention provides the high affinity of the protein specificity between the trichosanthin and the TLR7 molecule, the immune protection efficacy of the novel coronavirus vaccine is obviously enhanced by exciting the TLR7, the research and development and the updating of the novel coronavirus vaccine can be better promoted by reasonably utilizing the trichosanthin, the immune response of an organism to the novel coronavirus vaccine is enhanced and the protection to an individual is enlarged and enhanced under the condition of using the same immunogen.
Drawings
Fig. 1: the potential binding sites of TCS and mouse TLR7 protein are shown.
Fig. 2: co-localized immunofluorescence profile of TCS and TLR7 binding to each other in B cells.
Fig. 3: a graph of the detection of affinity between TCS and mouse, human TLR7 protein.
Fig. 4: TCS increases mouse antigen-specific antibody levels and enhances TLR7 expression in B cells.
Fig. 5: TCS produces a significant promotion of proliferation of germinal center B cells and plasma cells through TLR7 signaling pathways.
Detailed Description
Hereinafter, the technology of the present invention will be described in detail with reference to the specific embodiments. It should be understood that the following detailed description is merely intended to aid those skilled in the art in understanding the invention, and is not intended to limit the invention.
In the following examples, reagents and consumables were purchased from manufacturers of reagents conventional in the art unless specifically stated otherwise; unless otherwise indicated, all methods and techniques used are those conventional in the art.
EXAMPLE 1 high affinity of TCS with TLR7
TCS is predicted to have higher affinity for mouse TLR7 protein by molecular docking autodock. In the protein structure database PDB, TCS number 1NLI, mouse TLR7 protein number 5B 1R, predicted by website ClusPro for both conjugates and analyzed by PDBePISA for multiple binding sites with an interaction surface area ofThe energy was-9.2 kcal/mol, as shown in FIG. 1: TCS and TLR7 have a strong affinity.
In vitro immunofluorescence co-localization experiments prove that TCS and TLR7 in mouse spleen pan-B cells are mutually combined. After in vitro co-culturing of TCS and pan-B cells obtained by spleen sorting of WT C57BL/6J female mice, immunofluorescence co-localization detection is carried out by using a fluorescence confocal microscope, as shown by the result in FIG. 2, green fluorescence representing TCS and red fluorescence representing TLR7 can be overlapped at the same position of B cells to form yellow fluorescence, which indicates that TCS and TLR7 are combined in B cells.
The SPR technique was used to detect and verify the presence of interactions between TCS and TLR7 through the Biacore T200 full-function molecular interaction detection system. TCS is used as a ligand to be fixed on the surface of a CM5 chip, the coupling amount is 13896.9RU, and the combination of mouse and human TLR7 recombinant proteins with different concentrations and the TCS is detected. As shown in FIG. 3, TCS binds to mouse TLR7 protein with an affinity of 92.23nM, ka (1/Ms) of 4.884E+4, kd (1/s) of 0.04504 and KD (M) of 9.223E-7; TCS binds to human TLR7 protein with an affinity of 4.879. Mu.M, ka (1/Ms) of 4.359E+4, kd (1/s) of 0.2127 and KD (M) of 4.879E-7, further confirming the presence of specific protein affinity effects between TCS and TLR7 protein.
Example 2 tcs enhances the immune response of mice to novel coronavirus vaccines and upregulates TLR7 expression
Mouse immunization experiments demonstrate that TCS can effectively enhance mouse-specific antibody levels and remain for a longer period of time. Experiments mice were immunized with a novel coronavirus inactivated vaccine of klift (Sinovac), 6-week-old WT C57BL/6J female mice were randomly divided into two groups, a vaccine independent group (Sinovac) and a TCS mixed vaccine group (TCS/Sinovac), 5 each. Specifically, the TCS/Sinovac group: preparing 20 mug/ml TCS, taking 50 mu l and 100 mu l of the total volume of 50 mu l Sinovac to immunize the mice through the foot pad; sinovac groups: mice were immunized with 50 μl of injectable phosphate solution in a total volume of 50 μl l Sinovac μl via footpad. Boosting is performed every three weeks after primary immunization, blood is collected through the ocular fundus venous plexus of the mice one week after each immunization, and serum is left for ELISA detection. The TCS solution used in the experiment is prepared from radix Trichosanthis protein powder obtained by extracting and purifying radix Trichosanthis, wherein the radix Trichosanthis protein powder is derived from dried root of Trichosanthes kirilowii Maxim Trichosanthes kirilowii Maxim belonging to Cucurbitaceae, and is prepared with injectable phosphate solution. The mouse serum RBD-specific IgG antibody levels were found to be significantly elevated by ELISA detection, and high levels of antibody titers could be maintained until week 13. At week 13 post priming, mice spleen was taken and pan-B cell TLR7 mRNA levels in spleen were detected, and TLR7 mRNA levels in experimental group mice B cells were found to be significantly elevated compared to control group (fig. 4).
In vitro experiments show that TCS can obviously promote proliferation of germinal center B cells and plasma cells through TLR7 signal channels. In vitro separation of pan-B cells in spleen of WT female mice, flow detection of cell proportion after addition of TCS at different concentrations, and significant increase of germinal center B cell and plasma cell proportion, especially when TCS at 0.5 μg/ml concentration is added. This change, in turn, disappeared upon addition of TLR7 inhibitor IRS661, suggesting that TCS functions immunopotentiating through TLR7 (fig. 5).
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.
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