Application of cytisine type alkaloid and derivative thereof in preparation of medicine for preventing or treating respiratory syncytial virus infection

Abstract

The invention discloses application of a cytisine type alkaloid and a derivative thereof in preparation of a medicine for preventing or treating respiratory syncytial virus infection, and relates to the technical field of respiratory syncytial virus prevention and treatment. The research finds that the natural product cytisine shows good anti-respiratory syncytial virus infection activity in vivo and in vitro, and finds that the cytisine can obviously relieve lung injury caused by virus infection and reduce lung inflammation; the invention provides an experimental basis for developing an efficient and safe drug for resisting respiratory syncytial virus (RSV) infection. As a natural product, the cytisine reduces the social burden caused by treatment of respiratory syncytial virus infection and reduces the treatment cost.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of respiratory syncytial virus prevention and treatment, in particular, to the application of cytisine alkaloids and derivatives thereof in the preparation of a drug for preventing or treating respiratory syncytial virus infection. BACKGROUND

[0002] More than 10,000 herbs and 100,000 recipes in ancient Chinese books can prevent and treat viral diseases, providing a rich resource for screening effective drugs. There is a deep foundation for researching and developing new antiviral traditional Chinese medicines. Cytisine is a kind of alkaloid derived from Sophora flavescens. Sophora flavescens alkaloids are monomeric compounds extracted and separated from Sophora plants. They mainly include oxymatrine, matrine, sophoramine, cytisine (CTS), oxysophocarpine and sophocarpine, etc. They have a wide range of pharmacological effects, including antiviral, antioxidant, antibacterial and antitumor effects, etc. [1] Cytisine has a wide range of pharmacological properties, such as tyrosine and topoisomerase inhibition, and is an effective drug for preventing and treating cancer and other chronic diseases. [2] Cytisine can also induce apoptosis and cell proliferation inhibition, and differentiate cancer cells. [3] Cytisine has multiple molecular effects, such as inhibiting inflammation, regulating steroid hormone receptors and metabolic pathways. [4]

[0003] Cytisine (Cytisine) has the chemical name (1R, 5S)-1, 2, 3, 4, 5, 6-hexahydro-1, 5-methano-8H-pyrido[1, 2-a][1, 5]diazocin-8-one, and its molecular formula is C 11 H 14 N2O, is a natural quinolizidine alkaloid mainly extracted from leguminous plants. In recent years, it has attracted widespread attention in the fields of smoking cessation, neuroprotection, cardiovascular protection, etc. due to its unique pharmacological activity. Cytisine mainly acts as a partial agonist of nicotinic acetylcholine receptors (nAChRs), especially with high affinity to α4β2 receptors, which can mimic the effects of nicotine, reduce withdrawal symptoms and reduce the pleasure of smoking. In addition, it also has certain agonistic effects on α7 and α3β4 subtypes, which are involved in multiple biological effects such as neuroprotection, antidepressant, antiepileptic, etc.

[0004] Human respiratory syncytial virus (RSV) is a non-segmented single-stranded negative-strand RNA virus belonging to the Paramyxoviridae family, Pneumovirus genus [5]. RSV infection can cause acute lower respiratory tract infection (ALRTI) and even death in infants, immunodeficient people and the elderly [6]. Almost all children have been infected with RSV at least once before the age of 2 [7]. The severity of RSV infection in newborns is more severe than that in older children, and it is prone to outbreak infection [8]. Acute lower respiratory tract infection (i.e. pneumonia) caused by RSV is one of the main causes of neonatal death [9]. Although the structure and function of RSV, the infection mechanism, and the immune response of the host after infection have been extensively and in-depth explored, the only FDA-approved therapeutic drug, ribavirin, has certain efficacy, but due to its possible serious adverse reactions and teratogenicity, it has not been recommended for clinical use

[10] , and the only approved palivizumab monoclonal antibody is mainly used for passive immunization prevention, and its application range is limited due to its high cost and limitation to high-risk infants [11-12], and it has not been popularized in China so far. Studies have shown that sparteine and its structurally modified derivative sparteine 9-carboxamide exhibit high antiviral activity against influenza A virus (H1N1) with selectivity indexes (SI) of 47 and 59, respectively, showing a good balance between antiviral activity and low toxicity. The anti-influenza activity and selectivity index of sparteine-camphor conjugate are higher than those of the reference drug rimantadine, and the toxicity is lower. However, whether sparteine has inhibitory effect on RSV has not been deeply explored so far.

[0005] In view of this, the present application is proposed. SUMMARY

[0006] The present application aims to provide the application of sparteine alkaloids and their derivatives in the preparation of drugs for preventing or treating respiratory syncytial virus infection, so as to provide a highly efficient and safe therapeutic drug to solve the social burden caused by RSV and reduce the treatment cost.

[0007] The present application is implemented as follows: The present application provides the application of sparteine alkaloids and their derivatives in the preparation of drugs for preventing or treating respiratory syncytial virus infection.

[0008] The present application has the following beneficial effects: The application researches and finds that natural product sparteine shows good activity of resisting respiratory syncytial virus infection in vivo and in vitro, finds that sparteine can obviously relieve lung injury caused by virus infection and reduce lung inflammation, and provides experimental basis for developing efficient and safe anti-RSV infection drugs. As a natural product, sparteine reduces the social burden caused by treatment of respiratory syncytial virus infection and reduces the treatment cost. BRIEF DESCRIPTION OF DRAWINGS

[0009] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following will briefly introduce the drawings needed to be used in the embodiments. It should be understood that the following drawings only show some embodiments of the present application, and therefore should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can also be obtained without creative labor on the basis of these drawings.

[0010] Figure 1 Anti-GZ08-18 infection experiments of sparteine in HEp-2 cells and A549 cells. It is shown that sparteine inhibits RSV replication of GZ08-18 infected HEp-2 cells and A549 cells in a dose-dependent manner; (A) representative images show that after RSV GZ08-18 with an MOI of 0.05 was incubated with HEp-2 cells at 37°C for 1 hour, the virus supernatant was removed and the unbound virus was washed away with PBS, and then the maintenance medium containing 6.25, 1.56 and 0.39 μM sparteine was inoculated and incubated for 48 hours, and the blank medium and 50 μM ribavirin were used as negative and positive controls respectively (red frame indicates cytopathic effect, CPE; magnification 10x); (B) is the TCID50 result of HEp-2 cells infected with RSV and treated with sparteine, and the data is represented as mean ± standard deviation (n=3), wherein ** indicates p<0.01. (C) is similar to (A), but RSV GZ08-18 infects A549 cells with an MOI of 0.01, and the maintenance medium containing 6.25, 1.56 and 0.39 μM sparteine is inoculated and incubated for 48 hours, and the basal medium and 50 μM ribavirin are used as negative and positive controls respectively (red frame indicates cell CPE; magnification 10x). (D) is the TCID50 result of A549 cells infected with RSV and treated with sparteine, and the data is represented as mean ± standard deviation (n=3), wherein * indicates p<0.05, ** indicates p<0.01, *** indicates p<0.001, and ns indicates no significant difference; Figure 2GZ08-18 infected HEp-2 cells. (A) Six representative immunofluorescence images were collected to show the expression of RSV F protein (green fluorescence); (B) The mean fluorescence intensity of RSV F protein in each group was semi-quantitatively analyzed using Image J software, and the data were expressed as mean ± standard deviation (n = 3 for each group), where ** p < 0.01, *** p < 0.001, ns means no statistical significance; Figure 3 GZ08-18 infected mice. (A) The changes in body weight (upper panel) and survival rate (lower panel) of mice were shown, and the data were expressed as mean weight change ± standard deviation (n = 10), where ** p < 0.01, *** p < 0.001. (B) The viral gene copy number in bronchoalveolar lavage fluid at day 3 post-infection (DPI 3) was shown, and the data were expressed as mean ± standard deviation (n = 3), where ** p < 0.01, *** p < 0.001; Figure 4 GZ08-18 infected mice. (A) The changes in body weight (upper panel) and survival rate (lower panel) of mice were shown, and the data were expressed as mean weight change ± standard deviation (n = 10), where ** p < 0.01, *** p < 0.001. (B) The viral gene copy number in bronchoalveolar lavage fluid at day 3 post-infection (DPI 3) was shown, and the data were expressed as mean ± standard deviation (n = 3), where ** p < 0.01, *** p < 0.001; Figure 5 GZ08-18 infected mice. (A) The changes in body weight (upper panel) and survival rate (lower panel) of mice were shown, and the data were expressed as mean weight change ± standard deviation (n = 10), where ** p < 0.01, *** p < 0.001. (B) The viral gene copy number in bronchoalveolar lavage fluid at day 3 post-infection (DPI 3) was shown, and the data were expressed as mean ± standard deviation (n = 3), where ** p < 0.01, *** p < 0.001; Detailed Implementation

[0011] Reference will now be made to detailed embodiments of the present invention, one or more of which are described below. Each example is provided for explanation and not for limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the invention without departing from its scope or spirit. For example, features described or illustrated as part of one embodiment may be used in another embodiment to produce further embodiments.

[0012] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0013] Definition of noun Cytisine is a quinolizidine alkaloid (QAs).

[0014] The structural formula of cytisine is as follows:

[0015] The structural formula of N-acyl gentianine is as follows: ; The structural formula of N-ethylamine is as follows: ; The structural formula of N-methylcytisine is as follows: ; Polymers of isoflavones and cytisine are, for example, compounds having any of the following structural formulas: , .

[0016] As used herein, the term "prevention" means reducing the risk of disease in an individual or group, or mitigating the severity of disease or delaying its progression, through a series of proactive interventions. Specifically, in this application, "prevention" refers to administering the drug of this application prior to respiratory syncytial virus (RSV) infection, which can alleviate lung tissue damage and / or alveolar structural destruction following RSV infection. Disease prevention is a proactive health management concept; by "intervening" to avoid or mitigate the harm of disease, its value far exceeds that of treatment after disease onset.

[0017] As used herein, the term "treatment" means a series of medical actions by medical means, techniques or methods, aiming at eliminating the cause, relieving the symptoms, controlling the disease progression, promoting tissue repair, restoring function or alleviating pain for the disease that has occurred. Specifically in the present application, "treatment" refers to the administration of the drug of the present application after respiratory syncytial virus infection, which can improve the damage of lung tissue and / or the destruction of alveolar structure.

[0018] The present application provides a use of a sparteine alkaloid and a derivative thereof in the preparation of a drug for preventing or treating respiratory syncytial virus infection.

[0019] The present application finds that the natural product sparteine has good anti-RSV infection activity in vivo and in vitro, and sparteine can alleviate the lung damage caused by viral infection and reduce lung inflammation, which lays a foundation for the development of efficient and safe anti-RSV infection drugs.

[0020] In a preferred embodiment of the present application, the derivative of the sparteine alkaloid is selected from at least one of the following: N-acyl sparteine, N-ethyl sparteine, N-methyl sparteine, sparteine isoflavone polymer.

[0021] In a preferred embodiment of the present application, the sparteine alkaloid and the derivative thereof are derived from a plant of the Leguminosae family.

[0022] In a preferred embodiment of the present application, the sparteine alkaloid and the derivative thereof are derived from a plant of the Sophora, Thermopsis, Radermachera or Lupinus genus.

[0023] In a preferred embodiment of the present application, the sparteine alkaloid and the derivative thereof are derived from Radermachera fraxinifolia, Sophora tonkinensis or S. alopecuroides.

[0024] In a preferred embodiment of the present application, the drug is administered by injection or orally.

[0025] In a preferred embodiment of the present application, the drug has at least one of the following application modes: (1) improving the body weight of the subject; (2) inhibiting or eliminating the phenomena of shortness of breath and difficulty in breathing of the subject; (3) restoring the mental state of the subject; (4) improving the survival rate of the subject; (5) improving the damage of lung tissue and / or the destruction of alveolar structure; (6) inhibiting the level of inflammatory factors.

[0026] In a preferred embodiment of the present application, the inflammatory factors are selected from at least one of IL-6, IL-1β, MIP-1α and CXCL-10.

[0027] In a preferred embodiment of the application, the medicament further comprises a pharmaceutically acceptable vehicle.

[0028] In a preferred embodiment of the application, the excipient comprises, but is not limited to, a conventional pharmaceutical excipient, carrier or diluent.

[0029] The medicament further comprises a pharmaceutically acceptable carrier, such as water, saline, sugars, polysaccharides, buffers, excipients, biodegradable polymers, liposomes, stabilizers, and the like.

[0030] The pharmaceutically acceptable excipient comprises, but is not limited to, a filler, lubricant, disintegrant, binder, glidant, and the like.

[0031] In a preferred embodiment of the application, the pharmaceutically acceptable excipient comprises, but is not limited to, one or more of polyvinylpyrrolidone and its derivatives, polyvinyl alcohol and its derivatives, methylcellulose and its derivatives, ethylcellulose and its derivatives, hydroxypropylcellulose and its derivatives, hydroxypropylmethylcellulose, starch and its derivatives, polyethylene glycol and its derivatives, lactose, lactose starch complex, lactose cellulose complex, sucrose, mannitol, mannitol starch complex, trehalose, sorbitol, dextrin, microcrystalline cellulose, acrylic resin, povidone, copovidone, calcium hydrogen phosphate, calcium stearate, sodium stearyl fumarate, silicon dioxide, titanium dioxide, talc, color indigo, low-substituted hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked povidone, magnesium stearate, sodium stearyl fumarate, talc, one or more of stearic acid, or a combination thereof.

[0032] In an alternative embodiment, the medicament is a liquid pharmaceutical formulation (e.g., as an injection), such as a solution, suspension, and gel, typically containing a liquid carrier, such as water and / or a pharmaceutically acceptable organic solvent. In addition, such liquid formulations can also include pH adjusting agents, emulsifying or dispersing agents, buffers, preservatives, wetting agents, gelling agents (e.g., methylcellulose), such as defined above. The medicaments can be isotonic, i.e., they can have the same osmotic pressure as blood. The isotonicity of the medicaments can be adjusted by the use of sodium chloride and other pharmaceutically acceptable agents, such as dextrose, maltose, boric acid, sodium tartrate, propylene glycol, and other inorganic or organic soluble substances. The viscosity of the liquid composition can be adjusted by pharmaceutically acceptable thickening agents, such as methylcellulose. Other suitable thickening agents include, for example, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, and the like. The preferred concentration of the thickening agent depends on the agent selected.

[0033] In a preferred embodiment of the application, the medicament is in the form of a tablet, pill, powder, suspension, gel, emulsion, cream, granule, nanoparticle, capsule, suppository, injection, spray, or needle.

[0034] The features and properties of the present application are further described in detail below in connection with the examples.

[0035] Geniposide was purchased from Shanghai Yuenye Biotech Co., Ltd., CAS NO. 485-35-8, Item No. s31403.

[0036] Example 1 In vitro antiviral experiment.

[0037] A549 cells and HEp-2 cells were cultured in RPMI Medium 1640 containing 10% fetal bovine serum and 1% penicillin-streptomycin and DMEM / F12-GlutaMAX containing 5% fetal bovine serum and 1% penicillin / streptomycin, respectively, at 1×10 4 Cells were plated in 96-well plates at 37 °C and 5% CO2 for 24 h. GZ08-18 virus liquid was inoculated at a multiplicity of infection (MOI) of 0.05, and the supernatant was discarded after 1 h of infection. According to the MTT experiment results on A549 cells, 6.25, 1.56, and 0.39 μM of geniposide were selected for subsequent virus infection experiments. 50 μM of ribavirin was set as a positive control. The supernatant was collected after 48 h, and the TCID 50 The virus titer was determined and recorded.

[0038] The cell pathological effect (CPE) photos of RSV-infected HEp-2 cells are presented in Fig. 1A, and the cell pathological effect (CPE) photos of RSV-infected A549 cells are presented in Fig. 1C, Figure 1 Figure 1 Figure 1 Fig. 1B and Fig. 1D are the TCID 50 The experimental results. Geniposide inhibited RSV replication in RSV-infected HEp-2 cells and A549 cells in a dose-dependent manner, significantly reduced the replication of RSV genes, and showed similar antiviral effects to ribavirin in HEp-2 cells and A549 cells, with dose-dependent inhibition ( Figure 1 ).

[0039] In the cell immunofluorescence experiment, sterile cell slides were placed in a 12-well plate, and 2×10 5 ​​HEp-2 cells were seeded at a density of one cell and incubated at 37 °C, 5% CO2 for 24 h. After the cells adhered to the appropriate density, the cells were inoculated with GZ08-18 virus liquid at an MOI of 0.05 and adsorbed at 37 °C, 5% CO2 for 1 h. Then the virus liquid was discarded, and the maintenance medium containing different concentrations of drugs was added for continuous culture for 48 h. After the end of the culture, the cell climbing sheets were collected, fixed with 4% polyformaldehyde, permeated, blocked, incubated with RSV F primary antibody at 4 °C overnight (1:100), incubated with fluorescent secondary antibody at room temperature for 1 h (1:300), DAPI restained, and sealed with an anti-fluorescence quencher. After sealing, the pictures were collected by a laser confocal microscope, and the average fluorescence intensity was counted by Image J software.

[0040] Figure 2 Figure 6A is six groups of representative immunofluorescence images, which are: negative control HEp-2 cells (Mock), HEp-2 cells infected with GZ08-18, HEp-2 cells infected with GZ08-18 and treated with 50.00 μM ribavirin, and HEp-2 cells infected with GZ08-18 and treated with different concentrations (0.39 μM, 1.56 μM, 6.25 μM) of sparteine. The nuclei are stained with DAPI to blue fluorescence. The MOI of GZ08-18 is 0.01, and the scale is 50 μm. Figure 2 Figure 6B is a semi-quantitative analysis result, which shows that sparteine effectively inhibits the expression of RSV F protein in a dose-dependent manner. Figure 2 In general, these findings strongly suggest that sparteine has the activity of inhibiting RSV replication in vitro.

[0041] Example 2 In vivo antiviral experiment.

[0042] The weight change rate and survival rate of five groups of mice after infection were counted, and the mice were divided into the following five groups, 10 in each group: Mock group (mock infection group), GZ08-18 challenge group (GZ08-18+Saline), GZ08-18 challenge plus 2 mg / kg sparteine treatment group, GZ08-18 challenge plus 1 mg / kg sparteine treatment group, and GZ08-18 challenge plus 25 mg / kg ribavirin positive drug treatment group. Except for the Mock group, the mice in the other groups were inhaled with a total amount of 360 μl of GZ08-18 virus liquid through the tracheal route in three times within 2 d (each challenge of 120 μl, approximately equal to 1.2 x 10 10 TCID 50Viral load was measured to establish a lethal RSV infection model. Treatment groups received intraperitoneal (IP) injections of appropriate concentrations of cytisine or ribavirin one hour after each challenge. Day 0 post-infection (D0 DPI) was defined as the last challenge. Mouse weight was recorded daily based on the previous day's weight, and mouse status and survival were observed and recorded morning and evening until day 21 post-infection (21 DPI). Lung tissue was collected from each group on day 3 post-infection to determine viral load. Immunofluorescence laser confocal microscopy was used to observe changes in viral F protein expression, and hematoxylin-eosin (H&E) staining of lung tissue was used to observe pathological changes. The mRNA copy numbers of inflammatory factors IL-6, IL-1β, MIP-1α, and CXCL-10 in lung homogenates were detected by qRT-PCR.

[0043] All groups infected with GZ08-18 experienced weight loss, with infected mice losing approximately 15% of their body weight by day 3. Meanwhile, the virus control group continued to lose weight, leading to irreversible weight loss, with a survival rate of 0% (0 / 10) by day 6; mice treated with 1 mg / kg cytisine had a survival rate of 0% (0 / 10) by day 7. However, mice treated with 50 mg / kg ribavirin and 2 mg / kg cytisine successfully recovered their lost weight. Notably, mice treated with 2 mg / kg cytisine began to recover weight at 6 DPI, ultimately achieving a survival rate of 50% (5 / 10), while the survival rate in the 50 mg / kg ribavirin treatment group was 70% (7 / 10). Figure 3 (A) Meanwhile, the TCID of bronchoalveolar lavage fluid... 50 The results clearly showed that the viral load in the lung tissue of mice was significantly reduced after treatment with cytisine. Figure 3 (B in the text). These results demonstrate that cytisine has a significant protective effect against fatal GZ08-18 infection in vivo.

[0044] Immunofluorescence staining was performed on mouse lung tissue sections to detect the expression level of viral F protein. Figure 4 (A in the original text). The results showed that the viral F protein expression level was highest in the GZ08-18 infection group. In contrast, the F protein expression levels were decreased in the ribavirin and cytisine treatment groups. Figure 4 (B in the figure represents the semi-quantitative fluorescence analysis of each group). The fluorescence intensity of all cytisine treatment groups was lower than that of the virus control group, with the 2 mg / kg cytisine treatment group showing a more significant inhibitory effect than the 1 mg / kg treatment group. In terms of histopathology, Figure 4C shows that compared with the mock infection control group, the lungs of mice infected with GZ08-18 showed obvious pathological damage, including extensive fusion and destruction of alveolar structure, a large number of red blood cell infiltration in alveolar cavity, significant thickening of alveolar septum, focal atelectasis and a large number of inflammatory cell infiltration. In the treatment group, no obvious pathological improvement was found in the 1 mg / kg sparteine treatment group; however, the lung damage degree of the 2 mg / kg sparteine treatment group and the ribavirin positive drug control group was reduced, showing more complete alveolar structure and alleviated inflammatory infiltration. Figure 4 The lung injury score in D shows that the injury degree of all sparteine treatment groups is lower than that of the virus control group, among which the score of the 1 mg / kg sparteine treatment group has no statistical difference with the GZ08-18 infection group, while the 2 mg / kg sparteine treatment group shows a significant reduction.

[0045] In the lung tissue homogenate samples of mice infected with GZ08-18 on the 3rd day, the inflammatory cytokine genes IL-6, IL-1β, MIP-1α and CXCL-10 are significantly up-regulated. Both ribavirin and sparteine significantly inhibit these inflammatory cytokines. Notably, for IL-1β, sparteine shows a stronger inhibitory effect than ribavirin; the transcription level of IL-1β can be used as a surrogate marker for NLRP3 activity, providing new information for evaluating the severity of pathogen-induced inflammation. Figure 5

[0046] In summary, the present application uses the successfully established human respiratory syncytial virus human laryngeal carcinoma epithelial cell (HEp-2) infection model, intervenes RSV infected cells with different concentrations of sparteine, and uses TCID 50 and fluorescence quantitative PCR and other experimental methods to determine the virus titer, combined with cytotoxicity experiments, to evaluate the activity of sparteine against RSV cell infection, and based on the lethal RSV infected mouse model, the in vivo antiviral activity of sparteine is systematically evaluated, and the possible anti-inflammatory mechanism of sparteine against infection is explored.

[0047] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

[0048] Reference: [1] Wu Q, Gao Y. Research Progress on Molecular Mechanism of Oxymatrine Pharmacological Action [J]. Chinese Pharmacological Bulletin, 2015, 31(06): 759-762. ​[2] Ganai AA, Farooqi H. Bioactivity of genistein: a review of invitro and in vivo studies[J]. Biomedicine&pharmacotherapy, 2015, 76: 30-38. [3] Jaiswal N, Akhtar J, Singh SP, et al. An overview on genisteinand its various formulations[J]. Drug research, 2019, 69(06): 305-313. [4] Mukund V, Mukund D, Sharma V, et al. Genistein: Its role inmetabolic diseases and cancer[J]. Critical reviews in oncology / hematology, 2017, 119: 13-22. [5]Nam HH, Ison M G. Respiratory syncytial virus infection in adults[J]. BMJ, 2019: l5021. [6]Russell CD, Unger SA, Walton M, et al. The Human Immune Response to Respiratory Syncytial Virus Infection[J]. Clinical Microbiology Reviews, 2017, 30(2): 481–502. [7]Baker KA, Ryan M E. RSV infection in infants and young children:What's new in diagnosis, treatment, and prevention?[J]. PostgraduateMedicine, 1999, 106(7): 97–111. [8] Huang Xiaoxi, Du Kun. Research progress on different subtypes of neonatal respiratory syncytial virus [J]. China Contemporary Medicine, 2022, 29(15): 31–35. [9] Xia W, Wei H. Research status of neonatal respiratory syncytial virus infection and prevention[J]. Journal of Pediatric Pharmacy, 2022, 28(3): 56-58.

[10] Shang Z, Tan S, Ma D. Respiratory syncytial virus: from pathogenesis to potential therapeutic strategies[J]. International Journal of Biological Sciences, 2021, 17(14): 4073-4091.

[11] Garegnani L, Roson Rodriguez P, Escobar Liquitay C M, et al. Palivizumab for preventing respiratory syncytial virus (RSV) infection in children[J]. Cochrane Acute Respiratory Infections Group. Cochrane Database of Systematic Reviews, 2020.

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Claims

1. Application of cytisine-type alkaloids and their derivatives in the preparation of drugs for the prevention or treatment of respiratory syncytial virus infection.

2. The application according to claim 1, characterized in that, The derivatives of the cytisine-type alkaloids are selected from at least one of the following: N-acylcytisine, N-ethoxycytisine, N-methylcytisine, and cytisine isoflavone polymers.

3. The application according to claim 1, characterized in that, The alkaloids and their derivatives are derived from leguminous plants.

4. The application according to claim 3, characterized in that, The alkaloids and their derivatives are derived from plants of the genera *Sophora*, *Sophora*, *Cassia*, or *Lupinus*.

5. The application according to claim 4, characterized in that, The alkaloids and their derivatives are derived from Senna lanceolata, Sophora japonica, or Sophora tonkinensis.

6. The application according to claim 1, characterized in that, The drug can be administered by injection or orally.

7. The application according to any one of claims 1-6, characterized in that, The drug has at least one of the following application methods: (1) Increase the weight of the subjects; (2) Suppress or eliminate the subject's shortness of breath and difficulty breathing; (3) Restore the mental state of the subject; (4) Improve the survival rate of subjects; (5) Improves lung tissue damage and / or alveolar structure disruption; (6) Inhibit the level of inflammatory factors.

8. The application according to claim 7, characterized in that, The inflammatory factor is selected from at least one of IL-6, IL-1β, MIP-1α, and CXCL-10.

9. The application according to any one of claims 1-6, characterized in that, The medication also includes pharmaceutically acceptable dressings.

10. The application according to claim 1, characterized in that, The dosage form of the drug is tablet, pill, powder, suspension, gel, emulsion, cream, granule, nanoparticle, capsule, suppository, injection, spray or injection.

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