CN114984030A - Application of ribavirin in preparation of tick-borne encephalitis virus resistant drugs - Google Patents
Application of ribavirin in preparation of tick-borne encephalitis virus resistant drugs Download PDFInfo
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- CN114984030A CN114984030A CN202210718410.4A CN202210718410A CN114984030A CN 114984030 A CN114984030 A CN 114984030A CN 202210718410 A CN202210718410 A CN 202210718410A CN 114984030 A CN114984030 A CN 114984030A
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- ribavirin
- tick
- encephalitis virus
- borne encephalitis
- virus
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses an application of ribavirin in preparing a tick-borne encephalitis virus resistant medicine, wherein the tick-borne encephalitis virus resistant medicine takes ribavirin as a unique active ingredient or a pharmaceutical composition containing ribavirin, and the tick-borne encephalitis virus resistant medicine is a medicine for preventing or treating tick-borne encephalitis virus infection. The invention utilizes human hepatoma cell Huh-7 and human lung adenocarcinoma cell A549 to detect the tick-borne encephalitis virus resistance activity of ribavirin. Experimental results prove that ribavirin can effectively inhibit tick-borne encephalitis virus from infecting target cells, has an obvious protective effect on infected cells, remarkably inhibits replication and proliferation of intracellular tick-borne encephalitis virus, can be used as a tick-borne encephalitis virus resistant drug, and has further development prospects.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of ribavirin in preparation of a tick-borne encephalitis virus resistant medicine.
Background
Ribavirin (Ribavirin) is an artificially synthesized guanosine nucleoside analog, first synthesized in 1972. Ribavirin was first approved in 1986 for the treatment of respiratory syncytial virus infection. Research has shown that ribavirin has antiviral activity against a variety of DNA and RNA viruses, including dengue virus, japanese encephalitis virus, zika virus, yellow fever virus, and the like. Ribavirin has been used to treat respiratory syncytial virus, lassa virus and hepatitis c virus infections.
The chemical formula of ribavirin is C 8 H 12 N 4 O 5 The chemical structural formula is as follows:
tick-borne encephalitis virus (TBEV) is the causative agent of Tick-borne encephalitis, a natural epidemic disease that causes lesions in the human central nervous system. Tick-borne encephalitis is transmitted by tick bites, has a fatality rate of over 40 percent, and is popular mainly in europe and many regions of asia. Tick-borne encephalitis is a high incidence of disease and is becoming a global public health problem. At present, no effective antiviral therapeutic drug exists. Tick-borne encephalitis virus is the first pathogenic microorganism with high pathogenicity, and the research on tick-borne encephalitis virus can be only carried out in a biosafety third-level laboratory. Researchers have been working on developing drugs that are effective against tick-borne encephalitis virus.
Disclosure of Invention
The invention aims to provide application of ribavirin in preparation of tick-borne encephalitis virus resistant medicaments.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides application of ribavirin in preparation of a tick-borne encephalitis virus resistant medicament.
The tick-borne encephalitis virus resistant medicine takes ribavirin as the only active ingredient, or a medicine composition containing ribavirin.
The medicinal composition containing ribavirin is a medicinal composition consisting of ribavirin and one or more pharmaceutically acceptable auxiliary materials.
The content of ribavirin in the tick-borne encephalitis virus resisting medicine is 0.1-99 wt%; preferably 0.5 to 90 wt%.
The tick-borne encephalitis virus resistant drug is a drug for preventing or treating tick-borne encephalitis virus infection.
The auxiliary material is at least one of diluent, excipient, adhesive, filler, disintegrating agent, flavoring agent and sweetener. The pharmaceutically allowable adjuvant or adjuvants refer to conventional pharmaceutical adjuvants in the pharmaceutical field, wherein diluents and excipients such as water; binders such as cellulose derivatives, gelatin, or polyvinylpyrrolidone, etc.; fillers such as starch and the like; disintegrating agents such as calcium carbonate or sodium bicarbonate; other adjuvants such as flavouring and/or sweetening agents may also be added to the pharmaceutical composition.
The ribavirin can be prepared into a pharmaceutical preparation with a conventional pharmaceutical adjuvant in pharmaceutics.
The pharmaceutical formulation is at least one of a capsule, a suspension, a tablet, a powder, an emulsion, a solution, a syrup, or an injection. The medicinal preparation can be prepared into various medicinal preparations by taking ribavirin as all or part of active ingredients and conventional pharmaceutic adjuvants in pharmaceutics by adopting a conventional method in the medical field. When orally taken, the medicine can be prepared into conventional solid preparations such as tablets, powder or capsules; when used for injection, the composition can be prepared into injection.
The administration mode of the pharmaceutical preparation is oral administration and injection.
The chemical structural formula of the ribavirin is as follows:
due to the adoption of the technical scheme, the invention has the following advantages and beneficial effects:
the invention utilizes human hepatoma cell Huh-7 and human lung adenocarcinoma cell A549 to detect the tick-borne encephalitis virus activity of ribavirin. Experimental results prove that ribavirin can effectively inhibit tick-borne encephalitis virus from infecting target cells, has an obvious protective effect on infected cells, remarkably inhibits replication and proliferation of intracellular tick-borne encephalitis virus, can be used as a tick-borne encephalitis virus resistant drug, and has further development prospects.
Drawings
FIG. 1: the effect of ribavirin on a549 cell survival rate; treating cells for 48 hours by using ribavirin with different concentrations, and detecting the cell survival rate by using an MTS method; 0 μ g/ml is a control group without ribavirin treatment; student's t-test analyzed statistical differences, P < 0.05.
FIG. 2: the protective effect of ribavirin on tick-borne encephalitis virus infected a549 cells; ribavirin treats virus infected cells for 48 hours, and virus cytopathic effect is observed under a microscope; mock is a control group not infected with virus, 0. mu.g/ml is a tick-borne encephalitis virus infected group, 50. mu.g/ml is a 50. mu.g/ml ribavirin-treated virus infected group, and the microscopic magnification is 100X.
FIG. 3: ribavirin inhibits the expression of viral antigens in tick-borne encephalitis virus infected a549 cells; treating cells with different concentrations of ribavirin and virus for 48 hours, and detecting the expression of virus antigen by an immunofluorescence method; 0 μ g/ml is tick-borne encephalitis virus infected group, PBS is drug solvent control group, and microscope magnification is 100 ×.
FIG. 4: ribavirin reduces the level of viral RNA in tick-borne encephalitis virus infected a549 cells; treating cells for 48 hours by using ribavirin and viruses with different concentrations, and detecting the level of virus RNA in the cells by using a real-time fluorescent quantitative PCR method; 0 mug/ml is tick-borne encephalitis virus infected group, PBS is drug solvent control group; student's t-test analyzed statistical differences, P < 0.005 and P < 0.001.
FIG. 5: ribavirin reduces the virus titer in the supernatant of tick-borne encephalitis virus infected a549 cells; treating cells for 48 hours by using ribavirin and viruses with different concentrations, and detecting the virus titer in cell supernatant by using a plaque experiment; 0 mug/ml is tick-borne encephalitis virus infected group, PBS is drug solvent control group; student's t-test analyzed statistical differences, P < 0.002, P < 0.001.
Detailed Description
In order to more clearly illustrate the present invention, the present invention is further described below in conjunction with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Ribavirin used in embodiments of the invention can be purchased commercially.
Example 1
First, experimental material
1. Drug depot with ribavirin: the Drug library, which includes 2580 American Food and Drug Administration (FDA) certified drugs, is available from Selleck Chemicals, USA and ribavirin is available from EMD Millipore, USA.
2. Tick-borne encephalitis virus and virus antibodies: ascites from mice immunized with tick-borne encephalitis virus and virus were stored in the biosafety third-order laboratory of naval medical university. Viral infection experiments were performed in this laboratory. Viral titers were expressed in Plaque forming units (PFU/ml).
3. Cell: human hepatoma cell Huh-7 and human lung adenocarcinoma cell A549 were purchased from Shanghai cell institute of Chinese academy of sciences and stored in the biomedical protective research laboratory of the naval medical department of the naval military medical university.
4. Cell culture reagents: DMEM complete medium containing 10% fetal bovine serum, 1% glutamine, 1% nonessential amino acids, 1% penicillin and streptomycin, 0.05% pancreatin-ethylenediaminetetraacetic acid, Phosphate Buffered Saline (PBS), all by Gibco corporation of america.
5. Bovine serum albumin (Bovine serum albumin, BSA): affymetrix, USA.
Alexa Fluor 488-labeled goat anti-mouse IgG, DAPI sealant: product of Abcam, UK.
7.Cell Titer
Aquous cell proliferation assay kit (MTS): manufactured by Promega corporation, usa.
8. Sodium carboxymethylcellulose: Sigma-Aldrich, USA.
M-MLV reverse transcriptase, dNTP Mix, Eastep qPCR Master Mix: promega corporation, USA.
10. Random primers, tick-borne encephalitis virus primers, glyceraldehyde triphosphate dehydrogenase (GAPDH) internal reference primers: synthesized by Beijing Liu He Hua Dagen science and technology GmbH.
Second, experimental methods and results
Tick-borne encephalitis virus resisting activity of 7 antiviral drugs
Inoculating human liver cancer cell Huh-7 with good growth state in 96-well cell culture plate, at 37 deg.C and 5% CO 2 The cell density was about 95% at 12 hours in the incubator. According to the instruction of the drug library, 10mM drug stock solution was prepared by dissolving the drug in the corresponding solvent, and DMEM complete medium was diluted to a drug use concentration of 40. mu.M. To study this subject, the Multiplicity of infection (MOI) of tick-borne encephalitis virus was 0.1. Tick-borne encephalitis virus and diluted drug were mixed rapidly (1:1 by volume) in a horizontal shaker and added to a 96-well cell-containing plate to give a final concentration of 10. mu.M. Meanwhile, a virus infection control group and a drug solvent control group are arranged, and the drug group and the control group are 3 holes per group. After 24 hours of culture, the inhibitory activity of the drug to the virus is evaluated by an immunofluorescence method for detecting tick-borne encephalitis virus antigen, a full-automatic cell imaging multifunctional microplate detection system scans a 96-well cell culture plate, and Gen53.10 software is used for image acquisition and data processing. Calculating the inhibition rate of the drug to the virus: viral infection rate (number of virus-infected cells per well/total number of cells per well) -drug group infection rate (number of virus-infected cells per well/total number of cells per well). The inhibition rate of 7 antiviral drugs against tick-borne encephalitis virus is shown in table 1.
TABLE 17 inhibition of tick-borne encephalitis Virus by antiviral drugs
According to the above drug research progress, ribavirin was selected for tick-borne encephalitis virus resistance studies, in combination with the description of the role of the drug in the drug library.
Toxic effect of (di) ribavirin on A549 cells
First, the toxic effect of ribavirin on a549 cells was examined to determine the range of drug concentrations active against tick-borne encephalitis virus. A549 cells were seeded in 96-well cell culture plates and cultured to a cell density of about 100%. The well culture solution was aspirated and discarded, ribavirin (drug group) of different concentrations diluted in DMEM complete medium was added, and a control group (DMEM complete medium was added) and a blank group (no cell but DMEM complete medium alone) were set, each of which was provided with 3 wells. After 48 hours of incubation, MTS solution was added and OD was detected using a multifunctional microplate reader 490 The value is obtained. Calculating the survival rate of the cells: OD Drug group -OD Blank group /OD Control group -OD Blank group . As shown in figure 1, when the concentration of ribavirin is less than or equal to 200 mug/ml, the ribavirin has no obvious toxic effect on A549 cells; when the concentration of the ribavirin inhibitor is 300 mug/ml, the toxicity effect on cells is strong, and compared with the cell survival rate of a control group, the reduction of the cell survival rate of the ribavirin-treated group with 300 mug/ml is statistically different (P < 0.05). The results show that ribavirin has no toxic effect on A549 cells in a larger concentration range.
Protective effect of ribavirin on tick-borne encephalitis virus infected A549 cells
Based on the results of the above-described detection of the cytotoxic effect of ribavirin on A549, the protective effect of 50. mu.g/ml ribavirin on cells infected with tick-borne encephalitis virus was observed. A549 cells were seeded in 12-well cell culture plates and cultured to a cell density of about 100%. The culture medium in the wells was aspirated, ribavirin (final concentration 50. mu.g/ml) and virus (MOI 0.1) were added, and a cell control (Mock group) and a virus infection control (0. mu.g/ml group) which were not infected with virus were set. Cultured for 48 hours and observed under a microscope for the cytopathic effect of the virus. As shown in FIG. 2, virus-infected A549 cells showed marked lesions, manifested by shrinkage of cell bodies, increased intercellular spaces, and cell shedding, compared to Mock cells. 50 mug/ml ribavirin has protective effect on virus infected cells, and is characterized in that the cytopathic effect of the virus is obviously weakened, and the number of diseased cells is reduced. The results show that ribavirin has protective effect on A549 cells infected by tick-borne encephalitis virus.
(tetra) ribavirin inhibits expression of tick-borne encephalitis virus antigens in A549 cells
The antiviral activity of ribavirin was verified in tick-borne encephalitis virus-susceptible human lung adenocarcinoma cells a 549. A549 cells were seeded in 96-well cell culture plates and cultured to about 90% cell density, tick-borne encephalitis virus infected cells (MOI 0.1) with varying concentrations of ribavirin added. Virus infection control (0 μ g/ml group), drug solvent control (PBS group) were set, and 3 wells were set for each group. After culturing for 48 hours, detecting the expression of the virus antigen by an immunofluorescence method, scanning by a full-automatic cell imaging multifunctional microplate detection system, and collecting images. As shown in figure 3, ribavirin has strong antiviral activity in A549 cells, can inhibit the expression of virus antigens (positive signals-green fluorescence), and has concentration-dependent inhibition. Data processing and analysis are carried out by Gen53.10 software, and the inhibition rate of 60 mu g/ml ribavirin is found to be as high as 89%. The percentage of virus-infected cells after ribavirin treatment is shown in table 2. The Half Inhibition Concentration (IC) of the drug was calculated using GraphPad Prism 8.0 software 50 ). Ribavirin IC in A549 cells 50 35.57. mu.g/ml. The results show that ribavirin inhibits the expression of viral antigens in tick-borne encephalitis virus infected a549 cells.
TABLE 2 The percentage of tick-borne encephalitis virus-infected cells from ribavirin-treated A549 cells
(V) ribavirin inhibits the synthesis of tick-borne encephalitis virus RNA in A549 cells
The effect of ribavirin on RNA synthesis and viral proliferation of tick-borne encephalitis virus was next investigated. A549 cells were seeded in 12-well cell culture plates and cultured to a cell density of about 100%. The culture medium in the wells was aspirated, ribavirin and tick-borne encephalitis virus (MOI ═ 0.1) at different concentrations were added, virus infection control (group 0) and drug solvent control (PBS group) were set, and 3 wells were set for each group. After 48 hours of culture, culture supernatant (for detecting virus titer in a plaque experiment) and Trizol cell lysate (for detecting virus RNA in real-time fluorescent quantitative PCR) are collected respectively. Trizol extracts the total RNA of the cells, and reverse transcribes the total RNA into cDNA by using a random primer. The GAPDH gene is used as an internal reference, and the real-time fluorescent quantitative PCR method is adopted to detect the level of virus RNA in a ribavirin-treated tick-borne encephalitis virus infected cell. GAPDH primer sequence: forward primer 5'-TGGGCTACACTGAGCACCAG-3', reverse primer 5'-AAGTGGTCGTTGAGGGCAAT-3'; tick-borne encephalitis virus primer sequences: the forward primer is 5 '-TGGAYTTYAGACAGGAAYCAACACA-3' and the reverse primer is 5 '-TCCAGAGACTYTGRTCDGTGTGGA-3'. The detection result shows that the virus RNA level is reduced in a ribavirin concentration-dependent manner in the ribavirin-treated A549 cells. As shown in FIG. 4, ribavirin at 10. mu.g/ml significantly reduced viral RNA levels (P < 0.005) compared to the virus-infected group, whereas ribavirin at 20. mu.g/ml and 50. mu.g/ml exhibited greater inhibitory effects (P < 0.001). The viral RNA levels of the PBS drug solvent control group were not significantly different compared to the virus infected group. Therefore, ribavirin significantly reduced the level of viral RNA in tick-borne encephalitis virus infected a549 cells, inhibiting replication of tick-borne encephalitis virus.
(six) ribavirin decreases titer of tick-borne encephalitis virus in supernatant of A549 cells
Using the cell culture supernatants collected above, viral titers in ribavirin-treated tick-borne encephalitis virus-infected A549 cell supernatants were determined using a plaque assay. Porcine kidney cells PK-15 are inoculated on a 12-hole cell culture plate and grow to a cell monolayer, collected culture supernatant is diluted by 10 times of DMEM complete culture medium in a gradient manner and added to the cell monolayer, 3 holes are formed in each group, the cells are adsorbed for 3 hours in an incubator at 37 ℃, 2% sodium carboxymethylcellulose covering fluid is added for culture for 6 days, 4% paraformaldehyde is used for fixation, 1% crystal violet is used for staining, the number of virus plaques is counted, and the virus titer is determined. The results showed that virus titer was decreased in ribavirin concentration-dependent manner in ribavirin-treated a549 cells. As shown in FIG. 5, ribavirin at 10. mu.g/ml significantly reduced viral titer (P < 0.002) compared to the virus-infected group, and at 20. mu.g/ml and 50. mu.g/ml, exhibited greater inhibition (P < 0.001). The virus titer of the PBS drug solvent control group was not significantly different from that of the virus-infected group. The relationship between the decrease in tick-borne encephalitis virus production and ribavirin concentration is shown in table 3. Therefore, ribavirin can remarkably reduce the virus titer in the supernatant of tick-borne encephalitis virus infected A549 cells and inhibit the proliferation of tick-borne encephalitis virus.
TABLE 3 ribavirin treatment of tick-borne encephalitis Virus titers in supernatants of A549 cells
The in vitro experiment result shows that ribavirin has obvious tick-borne encephalitis virus infection resisting activity and can be used for preparing tick-borne encephalitis virus resisting medicines.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Sequence listing
<110> university of navy, army and military medical science of liberty army of China
Application of <120> ribavirin in preparation of tick-borne encephalitis virus resistant drugs
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Claims (10)
1. Application of ribavirin in preparing tick-borne encephalitis virus resisting medicines.
2. The use of ribavirin as claimed in claim 1 in the manufacture of a medicament against tick-borne encephalitis virus, characterised in that: the tick-borne encephalitis virus resistant medicine takes ribavirin as the only active ingredient, or a medicine composition containing ribavirin.
3. The use of ribavirin as claimed in claim 1 in the manufacture of a medicament against tick-borne encephalitis virus, wherein: the medicinal composition containing ribavirin is a medicinal composition consisting of ribavirin and one or more pharmaceutically acceptable auxiliary materials.
4. The use of ribavirin as claimed in claim 1 in the manufacture of a medicament against tick-borne encephalitis virus, wherein: the content of ribavirin in the tick-borne encephalitis virus resisting medicine is 0.1-99 wt%.
5. The use of ribavirin as claimed in claim 4 in the manufacture of a medicament against tick-borne encephalitis virus, wherein: the content of ribavirin in the tick-borne encephalitis virus resisting medicine is 0.5-90 wt%.
6. The use of ribavirin as claimed in claim 1 in the manufacture of a medicament against tick-borne encephalitis virus, characterised in that: the tick-borne encephalitis virus resistant drug is a drug for preventing or treating tick-borne encephalitis virus infection.
7. The use of ribavirin as claimed in claim 1 in the manufacture of a medicament against tick-borne encephalitis virus, wherein: the auxiliary material is at least one of diluent, excipient, adhesive, filler, disintegrating agent, flavoring agent and sweetener.
8. The use of ribavirin as claimed in claim 1 in the manufacture of a medicament against tick-borne encephalitis virus, characterised in that: the ribavirin can be prepared into a pharmaceutical preparation with a conventional pharmaceutical adjuvant in pharmaceutics.
9. The use of ribavirin as claimed in claim 8 in the manufacture of a medicament against tick-borne encephalitis virus, wherein: the pharmaceutical formulation is at least one of a capsule, a suspension, a tablet, a powder, an emulsion, a solution, a syrup, or an injection.
10. The use of ribavirin as claimed in claim 8 in the manufacture of a medicament against tick-borne encephalitis virus, wherein: the administration mode of the pharmaceutical preparation is oral administration and injection.
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