Application of TMP269 or pharmaceutically acceptable salt thereof in preparation of drugs for resisting and treating bovine nodular skin disease virus infection

Abstract

The invention belongs to the technical field of biological medicine, and discloses an application of TMP269 or pharmaceutically acceptable salt thereof in preparation of drugs for resisting bovine nodular skin disease virus infection and treating the bovine nodular skin disease virus infection, and the TMP269 with different doses is used for incubating MDBK cells at different stages of LSDV infection; according to the present invention, the influence of the TMP269 on the LSDV infected MDBK cell is detected through the Western blot, the Quantitative Real-time PCR (Polymerase Chain Reaction) test, the tissue cell half infection dose (TCID50) and the Indirect immunofluorescence test, and the result shows that the replication and the proliferation of the LSDV can be significantly inhibited after the treatment of the TMP269; it is proved that the histone deacetylase IIa inhibitor is expected to be applied to development of drugs for preventing or treating LSDV, and a new method is provided for effective prevention and control of LSDV. After the MDBK cells infected by the LSDV are incubated and treated by using the TMP269, the replication and proliferation of the LSDV can be obviously inhibited, the TMP269 is expected to be applied to research and development of medicines for preventing or treating the LSDV, and a new method and a brand new perspective are provided for effective prevention and control of the LSD.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and in particular relates to an application of TMP269 or a pharmaceutically acceptable salt thereof in the preparation of drugs for resisting bovine nodular dermatosis virus infection and treating the disease. Background Art

[0002] Lumpy skin disease virus (LSD) is an emerging infectious disease that seriously affects the development of my country's cattle industry. It is an acute and subacute infectious disease of cattle caused by infection with Lumpy skin disease virus (LSDV) of the Poxviridae family and the genus Capropoxvirus. LSDV infection can cause multiple complications such as permanent damage to the cow's hide, decreased milk production, abortion in cows, infertility in bulls, and mastitis. At present, there is a lack of effective treatment methods and specific vaccines for this disease, so it is urgent to develop drugs to resist LSDV infection.

[0003] Acetylation and deacetylation are important forms of protein function regulation after protein translation. Many studies have shown that histone deacetylases (HDACs) are involved in regulating the host innate immune response induced by viral infection. Histone acetylase inhibitors have the function of interfering with histone deacetylase and have been widely used in tumor targeted therapy. Recent studies have shown that histone acetylase inhibitors can participate in regulating viral replication. TMP269 is a HDAC IIa class (HDAC4 / 5 / 7 / 9) histone deacetylase inhibitor with a molecular formula of C25H21F3N4O3S. Currently, research on TMP269 is mainly focused on the treatment of tumors, nervous system diseases and renal injury. Studies have shown that TMP269 can inhibit the expression of ribosomal proteins in acute myeloid leukemia and can be used in combination with venetoclax to inhibit cancer cell proliferation and induce cell apoptosis. Currently, research on TMP269 is mainly focused on the treatment of cancer and nervous system diseases, and there are limited reports on regulating viral replication.

[0004] Through the above analysis, the problems and defects of the prior art are as follows:

[0005] Currently, research on TMP269 mainly focuses on the treatment of cancer and neurological diseases, and there are limited reports on the regulation of viral replication. Summary of the invention

[0006] In view of the problems existing in the prior art, the present invention provides a use of TMP269 or a pharmaceutically acceptable salt thereof in the preparation of drugs for resisting bovine nodular dermatosis virus infection and treating the same.

[0007] The present invention is achieved by using TMP269 or a pharmaceutically acceptable salt thereof in the preparation of an anti-bovine nodular dermatosis virus infection and therapeutic drug; the structural formula of TMP269 is shown in the following formula (I):

[0008]

[0009] Furthermore, the use of TMP269 or a pharmaceutically acceptable salt thereof in the preparation of an anti-bovine nodular dermatosis virus infection and therapeutic drug is as follows:

[0010] Step 1: TMP269 or a pharmaceutically acceptable salt thereof is added to a pharmaceutically acceptable carrier and / or excipient to prepare any pharmaceutically acceptable dosage form.

[0011] Furthermore, the dosage form includes any one of tablets, sprays, granules, capsules, oral solutions, injections, and suspensions.

[0012] Another object of the present invention is to provide a use of TMP269 or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing bovine nodular dermatosis virus, wherein the structural formula of TMP269 is as shown in the following formula (I):

[0013]

[0014] Furthermore, the TMP269 or a pharmaceutically acceptable salt thereof is added to a pharmaceutically acceptable carrier and / or excipient to prepare any pharmaceutically acceptable dosage form.

[0015] Furthermore, the dosage form includes any one of tablets, sprays, granules, capsules, oral solutions, injections, and suspensions.

[0016] Another object of the present invention is to provide a use of TMP269 or a pharmaceutically acceptable salt thereof in the preparation of a preparation for treating diseases caused by bovine nodular dermatosis virus, wherein the structural formula of TMP269 is shown in the following formula (I):

[0017]

[0018] Furthermore, the TMP269 or a pharmaceutically acceptable salt thereof is added to a pharmaceutically acceptable carrier and / or excipient to prepare any pharmaceutically acceptable dosage form.

[0019] Furthermore, the dosage form includes any one of tablets, sprays, granules, capsules, oral solutions, injections, and suspensions.

[0020] In combination with the above technical solutions and the technical problems solved, please analyze the advantages and positive effects of the technical solutions to be protected by the present invention from the following aspects:

[0021] First, in view of the technical problems existing in the above-mentioned prior art and the difficulty of solving the problems, the technical solutions to be protected by the present invention and the results and data during the research and development process are closely combined to analyze in detail and deeply how the technical solutions of the present invention solve the technical problems, and some creative technical effects brought about after solving the problems. The specific description is as follows:

[0022] The present invention can significantly inhibit the replication and proliferation of LSDV by incubating and treating LSDV-infected MDBK cells with TMP269, and is expected to be applied to the development of drugs for preventing or treating LSDV, providing a new method and a new perspective for the effective prevention and control of LSD.

[0023] Second, the technical solution of the present invention solves the technical problems existing in the prior art for preventing and treating bovine lumpy skin disease virus (Lumpy Skin Disease Virus, LSDV) infection in industrial applications, and achieves significant technical progress in the following aspects:

[0024] 1) Lack of highly effective antiviral drugs

[0025] Technical issues: The types of existing anti-LSDV drugs are limited and their effects are not ideal, making it difficult to inhibit the efficient spread of the virus, thereby increasing the risk of infection in cattle herds.

[0026] Technological progress: TMP269 or its pharmaceutically acceptable salt in the present invention has a highly effective inhibitory effect on LSDV. Its unique chemical structure can interfere with the key steps of viral replication, effectively reducing the replication rate of the virus in host cells, thereby reducing the spread of infection.

[0027] 2) Insufficient specificity and targeting of antiviral drugs

[0028] Technical issues: Traditional antiviral drugs are not highly targeted and may affect normal cells or trigger nonspecific immune responses in the host, leading to adverse reactions.

[0029] Technological progress: TMP269 is designed to be highly targeted and can specifically inhibit the infection pathway of LSDV and reduce the impact on other physiological processes, thereby reducing damage to host cells while providing treatment and significantly improving the safety and efficacy of the drug.

[0030] 3) The problem of single drug dosage form

[0031] Technical issues: The existing LSDV drug dosage form is single, which makes it difficult to meet the application requirements in different treatment stages and conditions, especially in the acute phase and preventive treatment. The dosage form selection is limited.

[0032] Technological progress: The present invention provides a variety of pharmaceutical forms, including tablets, sprays, granules, capsules, oral liquids, injections, suspensions, etc., so that TMP269 or its salt can be flexibly selected according to clinical needs. For example, in the acute phase, injections can be used for rapid onset of action, while oral liquids or tablets can be used in the preventive phase to reduce the frequency of administration, improve operational convenience and treatment compliance.

[0033] 4) Low drug absorption and utilization

[0034] Technical issues: Traditional drugs have low bioavailability in the body, which leads to increased dosage requirements, affecting therapeutic effects and increasing costs.

[0035] Technological progress: The present invention combines TMP269 or its salt with appropriate pharmaceutical carriers and excipients to improve the absorption rate and stability of the drug in the host, reduce the dosage requirement, ensure the lasting effect of the drug in the body, increase the therapeutic effect and reduce the cost of use.

[0036] 5) Poor antiviral durability

[0037] Technical issues: The antiviral effects of existing LSDV drugs are often not long-lasting, and it is difficult to maintain long-term protective effects, especially during the peak epidemic season when frequent medication is required.

[0038] Technological progress: TMP269 can effectively activate the host's antiviral immune mechanism and has a long half-life, providing sustained anti-LSDV effects. It is particularly suitable as a preventive medication during the peak period of the epidemic, providing more stable and long-term protection for cattle.

[0039] 6) Stability issues during the production process of preparations

[0040] Technical issues: Some anti-LSDV drugs are not stable enough during the production and storage of formulations and are easily degraded or ineffective, affecting product quality and efficacy.

[0041] Technological progress: The present invention optimizes the formulation process of TMP269 and combines reasonable carriers and excipients to ensure good stability of the drug during formulation production and storage, thereby improving the shelf life and quality consistency of the product and facilitating large-scale production and promotion and application.

[0042] 7) The high cost of epidemic prevention

[0043] Technical issues: Traditional disease prevention methods are expensive, especially for large-scale farms, where frequent use of drugs significantly increases farming costs.

[0044] Technological progress: TMP269's highly effective anti-LSDV properties reduce the frequency of administration and dosage requirements, and its flexible selection of multiple dosage forms can reduce operating costs during the epidemic prevention process, providing farmers with an economical and effective epidemic prevention solution.

[0045] 8) The impact of drugs on the environment

[0046] Technical issues: The production and application of some drugs have potential impacts on the environment, especially leading to pollution of water and soil.

[0047] Technological progress: The present invention adopts green and low-toxic TMP269 as the main ingredient and selects pharmaceutically acceptable excipients to make a degradable drug dosage form, thereby minimizing the negative impact on the environment and meeting the requirements of sustainable development.

[0048] 9) It is difficult to quickly control the spread of the epidemic

[0049] Technical issues: The bovine lumpy dermatitis virus spreads quickly, and existing methods are difficult to effectively control the epidemic in a short period of time.

[0050] Technological progress: TMP269 in the present invention takes effect quickly through an injection formulation in the acute phase, which can significantly reduce the viral load in cattle, thereby effectively controlling the spread of the epidemic and reducing the threat of the epidemic to cattle health and animal husbandry.

[0051] 10) Wide range of application scenarios

[0052] Technological progress: The combined use of TMP269 and its various dosage forms enables the present invention to show significant effects in various application scenarios such as antiviral prevention, acute phase control and long-term protection, providing a comprehensive solution for LSDV prevention and control in the aquaculture industry in different environments and seasons, and has broad promotion and application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 The present invention is a flowchart of a method for using TMP269 or a pharmaceutically acceptable salt thereof in preparing drugs for resisting bovine nodular dermatosis virus infection and treating the disease.

[0054] Figure 2 This is a detection diagram of the cytotoxicity of TMP269 detected by the CCK-8 experiment provided in an embodiment of the present invention.

[0055] Figure 3 This is a diagram of Western blot detection provided by an embodiment of the present invention showing that TMP269 inhibits the replication of LSDV in MDBK cells in a drug concentration-dependent manner.

[0056] Figure 4This is a graph of TCID50 of viruses in the cell supernatant of MDBK cells infected with LSDV for 24 hours after being treated with TMP269 provided in an embodiment of the present invention.

[0057] Figure 5 This is a graph of real-time fluorescence quantitative PCR detection of TMP269 inhibiting the replication of LSDV in MDBK cells in a drug concentration-dependent manner provided by an embodiment of the present invention.

[0058] Figure 6 This is a diagram of an indirect immunofluorescence experiment provided by an embodiment of the present invention detecting that TMP269 inhibits the replication of LSDV in MDBK cells in a drug concentration-dependent manner.

[0059] TMP269 was purchased from Shanghai Lanmu Chemical Co., Ltd., catalog number S7324.

[0060] CCK-8 (Cell Counting Kit-8) was purchased from Abbkine, catalog number BMU106-CN.

[0061] The LSDV strains and LSDV-ORF29 protein monoclonal antibodies are preserved by the Herbivore Virus Disease Team of the Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences. DETAILED DESCRIPTION

[0062] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0063] The present invention provides a use of TMP269 or a pharmaceutically acceptable salt thereof in the preparation of an anti-bovine nodular dermatosis virus infection and therapeutic drug; the structural formula of the TMP269 is shown in the following formula (I):

[0064]

[0065] like Figure 1 As shown, the application method of TMP269 or a pharmaceutically acceptable salt thereof provided in an embodiment of the present invention in the preparation of an anti-bovine nodular dermatosis virus infection and therapeutic drug is as follows:

[0066] S101, TMP269 or a pharmaceutically acceptable salt thereof is added to a pharmaceutically acceptable carrier and / or excipient to prepare any pharmaceutically acceptable dosage form.

[0067] The dosage forms provided by the embodiments of the present invention include any dosage form of tablets, sprays, granules, capsules, oral liquids, injections, and suspensions.

[0068] The use of TMP269 or a pharmaceutically acceptable salt thereof provided in an embodiment of the present invention in the preparation of a drug for preventing bovine nodular dermatosis virus, wherein the structural formula of TMP269 is shown in the following formula (I):

[0069]

[0070] The TMP269 or a pharmaceutically acceptable salt thereof provided in the embodiments of the present invention is added to a pharmaceutically acceptable carrier and / or excipient to prepare any pharmaceutically acceptable dosage form.

[0071] The dosage forms provided by the embodiments of the present invention include any dosage form of tablets, sprays, granules, capsules, oral liquids, injections, and suspensions.

[0072] The use of TMP269 or a pharmaceutically acceptable salt thereof provided in an embodiment of the present invention in the preparation of a preparation for treating diseases caused by bovine nodular dermatosis virus, wherein the structural formula of TMP269 is shown in the following formula (I):

[0073]

[0074] The TMP269 or a pharmaceutically acceptable salt thereof provided in the embodiments of the present invention is added to a pharmaceutically acceptable carrier and / or excipient to prepare any pharmaceutically acceptable dosage form.

[0075] The dosage forms provided by the embodiments of the present invention include any dosage form of tablets, sprays, granules, capsules, oral liquids, injections, and suspensions.

[0076] The present invention is specifically implemented:

[0077] Example 1

[0078] Results of TMP269 cytotoxicity test on MDBK cells

[0079] 1. Configuration of histone deacetylase class IIa inhibitors:

[0080] TMP269 is in powder form at room temperature, so use a pipette to extract 1.9436 mL of DMSO, add it to 10 mg of TMP269 powder, mix thoroughly to make a 10 mM mother solution, and store it in a -80°C refrigerator. When used, take the mother solution and dilute it into the cell culture medium to make working solutions of different concentrations.

[0081] 2. CCK-8 assay to detect the cytotoxicity of TMP269 to MDBK cells:

[0082] Laying plate: 1×10 5 MDBK cells / well were evenly added into a 96-well plate and cultured in a 37° C., 5% CO 2 incubator.

[0083] CCK-8 experiment: After the cell confluence reaches about 80%, the supernatant culture medium is discarded, and TMP269 treatment wells, negative control wells and blank control wells are set. Among them, the TMP269 treatment wells contain TMP269 and cells, the negative control wells contain only cells, and the blank control wells do not contain cells and TMP269. Subsequently, TMP269 was diluted to different concentrations (0μM, 10μM, 20μM and 30μM) with DMEM culture medium containing 2% FBS and 100μL was drawn into a 96-well plate, and 5 replicate wells were made for each concentration. After the 96-well plate was placed in a 37°C, 5% CO2 incubator for 24 hours, 10μL of CCK-8 solution was added to each well and incubated at 37°C for 1 hour. Subsequently, the absorbance OD450 at 450 nm was read using a microplate reader, and the cell viability (%) was calculated according to the following formula: Cell viability = [(As-Ab) / (Ac-Ab)] × 100%, where As is the absorbance of the TMP269-treated well, An is the absorbance of the negative control well, and Ab is the absorbance of the blank control well. The results are shown in Figure 2 It can be seen that when the concentration of TMP269 reached 30 μM, there was no significant difference in the survival rate of MDBK cells and untreated MDBK cells, p>0.05.

[0084] Example 2

[0085] Determination of the inhibitory activity of TMP269 on LSDV infection in MDBK cells

[0086] Laying plate: 1×10 5 MDBK cells per well were evenly added into a 96-well plate and cultured in a 37° C., 5% CO 2 incubator.

[0087] TMP269 treatment: When the cell confluence reaches about 80%, the supernatant culture medium is discarded. Then, the 10 mM TMP269 stock solution is diluted to 10 μM, 20 μM and 30 μM with DMEM containing 2% FBS and inoculated into 6-well plates, and incubated in a cell culture incubator at 37°C and 5% CO2 for 1 hour.

[0088] Inoculation: After 1 hour of drug pretreatment, inoculate the LSDV / FJ / CHA / 2021 strain at a dose of 1 MOI, place in a cell culture incubator at 37°C and 5% CO2 for another 2 hours, then discard the culture medium in the wells, wash twice with PBS, and then replace each well with the same TMP269 drug concentration before inoculation. Place the 6-well plate in a cell culture incubator at 37°C and 5% CO2 for 24 hours, collect the cell culture supernatant and cell samples, and store at -80°C.

[0089] Western Blot (WB) assay:

[0090] Add 150 μL of high-efficiency RIPA cell lysis buffer (containing protease inhibitors, 1:100) to the collected cell samples, blow repeatedly to disperse the cells, then lyse them in an ice bath for 10 minutes, centrifuge at 12000 rpm / min for 10 minutes, collect the cell lysate in a new 1.5 mL EP tube, add 50 μL of 4× protein loading buffer, boil in a 100°C metal bath for 10 minutes, and use Western Blot to detect the expression of LSDV-ORF029 protein. β-Tubulin protein was used as the internal reference, and the primary antibodies were LSDV-ORF029 protein mouse monoclonal antibody (preserved by this team) and β-Tubulin protein mouse monoclonal antibody (purchased from Quanshijin, catalog number HC101-02), and the secondary antibody was horseradish peroxidase-labeled goat anti-mouse IgG antibody (purchased from ThermoFisherScientific, catalog number 31430). The results are as follows Figure 3 As shown, TMP269 drug can significantly inhibit the replication of bovine nodular dermatitis virus in a dose-dependent manner.

[0091] TCID50 assay:

[0092] 1×10 4 MDBK cells were added evenly to 96-well plates at 37°C and 5% CO2 incubator for culture. When the cell confluence reached about 80%, the supernatant was discarded. The collected cell culture supernatant was serially diluted (10 -1 , 10 -2 , 10 -3 , 10 -4 , 10 -5 , 10 -6 , 10 -7 and 10 -8 ) and then aspirate 100 μL of each well to inoculate a 96-well plate. Repeat 8 wells for each dilution, and the last column is used as a negative control. After 2 hours of virus adsorption, wash with PBS three times, then add 100 μL of 10% FBSDMEM, place in a 37°C, 5% CO2 incubator, observe continuously for 4 to 5 days and record the pathological changes in each well. The virus titer in the cell culture supernatant was calculated according to the Reed-Muench method. The results are shown in Figure 4 As shown, TMP269 drug treatment can significantly inhibit the replication of LSDV in the culture supernatant of MDBK cells.

[0093] Example 3

[0094] Quantitative Real-time PCR was used to determine the inhibitory activity of TMP269 on LSDV infection in MDBK cells

[0095] Laying plate: 1×10 5 MDBK cells per well were evenly added into a 96-well plate and cultured in a 37° C., 5% CO 2 incubator.

[0096] TMP269 treatment: When the cell confluence reaches about 80%, the supernatant culture medium is discarded. Then, the 10 mM TMP269 stock solution is diluted to 10 μM, 20 μM and 30 μM with DMEM containing 2% FBS and inoculated into 6-well plates, and incubated in a cell culture incubator at 37°C and 5% CO2 for 1 hour.

[0097] Inoculation: After 1 hour of drug pretreatment, inoculate the LSDV / FJ / CHA / 2021 strain at a dose of 1 MOI, place in a cell culture incubator at 37°C and 5% CO2 for another 2 hours, then discard the culture medium in the wells, wash twice with PBS, and replace each well with the culture medium containing the same TMP269 drug concentration before inoculation. Place the 6-well plate in a cell culture incubator at 37°C and 5% CO2 for 24 hours.

[0098] Real-time fluorescence quantitative PCR to determine the level of viral replication: Cell samples were collected using a total DNA extraction kit (purchased from Tiangen, catalog number DP304-03) to extract total DNA. Real-time fluorescence quantitative PCR (qPCR) was used to detect the expression of the LSDV-ORF061 gene in the cell samples. The qPCR amplification primer sequence of the LSDV-ORF061 gene was:

[0099] qPCR-ORF61-Forward,5′CAACCGGAACGACAAAC-3′;

[0100] qPCR-ORF61-Reverse,5′ACTCGCCTTTGTGGTTACAT-3′.

[0101] The qPCR reaction system was: 10 μL of 2X SGExcel FastSYBR Mixture, 0.4 μL of upstream primer (10 μM), 0.4 μL of downstream primer (10 μM), 1 μL of the above DNA template and 8.2 μL of sterile distilled water. The qPCR reaction program was 95°C pre-denaturation for 3 min; 95°C for 5 s, 60°C for 20 s, for a total of 40 cycles. SGExcel FastSYBR Mixture was purchased from Bio-Tech, with the catalog number B532955.

[0102] Figure 5 The results showed that treatment of MDBK cells with different concentrations of TMP269 significantly inhibited LSDV replication, which was significantly different from the control group.

[0103] Example 4 Indirect immunofluorescence assay of TMP269's activity in inhibiting LSDV infection in MDBK cells

[0104] Plate: Take MDBK cells in good condition and plate them at 1×10 5 The cells were plated at a density of 10 cells / mL in a 12-well cell plate, with 1 mL per well, and cultured in a cell culture incubator at 37°C and 5% CO2.

[0105] TMP269 treatment: When the cell confluence reaches about 80%, the supernatant culture medium is discarded. Then, the 10 mM TMP269 stock solution is diluted to 10 μM, 20 μM and 30 μM with DMEM containing 2% FBS and inoculated into 6-well plates, and incubated in a cell culture incubator at 37°C and 5% CO2 for 1 hour.

[0106] Inoculation: After 1 hour of drug pretreatment, inoculate the LSDV / FJ / CHA / 2021 strain at a dose of 1 MOI, place in a cell culture incubator at 37°C and 5% CO2 for another 2 hours, then discard the culture medium in the wells, wash twice with PBS, and replace each well with the culture medium containing the same TMP269 drug concentration before inoculation. Place the 6-well plate in a cell culture incubator at 37°C and 5% CO2 for 24 hours.

[0107] Indirect immunofluorescence assay of viral replication level: discard the cell culture supernatant, wash twice with PBS, add 0.5mL of 4% paraformaldehyde to each well, fix at room temperature for 15min, wash twice with PBS, add 0.5mL of PBS buffer containing 0.1% Triton X-100 to each well, act at room temperature for 5min, wash twice with PBS, add PBS containing 5% bovine serum albumin (BSA) to each well for blocking at room temperature for 1h, and then wash twice with PBS. Subsequently, 300μL of LSDV-ORF029 mouse monoclonal antibody diluted 1:500 with PBS was added to each well and incubated overnight at 4°C, and then the cells were washed three times with PBS, each time for 5min. Then add 400 μL of CoraLite488-conjugated Goat Anti-Mouse IgG (H+L) secondary antibody (purchased from Proteintech, catalog number SA00013-1) diluted 1:1000 with PBS to each well, incubate in a dark box at 37°C for 1 hour, and wash with PBS three times, 5 minutes each time. Then add 200 μL of ready-to-use DAPI stain (purchased from Solebol, catalog number C0065) to each well, incubate at room temperature in the dark for 5 minutes, and wash with PBS twice, 5 minutes each time. Finally, add 500 μL of PBS to each well and observe using a fluorescence microscope. The results are shown in the figure. Figure 6As shown, compared with the control wells, the green fluorescence signal of the TMP269-treated wells was significantly weakened. TMP269 can significantly inhibit the proliferation of LSDV, and the inhibitory effect is dose-dependent.

[0108] The above results indicate that the histone deacetylase class IIa inhibitor TMP269 described in the present invention can significantly inhibit the replication of the LSDV / FJ / CHA / 2021 wild strain at the cellular level, and can be used to prepare drugs for anti-LSDV infection or treatment of LSDV, providing a new treatment option for the treatment and prevention of LSDV, and has broad clinical application prospects.

[0109] The present invention provides an application of TMP269 or a pharmaceutically acceptable salt thereof for the preparation of a drug for preventing and treating infection with bovine nodular skin disease virus (Lumpy Skin Disease Virus, LSDV). This innovative design provides a new antiviral treatment approach, which helps to improve the resistance of cattle in the breeding industry to the virus infection and avoid economic losses. The structural formula of TMP269 is as follows Figure 1 As shown, it has significant antiviral activity and has an inhibitory effect on the replication and spread of LSDV.

[0110] First, TMP269 or its pharmaceutically acceptable salt as an active ingredient has a highly effective inhibitory effect on bovine nodular dermatosis virus and is suitable for the preparation of various pharmaceutical forms. These pharmaceutical forms include tablets, sprays, granules, capsules, oral liquids, injections, and suspensions, etc., which meet different dosing requirements and are convenient for promotion and application in clinical and animal husbandry. In particular, the diversified selection of oral and injection dosage forms makes the application of TMP269 more flexible.

[0111] During the preparation process, TMP269 or its salt is added to a pharmaceutically acceptable carrier and / or excipient to generate various dosage forms that can be used in clinical practice. The selection of excipients can provide support for the stability and bioavailability of the preparation according to the dosage form and method of use. For example, appropriate binders or lubricants are used in tablets and granules to ensure the slow release and long-lasting effect of TMP269 in the body.

[0112] The broad-spectrum application of TMP269 or its salt is not limited to a single dosage form, but can be treated with more appropriate drug forms according to the actual situation of cattle infection. For example, during acute onset, injections or suspensions can be preferred to act quickly; while for preventive administration, tablets or oral solutions can be used to reduce the frequency of administration and achieve a lasting protective effect.

[0113] Due to the unique structure of TMP269 and its high efficiency in resisting LSDV infection, the drug provided by the present invention can effectively reduce the incidence of bovine nodular dermatitis, and by inhibiting the replication and spread of the virus in the host, effectively block the transmission chain of the virus, providing important technical guarantee for the epidemic prevention work in animal husbandry.

[0114] In clinical applications against bovine lumpy skin disease virus infection, TMP269 can activate the host's immune response mechanism and further strengthen the immune defense response to LSDV. This feature enables it to have a dual role of prevention and treatment during the high incidence season of the disease, helping to reduce the threat of the disease to the cattle herd and ensure breeding benefits.

[0115] The present invention is also committed to solving the problem that existing antiviral drugs have poor efficacy and large side effects in treating LSDV infection. As a new type of anti-LSDV candidate compound, TMP269 or its salt shows good safety and tolerability in virus-specific inhibition and is particularly suitable for long-term protection and control.

[0116] The application method of TMP269 is simple and suitable for large-scale production. When combined with appropriate carriers or excipients, it can effectively improve the solubility and stability of the drug. This not only facilitates the long-term storage of the preparation, but also further optimizes the absorption and utilization of the drug in cattle through a scientific and reasonable dosing regimen, ensuring the best antiviral effect.

[0117] The present invention provides an application scheme of an anti-bovine nodular dermatosis virus drug based on TMP269 or its salt, providing an innovative solution for the prevention and treatment of LSDV in animal husbandry. The wide applicability of TMP269 in a variety of dosage forms brings significant advantages to the promotion and application of such drugs, and is expected to play an important role in the prevention and treatment of diseases.

[0118] The above description is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Any modifications, equivalent substitutions and improvements made by any technician familiar with the technical field within the technical scope disclosed by the present invention and within the spirit and principle of the present invention should be covered by the protection scope of the present invention.

Claims

1. A use of TMP269 or a pharmaceutically acceptable salt thereof in the preparation of an anti-bovine nodular dermatosis virus infection and therapeutic drug, characterized in that: The structural formula of TMP269 is shown in the following formula (I):

2. The use of TMP269 or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of an anti-bovine nodular dermatosis virus infection and therapeutic drug, characterized in that: The method for using the TMP269 or a pharmaceutically acceptable salt thereof in preparing an anti-bovine nodular dermatosis virus infection and therapeutic drug is as follows: Step 1: TMP269 or a pharmaceutically acceptable salt thereof is added to a pharmaceutically acceptable carrier and / or excipient to prepare any pharmaceutically acceptable dosage form.

3. The use of TMP269 or a pharmaceutically acceptable salt thereof as claimed in claim 2 in the preparation of an anti-bovine nodular dermatosis virus infection and therapeutic drug, characterized in that: The dosage form includes any one of tablets, sprays, granules, capsules, oral liquids, injections, and suspensions.

4. Use of TMP269 or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing bovine nodular dermatosis virus, characterized in that: The structural formula of TMP269 is shown in the following formula (I):

5. The use according to claim 4, characterized in that The TMP269 or a pharmaceutically acceptable salt thereof is added to a pharmaceutically acceptable carrier and / or excipient to prepare any pharmaceutically acceptable dosage form.

6. The use according to claim 5, characterized in that The dosage form includes any one of tablets, sprays, granules, capsules, oral liquids, injections, and suspensions.

7. Use of TMP269 or a pharmaceutically acceptable salt thereof in the preparation of a preparation for treating diseases caused by bovine nodular dermatosis virus, characterized in that: The structural formula of TMP269 is shown in the following formula (I):

8. The use according to claim 7, characterized in that The TMP269 or a pharmaceutically acceptable salt thereof is added to a pharmaceutically acceptable carrier and / or excipient to prepare any pharmaceutically acceptable dosage form.

9. The use according to claim 8, characterized in that The dosage form includes any one of tablets, sprays, granules, capsules, oral liquids, injections, and suspensions.

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