Use of thz2 in the preparation of a drug for treating influenza virus infection

Abstract

The application relates to the technical field of THZ2 application, in particular to application of THZ2 in preparation of a medicine for treating influenza virus infection. The application comprises avoiding or reducing influenza virus infection; inhibiting replication of the influenza virus; inhibiting proliferation of the influenza virus; inhibiting synthesis of influenza virus RNA; inhibiting synthesis of influenza virus NP protein; improving or avoiding cell damage of a body caused by the influenza virus infection; improving or avoiding alveolar structure damage of the body caused by the influenza virus infection; improving or avoiding myocardial tissue damage of the body caused by the influenza virus infection; or eliminating, improving or avoiding otitis media of the body caused by the influenza virus infection.

Description

Technical Field

[0001] This application relates to the field of THZ2 application technology, specifically to the application of THZ2 in the preparation of drugs for treating influenza virus infection. Background Technology

[0002] THZ2 (CAS: 1604810-84-5) is a potent selective inhibitor of CDK7. Cyclin-dependent kinases (CDKs) are a group of serine / threonine kinases that are activated by binding to cyclins and participate in cell cycle regulation. THZ2 is a covalent inhibitor of CDK7 with an IC50 value of 3.2 nM.

[0003] THZ2 can target and covalently modify the C312 residue outside the CDK7 kinase domain. In kinase binding assays, THZ2 exhibits good affinity, with an IC50 value of [missing value]. 50 The value was 3.2 nM. THZ2 effectively inhibited the growth of Jurkat and Loucy T-ALL cells, with an IC50 value of 3.2 nM. 50 The values ​​were 50 nM and 0.55 nM, respectively. THZ2 has been reported to disrupt the CDK7 signaling pathway in Jurkat and Loucy cells. THZ2 exhibited IC50 values ​​below 200 nM across various cancer cell lines. 50 The cell lines exhibit broad activity of THZ2. Among these cell lines, T-ALL showed particular sensitivity to THZ2, due to the transcriptional effect of RUNX1 induced by THZ2. Summary of the Invention

[0004] However, the inventors of this application have discovered that THZ2 has the potential to be used against influenza viruses.

[0005] Therefore, the embodiments of this application disclose at least the following technical solutions:

[0006] In a first aspect, the embodiments disclose the application of THZ2 in the preparation of anti-influenza virus drugs. The term "anti" means interfering with the infection process of influenza virus; inhibiting the growth of influenza virus; inhibiting the proliferation of influenza virus; inhibiting the synthesis of influenza virus mRNA; inhibiting the synthesis of influenza virus NP protein; improving or preventing cell damage to the body caused by influenza virus infection; improving or preventing alveolar structure damage to the body caused by influenza virus infection; improving or preventing myocardial tissue damage to the body caused by influenza virus infection; or eliminating, improving or preventing otitis media to the body caused by influenza virus infection.

[0007] In an embodiment of the first aspect, the influenza virus is selected from one or more of influenza A, B, C, and D types. In some embodiments, the influenza virus is selected from at least one of the H1N1, H2N2, and H3N2 subtypes of influenza A virus and all subtypes of avian influenza virus.

[0008] In an embodiment of the first aspect, the application is selected from at least one of the following: interfering with the infection process of influenza virus; inhibiting the growth of influenza virus; inhibiting the proliferation of influenza virus; inhibiting the synthesis of influenza virus mRNA; inhibiting the synthesis of influenza virus NP protein; improving or avoiding cell damage to the body caused by influenza virus infection; improving or avoiding alveolar structure damage to the body caused by influenza virus infection; improving or avoiding myocardial tissue damage to the body caused by influenza virus infection; or eliminating, improving or avoiding otitis media to the body caused by influenza virus infection.

[0009] In an embodiment of the first aspect, THZ2 at a concentration of not less than 0.15 μM inhibits the proliferation of influenza virus.

[0010] In an embodiment of the first aspect, THZ2 at a concentration of not less than 0.15 μM inhibits influenza virus mRNA synthesis.

[0011] In an embodiment of the first aspect, THZ2 at a concentration of not less than 0.15 μM inhibits the synthesis of influenza virus NP protein.

[0012] Secondly, the embodiments disclose a composition. The composition comprises THZ2 having an effective amount against influenza virus and pharmaceutically acceptable excipients.

[0013] In some embodiments of the second aspect, the pharmaceutically acceptable excipient is selected from one or more of solvents, dispersants, diluents, fillers, wetting agents, binders, disintegrants, lubricants, preservatives, suspending agents, emulsifiers, excipients, flavoring agents, and carriers. In some embodiments, the dosage form of the composition includes tablets, capsules, granules, pellets, liquid formulations, decoctions, suppositories, gels, aerosols, or patches.

[0014] Thirdly, the embodiments disclose an antiviral composition comprising THZ2 and other components. The other components are selected from antiviral drugs (amantadine, rimantadine, baloxavir, oseltamivir, zanamivir, peramivir, ribavirin, interferon, arbidol, remdesivir); nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen, naproxen, diclofenac, indomethacin, ketoprofen, meloxicam, celecoxib, piroxicam, sulinda); glucocorticoids (prednisone, methylprednisolone, dexamethasone, hydrocortisone, triamcinolone, betamethasone); and other anti-inflammatory drugs (colchicine, allopurinol, febuxostat, methotrexate, TNF inhibitors, IL-6 inhibitors, JAK inhibitors, selective COX-2 inhibitors).

[0015] Thirdly, the embodiments disclose an antiviral drug for influenza. The drug is a liquid formulation containing a concentration of not less than 0.01 μM THZ2. The drug can be in single-dose or multi-dose form. Optionally, the final concentration of THZ2 in the drug is 0.01 μM-500 μM. This concentration refers to the final concentration of THZ2 in the composition, such as the liquid formulation. The amount of THZ2 taken during treatment is adjusted according to the final concentration, dosage form, and the individual being treated to ensure a therapeutically effective dose.

[0016] In some embodiments of the third aspect, the drug is a liquid formulation containing a concentration of 0.15 μM THZ2. In some embodiments, the drug is a liquid formulation containing a concentration of 0.3 μM THZ2. In some embodiments, the drug is a liquid formulation containing a concentration of 0.6 μM THZ2. In some embodiments, the drug is a liquid formulation containing a concentration of 2.5 μM THZ2. In some embodiments, the drug is a liquid formulation containing a concentration of 5 μM THZ2. In some embodiments, the drug is a liquid formulation containing a concentration of 10 μM THZ2. In some embodiments, the drug is a liquid formulation containing a concentration of 15 μM THZ2. In some embodiments, the drug is a liquid formulation containing a concentration of 20 μM THZ2. In some embodiments, the drug is a liquid formulation containing a concentration of 25 μM THZ2. In some embodiments, the drug is a liquid formulation containing a concentration of 30 μM THZ2. In some embodiments, the drug is a liquid formulation containing a concentration of 35 μM THZ2. In some embodiments, the drug is a liquid formulation containing a concentration of 40 μM THZ2. In some embodiments, the drug is a liquid formulation containing 80 μM THZ2.

[0017] One test case found that THZ2 had almost no effect on the survival of A549 cells.

[0018] One test case showed that THZ2 significantly inhibited the proliferation of influenza virus in A549 cells at concentrations ranging from 0.15 to 0.6 μM, and exhibited a good dose-response relationship.

[0019] One test case showed that THZ2 significantly inhibited the synthesis of influenza virus mRNA in A459 cells within a concentration range of 0.15–0.6 μM, and exhibited a good dose-response relationship.

[0020] One test case showed that THZ2 significantly inhibited the synthesis of influenza virus proteins in A549 cells within a concentration range of 0.15–0.6 μM, and exhibited a good dose-response relationship.

[0021] The term "pharmaceutically acceptable excipient" refers to a component that does not interfere with the bioactivity of compound THZ2 and is not significantly toxic to the body at its therapeutically effective concentration. This includes any one or a combination of at least two of solvents, dispersants, diluents, fillers, wetting agents, binders, disintegrants, lubricants, preservatives, suspending agents, emulsifiers, excipients, flavoring agents, and carriers. The use of the aforementioned components in pharmaceutically active substances is well known in the art. For example, the solvents include, but are not limited to, dimethyl sulfoxide (DMSO) and ethanol, and the carriers include, but are not limited to, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, gypsum powder, sucrose, cyclodextrin, amylose, magnesium stearate, pectin, gum arabic, stearic acid, or lower alkyl ethers of cellulose. Each component can be used alone or in combination with several others.

[0022] The terms "effective amount" and "therapeutic effective amount" refer to the amount of a compound, reagent, preparation, or composition required, when taken orally, to provide some degree of relief for one or more symptoms of a disease or condition being treated, with the intended goal of reducing and / or alleviating symptoms or causes, or any other desired change in the body. For example, a therapeutic effective amount is the amount of a composition containing the compounds disclosed in this application required to provide significant symptom relief in a clinical setting, and the effective amount suitable for any individual case can be determined using techniques such as dose escalation testing. The therapeutic effective amount will vary depending on the compound activity, the severity of the symptom caused by the viral infection, and the size and health status of the individual being treated. Exemplarily, a therapeutic effective amount in a mouse model can be 1 mg / kg to 150 mg / kg, preferably 1 mg / kg to 100 mg / kg, more preferably 5 mg / kg to 30 mg / kg, such as 10 mg / kg or 20 mg / kg, twice daily.

[0023] The term "treatment" and similar terms encompass any therapeutic action on humans or animals other than humans. Treatment can be directed at an existing condition or can be preventative (preventative treatment), including curative, ameliorative, or preventative effects. Treatment can also include curing, ameliorating, or preventing symptoms associated with a disease rather than acting on the underlying cause of the disease. The term "prevention" and similar terms include reducing the likelihood of a patient developing or experiencing a disease or symptom worsening, such as during the period of medication administration following exposure to the influenza virus but before infection occurs. Treatment can also be directed at the initial infection or infection following the activation of the latent virus.

[0024] The compositions provided in this application are adaptable to any route of administration for the prevention and / or treatment of influenza viruses, including but not limited to oral, nasal, transdermal, intravenous, and gastrointestinal administration, with oral administration being preferred. Those skilled in the art can select appropriate formulations based on the route of administration; for example, for oral administration, conventional solid and liquid formulations can be prepared. In some specific embodiments, dosage forms include, but are not limited to: tablets, capsules, granules, pellets, liquid formulations, decoctions, suppositories, gels, aerosols, or patches. Attached Figure Description

[0025] Figure 1 The graph shows the effect of different concentrations of THZ2 on the survival rate of A549 cells provided in the examples. "***" indicates a highly significant difference from the untreated control wells (Cell) (P<0.001). "THZ2+Concentration" indicates the drug-treated wells.

[0026] Figure 2 The figure shows the results of the inhibitory effect of different concentrations of THZ2 on influenza virus proliferation in A549 cells, as provided in the examples. "***" indicates a highly significant difference from the virus group (P<0.001). "Mock" represents the blank cell group without virus infection, and "ND" indicates not detected. "Virus" represents the virus group, and "Virus+THZ2" represents the test group.

[0027] Figure 3 The figure shows the inhibitory effect of different concentrations of THZ2 on influenza virus mRNA synthesis in A549 cells, as provided in the examples. "***" indicates a highly significant difference from the virus group (P<0.001). "Mock" represents the uninfected blank cell group, and "ND" indicates not detected. "Virus" represents the virus group, and "Virus+THZ2" represents the test group.

[0028] Figure 4 The figure provided in the example shows the results of Western blotting analysis of the inhibitory effect of different concentrations of THZ2 on the synthesis of influenza virus NP protein in A549 cells. "IAV" represents influenza A virus, "+" indicates infection with influenza virus, and "-" indicates no infection with influenza virus. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of this application clearer, the following detailed description is provided in conjunction with embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application. Reagents not specifically described in detail herein are all conventional reagents and are commercially available; methods not specifically described in detail are all conventional experimental methods and can be learned from the prior art.

[0030] Influenza viruses belong to the family Orthomyxoviridae, genus *Influenzavirus*. Based on the antigenic and genetic characteristics of their nucleoprotein (NP) and matrix protein (M), influenza viruses are classified into three types: A, B, and C, also known as types A, B, and C. The complete genome of type A influenza virus consists of eight single-stranded negative-sense RNAs of varying sizes, named segments 1 through 8. The viral genome is approximately 13.6 kb in length, encoding 10 structural proteins (PB2, PB1, PA, HA, NP, NA, M1, M2, PB1-F2, and NS2 / NEP) and a non-structural protein (NS1). Based on the differences in the viral particle surface glycoproteins hemagglutinin (HA) and neuraminidase (NA), type A influenza viruses can be further divided into 17 H (H1-H17) and 10 N (N1-N10) subtypes. Human influenza viruses are mainly of the H1, H2, and H3 subtypes. Currently, the most dangerous highly pathogenic avian influenza strains are H5, H7, and H9 subtypes, with H5N1 having the highest mortality rate. Type B influenza viruses often cause localized epidemics, not global pandemics, and are only found in humans and seals. Type C influenza viruses exist sporadically, primarily affecting infants and young children, generally not causing epidemics, but can infect humans and pigs. Since their discovery in the early 20th century, influenza viruses have caused five major pandemics globally, with an outbreak occurring approximately every ten years, resulting in enormous losses worldwide. Influenza epidemics cause 250,000 to 500,000 deaths and 3 million to 5 million severe cases annually, infecting approximately 5% to 15% of the global population. Influenza outbreaks place a huge burden on the global economy and seriously threaten human health. Although influenza can be prevented and treated with vaccines and existing antiviral drugs, the high variability of the influenza virus makes vaccines delayed, unable to prevent the spread of new strains, and rendering existing drugs ineffective against drug-resistant strains. Therefore, there is an urgent need to develop new antiviral drugs, especially antiviral drugs targeting new targets.

[0031] In this application, some test cases tested the inhibitory effect of THZ2 on influenza virus replication. Some test cases tested the inhibitory effect of THZ2 on influenza virus mRNA synthesis. Some test cases tested the inhibitory effect of THZ2 on influenza virus NP synthesis.

[0032] 1. Test materials

[0033] A549 cells: purchased from the American Type Culture Collection (ATCC);

[0034] Virus strain: Influenza A virus H1N1 subtype A / Puerto Rico / 8 / 1934, provided by the Virus Preservation Center of Wuhan Institute of Virology, Chinese Academy of Sciences.

[0035] THZ2 was purchased from Taoshu Biotechnology Co., Ltd.

[0036] DMEM medium and fetal bovine serum (FBS) were purchased from GIBCO.

[0037] Cell The Luminescent cell proliferation assay kit was purchased from Promega.

[0038] 2. THZ2 non-cytotoxicity test

[0039] (1) Cell Culture

[0040] After resuscitating frozen A549 cells and passaged twice, the cells were expanded into DMEM medium containing 10% fetal bovine serum and penicillin 100 U / mL and streptomycin 100 μg / mL, with a seeding density of at least 5 × 10⁶ cells / mL. 5 cell / mL, passage density not exceeding 2×10 6 cell / mL.

[0041] (2) Preparation of the test solution

[0042] Prepare a DMSO solution containing 10 mM THZ2 as the test solution.

[0043] (3) Cytotoxicity test

[0044] Drug treatment wells (THZ2+ Concentration): A549 cells were processed at a concentration of 2.5 × 10⁻⁶ cells / well. 5 Cells were seeded per well (100 μL) in 96-well cell culture plates. The test solution was diluted with fresh DMEM to create 10 concentration gradients, with 3 replicates for each gradient, resulting in final concentrations of 2.5 μM, 5 μM, 10 μM, 20 μM, 40 μM, and 80 μM. After 24 h of culture, the supernatant was discarded. 100 μL of phosphate-buffered saline (PBS) containing 30% Cell titer-glo reagent was added to the remaining cells, and the cells were incubated at room temperature for 10 min. OD450 readings were then measured using a Varioskan LUX microplate reader.

[0045] Untreated control wells (Cell): The difference from drug-treated wells is that no test solution is added.

[0046] Cell viability (%) = (OD450 of drug-treated wells / OD450 of untreated control wells) × 100%

[0047] like Figure 1 It can be seen that THZ2 is not toxic to the survival of A549 cells.

[0048] 3. Virus proliferation inhibition test

[0049] (1) Preparation of virus-infected cell fluid

[0050] After resuscitating frozen A549 cells and passaged twice, the cells were expanded into DMEM medium containing 10% fetal bovine serum and penicillin 100 U / mL and streptomycin 100 μg / mL, with a seeding density of at least 5 × 10⁶ cells / mL. 5 cell / mL, passage density not exceeding 2×10 6 cell / mL.

[0051] Remove 2×10 6 The culture medium in A549 cell solution was washed twice with PBS, and then H1N1 PR8 virus diluted to 0.3 MOI (multiple of infection) with fresh DMEM was added for infection. The cells were incubated at 37°C for 1 h, the viral supernatant was discarded, and the cells were washed once with PBS to obtain the virus-infected cell solution.

[0052] (2) Group Test

[0053] The obtained H1N1 PR8 virus solutions were divided into a test group (Virus+THZ2) and a virus group (Virus). Additionally, using the aforementioned 2×10... 6 A549 cell slurry at a concentration of 1 cell / mL was used as a blank cell group (Mock), without inoculation with virus or THZ2 treatment.

[0054] In this study, the test groups were diluted with fresh DMEM and THZ2 was added to the virus solution to final concentrations of 0.15 μM, 0.3 μM, and 0.6 μM, respectively. The virus group and the blank cell group were not treated with THZ2. The virus solution or cell solution in each group was cultured for 24 hours, after which the culture was terminated and samples were collected. The cells were repeatedly frozen and thawed at -80℃ and 4℃ to ensure complete cell lysis, releasing all the virus into the cell supernatant. The supernatant from each well was then collected. The frozen and thawed samples were placed on ice and serially diluted 10-fold eight times with fresh DMEM. A549 cells were removed and washed with PBS. The diluted samples were seeded at 100 μL / well, one column per dilution. Each group was seeded with virus-free maintenance medium as a negative control, and cultured for another period. After 2 hours, the cells were washed twice with PBS, the blank maintenance medium was replaced, and cultured for another period. After 72 hours, cytopathic effects were recorded, and the viral titer (TCID50 value) was calculated.

[0055] like Figure 2 It can be seen that THZ2 has a significant inhibitory effect on the proliferation of influenza virus in A549 cells in the concentration range of 0.15 to 0.6 μM, and shows a good dose-response relationship.

[0056] 4. Inhibition test of influenza virus mRNA synthesis

[0057] (1) Preparation of virus-infected cell fluid

[0058] After resuscitating frozen A549 cells and passaged twice, the cells were expanded into DMEM medium containing 10% fetal bovine serum and penicillin 100 U / mL and streptomycin 100 μg / mL, with a seeding density of at least 5 × 10⁶ cells / mL. 5 cell / mL, passage density not exceeding 2×10 6 cell / mL.

[0059] Remove 2×10 6 The culture medium in A549 cell solution was washed twice with PBS, and then H1N1 PR8 virus diluted to 0.3 MOI (multiple of infection) with fresh DMEM was added for infection. The cells were incubated at 37°C for 1 h, the viral supernatant was discarded, and the cells were washed once with PBS to obtain the virus-infected cell solution.

[0060] (2) Group Test

[0061] The obtained H1N1 PR8 virus solutions were divided into a test group (Virus+THZ2) and a virus group (Virus). Additionally, using the aforementioned 2×10... 6 A549 cell slurry at a concentration of 1 cell / mL was used as a blank cell group (Mock), without inoculation with virus or THZ2 treatment.

[0062] In this study, the test groups were diluted with fresh DMEM and THZ2 was added to the virus solution to final concentrations of 0.15 μM, 0.3 μM, and 0.6 μM, respectively. The virus group and the blank cell group were not treated with THZ2. The virus solution or cell solution in each group was cultured for 24 hours, after which the culture was terminated and samples were collected. The cells were repeatedly frozen and thawed at -80℃ and 4℃ to ensure complete cell lysis, resulting in the release of all the virus into the cell supernatant. The supernatant from each well was then collected. Total RNA was extracted from the collected cell supernatant using the recommended procedure of the Total RNA Rapid Extraction Kit (Shanghai Feijie Biotechnology Co., Ltd.). Immediately after RNA extraction, reverse transcription was performed. Using cDNA as a template and GAPDH as an internal reference gene, Real-Time PCR was used to detect the copy number of the influenza virus NP gene. The changes in NP mRNA were evaluated using a normal control group as a reference.

[0063] Among them, the upstream and downstream primer sequences of the influenza virus NP gene are:

[0064] NSP9-F:AGCATTGTTTCCAACTCCTTT, SEQ ID NO.1

[0065] NSP9-R:GACGATGCAACGGGCTGGTCTG, SEQ ID NO.2

[0066] GAPDH gene upstream and downstream primer sequences:

[0067] GAPDH-F:TGGGGAAGGTGAAGGTCG, SEQ ID NO.3

[0068] GAPDH-R:TAAAAGCAGCCCTGGTGACC, SEQ ID NO.4.

[0069] like Figure 3 It can be seen that THZ2 has a significant inhibitory effect on the synthesis of influenza virus mRNA in A459 cells within the concentration range of 0.15 to 0.6 μM, and shows a good dose-response relationship.

[0070] 5. Inhibition test of influenza virus NP protein synthesis

[0071] (1) Preparation of virus-infected cell fluid

[0072] After resuscitating frozen A549 cells and passaged twice, the cells were expanded into DMEM medium containing 10% fetal bovine serum and penicillin 100 U / mL and streptomycin 100 μg / mL, with a seeding density of at least 5 × 10⁶ cells / mL. 5 cell / mL, passage density not exceeding 2×10 6 cell / mL.

[0073] Remove 2×10 6 The culture medium in A549 cell solution was washed twice with PBS, and then H1N1 PR8 virus diluted to 0.3 MOI (multiple of infection) with fresh DMEM was added for infection. The cells were incubated at 37°C for 1 h, the viral supernatant was discarded, and the cells were washed once with PBS to obtain the virus-infected cell solution.

[0074] (2) Group Test

[0075] The obtained H1N1 PR8 virus solutions were divided into a test group (Virus+THZ2) and a virus group (Virus). Additionally, using the aforementioned 2×10... 6 A549 cell slurry at a concentration of 1 cell / mL was used as a blank cell group (Mock), without inoculation with virus or THZ2 treatment.

[0076] In this study, the test groups were diluted with fresh DMEM and added to the virus solution to final concentrations of 0.15 μM, 0.3 μM, and 0.6 μM THZ2, respectively. The virus group and the blank cell group were not treated with THZ2. The virus solution or cell solution of each group was cultured for 24 hours, after which the culture was terminated and samples were collected. The supernatant was discarded, and the cells were washed twice with PBS. The cell culture plates were placed on ice, lysed with RIPA lysis buffer, and centrifuged at 12,000 rpm for 10 minutes. The supernatant was collected, and the protein concentration of each sample was determined using the BCA method. Western blotting was then used to detect the bands of the influenza virus NP protein and the internal reference protein GAPDH. All reagents required for the experiment were purchased from Shanghai Beyotime Biotechnology Co., Ltd.

[0077] like Figure 4 It can be seen that THZ2 has a significant inhibitory effect on the synthesis of influenza virus protein in A549 cells within the concentration range of 0.15 to 0.6 μM, and shows a good dose-response relationship.

[0078] The results in summary show that THZ2 has good anti-influenza virus activity in A549 cells and can be used to develop drugs for the treatment of influenza virus infection, with broad application prospects.

[0079] The above description is merely a preferred embodiment of this application, but the scope of protection of this application is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this application should be included within the scope of protection of this application.

Claims

1. The application of THZ2 in the preparation of anti-influenza virus drugs, characterized in that, The influenza virus in question is the H1N1 subtype of influenza A virus.

2. The application according to claim 1, characterized in that, The application is selected from: To avoid or reduce the infection rate of influenza virus; Inhibit the growth of influenza virus; Inhibit the proliferation of influenza virus; Inhibit influenza virus RNA synthesis; Inhibit influenza virus NP protein synthesis At least one of them.

3. The application according to claim 1, characterized in that, THZ2 at a concentration of not less than 0.15 μM inhibits the proliferation of influenza virus.

4. The application according to claim 1, characterized in that, THZ2 at a concentration of not less than 0.15 μM inhibits influenza virus mRNA synthesis.

5. The application according to claim 1, characterized in that, THZ2 at a concentration of not less than 0.15 μM inhibits the synthesis of influenza virus NP protein.

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