CN111803635A - Application of small molecule inhibitor in treating respiratory viral pneumonia - Google Patents

Abstract

The application provides application of a small molecule inhibitor in treating respiratory viral pneumonia. In particular to a new application of the AhR inhibitor in treating or improving respiratory virus infection. The inhibitor for treating virus infection provided by the application can effectively inhibit pathological mucus generated by virus-induced organism lung tissues, and the AhR inhibitor is expected to become a potential drug for treating lung diseases caused by respiratory virus infection.

Description

Application of small molecule inhibitors in the treatment of respiratory viral pneumonia

This application claims priority from patent application 202010552732.7 (priority date June 17, 2020).

technical field

This application relates to biological, medical and clinical fields. In particular, it relates to small molecule inhibitors and their use in the treatment of viral pneumonia.

Background technique

Viral pneumonia can be outbreaks or sporadic epidemics. Viral pneumonia can occur at any time of the year, but is more common in winter and spring. Initially, the upper respiratory tract virus infection is the main cause, and as the virus spreads down to the lungs, it causes pneumonia.

Viral pneumonia can be transmitted through droplets. The clinical manifestations are generally mild and mainly include headache, fatigue, fever, cough and other similar symptoms of respiratory diseases. Respiratory infections are one of the leading causes of death worldwide, especially in patients with severe pneumonia, which have high mortality and severe sequelae. At present, viruses such as influenza virus and coronavirus are the main pathogens that cause regional outbreaks of severe pneumonia, with strong infectivity and high fatality rate.

Once the new type of coronavirus pneumonia (COVID-19) enters the severe stage, its process will become very difficult to control, and it will easily lead to the death of patients. At present, the cause of death of patients with new coronavirus infection is not clear. It is generally believed that the uncontrolled severe inflammatory response caused by new coronary pneumonia may be involved in the process of patient death. Clinically, drugs targeting the key inflammatory cytokine IL-6 have been tested in critically ill patients with novel coronavirus pneumonia. This inflammatory cytokine can damage alveolar epithelial cells and endothelial cells, leading to increased pulmonary capillary permeability and pulmonary interstitial fibrosis, thereby hindering the exchange of oxygen and carbon dioxide in the body, leading to the death of patients due to hypoxia. It is the key cause of death in critically ill patients with novel coronavirus pneumonia. However, clinical symptoms of hypoxia appear to appear in the early stages of 2019-nCoV pneumonia patients, while uncontrolled inflammatory responses may appear at a relatively later stage. Clinical practice has found that many asymptomatic patients with novel coronavirus pneumonia have early clinical manifestations of hypoxia, which suggests that other factors before the outbreak of inflammatory cytokines may also lead to hypoxia in patients with novel coronavirus pneumonia. The autopsy report shows that mucus and mucus plugs can be seen in the alveolar cavity of patients with new coronavirus pneumonia.

Therefore, how to provide can reduce the production of mucus in the patient's respiratory system, thereby effectively improving the dyspnea and hypoxemia of the new crown patient, has become a problem to be solved at present.

SUMMARY OF THE INVENTION

According to some embodiments of the present application, there is provided an AhR (arylhydrocarbonreceptor) inhibitor useful as a viral pneumonia agent. The viral pneumonia formulation includes an AhR inhibitor.

In the present application, the term "inhibitor" refers to a natural or synthetic compound that inhibits (or reduces or downregulates) the expression of genes and/or proteins, and/or inhibits (or reduces or downregulates) genes and/or The activity of the protein, and/or the modulation of the associated signaling pathway with the gene and/or protein. As a non-limiting example, the inhibitor can act on any one or combination of the following genes and/or proteins: such as, but not limited to, translation, post-translational processing, stability, degradation, nuclear localization, cytoplasmic localization, transcription , post-transcriptional processing, activation, inactivation, modification, signaling. Inhibitors are allowed to be competitive, noncompetitive, fully antagonistic, or partially antagonistic.

Thus, an AhR inhibitor refers to a compound that inhibits (or reduces or downregulates) the expression of AhR-encoding genes, and/or the expression of AhR, and/or the activity of AhR, and/or modulates AhR-related signaling pathways (eg, but not limited to upstream of AhR-related signaling pathways). According to some embodiments of the present application, there is provided the use of an AhR inhibitor in the preparation of a medicament, wherein the medicament is used for any one or a combination selected from the group consisting of preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia or its symptoms.

In some embodiments, the virus is selected from one or a combination of the following: coronavirus, influenza A, influenza B, influenza C, measles, mumps, respiratory syncytial virus, parainfluenza, Human metapneumovirus, Hendra virus, Nipah virus, Rubella virus, Rhinovirus, Adenovirus, Reovirus, Coxsackie virus, ECHO virus, and variants thereof.

In some embodiments, the medicament is prepared in a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral dosage forms, dosage forms suitable for mucosal administration.

AhR inhibitors suitable for use in the present application are, for example, but not limited to, compounds disclosed in the prior art: WO2019036657, WO2018195397, CN106860471A, WO2013034685, WO2012015914.

In some exemplary embodiments, the AhR inhibitor is selected from one or a combination of: AhR Antagonist 1, α-NF, CB7993113, CMLD-2166, CH223191, DMF, GNF351, PDM2, StemRegenin 1, SR1, IDO inhibitors.

In some embodiments, there is provided an IDO (indoleamine 2,3-dioxygenase) inhibitor useful as a viral pneumonia agent. The viral pneumonia formulation includes an IDO inhibitor.

IDO (eg, IDO1) is an active molecule located upstream of the AhR signaling pathway. Therefore, inhibitors acting on IDO can indirectly modulate the activity of AhR.

An IDO inhibitor refers to a compound that inhibits (or reduces or downregulates) the expression of a gene encoding IDO, and/or the expression of IDO, and/or the activity of IDO.

In the art, IDO inhibitors can generally be divided into the following types according to their structures:

- Tryptophan analogs: an exemplary compound is the N-methyl derivative of tryptophan, L1MT;

- Quinones: mainly obtained from natural products;

-Imidazole and triazole compounds: 4-benzimidazole and its derivatives can coordinate with the iron atom of heme and have strong IDO inhibitory activity. An exemplary compound is NLG919 from NewLink Genetics;

-N-Hydroxyamidine compounds: N-Hydroxyamidine compounds can combine with the iron atom of heme and form a hydrogen bond with the nitrogen atom on the adjacent amide group. An exemplary compound is INCB024360.

IDO inhibitors suitable for use in the present application are, for example, but not limited to compounds disclosed in the prior art: CN106866648B, CN106883224B, CN107501272B, CN109438513B, CN109748838B, CN105567690B, CN107260743B, WO2015173764.

In some exemplary embodiments, the IDO inhibitor is selected from one or a combination of the following: tryptophan analogs, quinones and derivatives thereof, imidazoles and derivatives thereof, triazoles and derivatives thereof, N -Hydroxyamidine and its derivatives.

In some embodiments, the IDO inhibitor is selected from one or a combination of: 1-MT, Epacadostat, DO-IN-2, NLG919, PF-06840003, INCB024360, Exiguamine A, benzimidazole.

In some embodiments, the amount of the AhR inhibitor in a unit formulation is 10 mg to 10 g. Mention may be made of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, 1.5 g, 2 g, 2.5 g, 3 g , 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, 10g or a range between any two of the foregoing values.

In some embodiments, the amount of IDO inhibitor in a unit formulation is 1 g to 10 g.

In other embodiments, the amount of the AhR inhibitor in a unit formulation is 10 mg to 80 mg.

In some embodiments, the coronavirus is selected from the group consisting of: SARS, MERS, 2019-nCoV, and variants thereof.

In some embodiments, the treatment is embodied as one or a combination selected from the group consisting of:

Improve blood oxygen saturation, improve PaO ₂ /FiO ₂ , relieve respiratory distress, reduce RRS respiratory system resistance, improve ERS, improve PV-k level, improve Eta level, reduce airway mucus, regulate the expression level of mucin, delay or prevent The disease develops to severe disease, improves the survival rate, and prolongs the survival period.

In some embodiments, the viral pneumonia is selected from: mild, normal, severe, critical.

According to some embodiments, there is provided a pharmaceutical composition comprising an AhR inhibitor, and optionally a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is for use in any one or a combination selected from the group consisting of preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia or symptoms thereof.

In some embodiments, the virus is selected from one or a combination of the following: coronavirus, influenza A virus, influenza B virus, influenza C virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza Viruses, human metapneumovirus, Hendra virus, Nipah virus, Rubella virus, Rhinovirus, Adenovirus, Reovirus, Coxsackie virus, ECHO virus, and variants thereof.

In some embodiments, the coronavirus is selected from the group consisting of: SARS, MERS, 2019-nCoV, and variants thereof.

In some embodiments, the pharmaceutical composition is in a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral dosage forms, dosage forms suitable for mucosal administration.

According to some embodiments, there is provided a method of preventing or treating viral pneumonia comprising administering to a subject a prophylactically effective amount or a therapeutically effective amount of an AhR inhibitor. In some embodiments, routes of administration that may be mentioned include, but are not limited to: intramuscular, intravenous, subcutaneous, intradermal, oral, intranasal, respiratory, transmucosal, sublingual, parenteral.

In some embodiments of the methods according to the present application, an "effective amount" or "effective dose" refers to the amount of drug, compound, pharmaceutical composition necessary to obtain any one or more beneficial or desired therapeutic results. Beneficial or desired outcomes include: improvement in clinical outcome (eg, reduction in morbidity, mortality, improvement in one or more symptoms), reduction in severity, delay in onset of the disorder (including the disorder or its complications, progression of the disorder) intermediate pathological phenotypes, biochemical, histological and/or behavioral symptoms present in

In some embodiments, the unit formulation is a formulation that satisfies the required active ingredient (AhR inhibitor) for one-time administration, such as a unit (injection) injection and the like.

The amount of drug required for a single administration to a patient can be conveniently obtained by calculating the product of the patient's body weight and the dose per unit body weight required for a single administration of the patient. For example, in the process of preparing the medicine, it is generally considered that the weight of an adult is 50-70 kg, and the dosage can be determined initially through the equivalent dose conversion relationship between the doses per unit body weight of experimental animals and humans. For example, it can be based on the guidance provided by the FDA, SFDA and other drug regulatory agencies, or refer to (Huang Jihan et al., "Conversion of Equivalent Dose Between Animals and Between Animals and Humans in Pharmacological Experiments", "Chinese Clinical Pharmacology and Therapeutics" , 2004 Sep;9(9):1069-1072) to determine.

In the embodiment of the present application, the dose of human and mouse can be converted using a conversion factor of 0.0026 according to the body surface area of human and mouse.

In the protocol of the present application, for example, for a mouse weighing 20 g, the IDO inhibitor is administered to the mouse in an amount of 1000 mg/kg (for example, for a 20 g mouse, the IDO inhibitor is formulated in water as a 5 mg/mL solution , the mice were administered 4 mL of this solution every day).

According to some embodiments, there is also provided a method of preventing respiratory viral pneumonia from becoming severe, comprising administering the anti-respiratory viral pneumonia formulation to a patient with respiratory viral pneumonia or an individual with a tendency to become severe the process of. The specific process is intravenous or oral AhR inhibitor.

According to the scheme of the present application, the amount of the AhR inhibitor in the anti-respiratory viral pneumonia preparation can be controlled as required, so as to facilitate the administration to patients with viral pneumonia at different stages.

Without being bound by any theory, interferon is the first alarm of viral invasion, and its signal activates a series of antiviral genes to exert direct antiviral effects. However, delayed interferon responses may cause immunopathological changes in the body through the recruitment and activation of innate immune cells that produce high levels of inflammatory factors. In the applicant's study, it was found that IFN-β and IFN-γ up-regulated the expression of mucin in BAES-2B cells, and the mucus produced was blocked in the alveolar space of the patient, thereby causing dyspnea and hypoxemia in the patient, resulting in the death of the patient. The applicant has unexpectedly discovered through a large number of experimental studies that AhR inhibitors can effectively block the mucus produced by the respiratory system induced by IFN-β and IFN-γ, and can realize the clinical treatment and prevention of critically ill respiratory viral pneumonia patients with viral pneumonia. value.

In some embodiments of the methods according to the present application, a patient refers to a virus carrier, in particular a patient who has developed or may develop symptoms due to the presence of the virus. In particular embodiments, the patient is especially a patient at risk of developing severe or critical illness.

Description of drawings

Figure 1 shows that there may be a large amount of mucus-like substances in the bronchoalveolar lavage fluid of patients with COVID-19 after PAS staining experiments.

Figure 2A and Figure 2B show that humanized ACE2 transgenic mice were used as an animal model for SARS-CoV-2 infection, and it was observed that compared with the control group (Mock group, hACE2 mice that were not infected with the virus), the infected group mice The up-regulated expression and nuclear localization of AhR protein in lung epithelial cells (Fig. 2A), and the expression of IFN-β in lung tissue was found to be elevated in the infected group (Fig. 2B).

Figures 3A to 3E show that the lung function of mice was damaged after treatment with IFN-β or IFN-γ by bronchial aerosol inhalation. After intravenous injection of AhR inhibitor, the lung function of mice returned to normal. .

Figure 4A, after the mice were treated with IFN-β or IFN-γ by bronchial inhalation, the mucin levels in the lungs of the mice were significantly increased by immunohistochemical staining.

Figure 4B shows that the marked increase in mucin levels in the lungs of mice was reversed after intravenous injection of the AhR inhibitor.

Figures 5A to 5F show that humanized ACE2 (hACE2) transgenic mice were used as an animal model for SARS-CoV-2 infection, and it was observed that compared with the control group (Mock group-virus-uninfected hACE2 mice), the The expression levels of IFN-β and IFNγ in lung tissue were found to be increased in the infected group (FIG. 5A to FIG. 5D). The expression of IFN-[beta] was measured at different time points by real-time PCR (Fig. 5E). The expression of IFN-γ was measured by real-time PCR at different time points after infection of hACE2 transgenic mice with SARS-CoV-2 (Fig. 5F).

Figures 6A to 6C show (bar: 50 μm): SARS-CoV-2-infected humanized ACE2 transgenic mice as an animal model, it was observed that administration of an AhR inhibitor reversed the pneumonia symptoms in the infected mice. Fig. 6A control group; Fig. 6B model group; Fig. 6C treatment group.

Detailed ways

1. Various cell lines, drugs and experimental animals used in the following examples:

BEAS-2B human lung epithelial cell line was purchased from China Type Collection Center CCTCC;

4-6-week-old female Balb/c mice were purchased from the Experimental Animal Center of Union Medical College, Chinese Academy of Medical Sciences;

4-6 week old C57-humanized ACE2 mice were obtained from the Institute of Laboratory Animals, Union Medical College, Chinese Academy of Medical Sciences;

IDO inhibitor (1-MT) was purchased from SIGMA Company in the United States;

AhR inhibitor (CH223191) was purchased from MCE Company, USA.

2. Patient sample source:

Collection of paraffin-embedded BAL samples from SARS-CoV-2 patients. BAL samples were obtained from patients aged 22-82 years, 4 males and 4 females.

3. The clinical classification of patients is divided into four types:

Mild: The clinical symptoms are mild, and no pneumonia is found on imaging.

Ordinary type: with symptoms such as fever and respiratory tract, and pneumonia can be seen on imaging.

Heavy: Meets any of the following:

Respiratory distress, RR≥30 beats/min;

In the resting state, the oxygen saturation is less than or equal to 93%;

Arterial partial pressure of oxygen (PaO2)/inhaled oxygen concentration (FiO2)≤300mmHg

(1 mmHg=0.133 kPa).

Critical type: Those who meet one of the following conditions:

Respiratory failure occurs and requires mechanical ventilation;

shock;

Combined with other organ failure, ICU monitoring and treatment are required.

Embodiment 1. SARS-COV-2 virus infection causes the expression of a large amount of mucin in patient's lung tissue

1. Experimental procedure

Eight clinical subjects were recruited, and bronchoalveolar lavage fluid was obtained and bacterial culture was performed according to fiberoptic bronchoscopy procedures.

The operation method is as follows: intramuscular injection of atropine and phenobarbital sodium 2 hours before the operation, and local anesthesia with lidocaine hydrochloride 0.1 g, among which patients with poor compliance and nervousness and anxiety are given intravenous painless anesthesia; after the anesthesia is completed, the Olympus The electronic bronchoscope was extended through the patient's nasal cavity to the lesion and the site with a lot of secretions in the lower respiratory tract, and 50ml of sterile 0.9% sodium chloride solution was given for lavage or repeated lavage after brushing, and then the lavage fluid was collected and collected. Put it into a sterile sputum collection bottle and send it for inspection within 2 hours.

The specimens submitted for inspection were separated and identified in accordance with the corresponding requirements of the "National Clinical Inspection Procedures". The isolated bronchoalveolar lavage (BAL) specimens were fixed with 10% neutral formalin, embedded in paraffin, stained with conventional HE, immunohistochemical and PAS stained, and observed under light microscope.

2. Experimental results

PAS staining showed a large amount of mucus in the bronchoalveolar lavage fluid (BAL) (Figure 1), and the results indicated that viral infection resulted in the expression of a large amount of mucin in the lung tissue of patients with new coronary pneumonia.

Embodiment 2. SARS-COV-2 virus stimulates the nuclear localization phenomenon of lung tissue AHR

1. Experimental steps

C57-humanized ACE2 transgenic mice were infused with unexposed intratracheal infusion. The normal group was injected with the same volume of normal saline as the treatment group at one time through the trachea, and the treatment group was perfused with 10 ⁵ units of SARS-CoV-2 virus particles through the trachea at one time.

Immediately after injection, the animals were rotated fully upright to make the drug evenly distributed in the lungs, and the model was waited for 1 week. Lung tissue collection: After the mice were anesthetized with sodium barbital, after the mice were sacrificed, the lung tissue was removed by opening the chest, and the blood stains on the surface of the lung tissue were washed with prepared normal saline. Store at –80°C. A portion of lung tissue was immediately preserved in 4% paraformaldehyde for preparation of immunofluorescence staining.

2. Experimental results

In the lung tissue of human ACE2 transgenic mice infected with SARS-CoV-2, the inventors found that compared with the control group mice (MOCK group, uninfected with virus), the results of immunofluorescence staining showed that the AHR in the lung tissue of the mice was significantly higher. Expression was up-regulated, and nuclear localization appeared (Fig. 2A).

In the lung tissue of human ACE2 transgenic mice infected with SARS-CoV-2, the inventors found that compared with the control mice, the results of immunohistochemical staining showed that the expression of IFNβ and IFNγ in the lung tissue of the mice was significantly up-regulated (Figure 5A). and Figure 5B, Figure 5C and Figure 5D).

At the RNA level, it can be found that the expression of IFNβ RNA in lung tissue increases with time, with obvious time dependence, and the expression of IFNγ is also significantly up-regulated in the virus-infected group (Figure 5E and Figure 5F).

Example 3. AHR inhibitor reverses IFN-β or IFN-γ-induced lung damage in mice

1. Experimental steps:

C57 mice were treated with unexposed intratracheal infusion. The normal group was injected with the same amount of normal saline as the treatment group at one time through the trachea, and the experimental group was injected with 5 μg/mouse IFN-β or 10 μg/mouse IFN-γ through the trachea at one time. Immediately after injection, the animals were rotated fully upright to distribute the drug evenly in the lungs. Blood gas analysis and mouse lung function tests were performed after administration once a day for four consecutive days.

Control group (PBS): PBS was administered to the trachea every day;

Experimental group 1 (IFN-β modeling group + PBS): 5 μg/mouse IFN-β + PBS was administered to each trachea;

Experimental group 2 (IFN-β modeling group + CH223191): 5 μg/mouse IFN-β + 10 mg/kg CH223191 was administered to the trachea every day;

Experimental group 3 (IFN-γ modeling group + CH223191): 10 μg/mouse IFN-γ + 10 mg/kg CH223191 was administered to the trachea every day;

Experimental group 4 (IFN-γ modeling group + PBS): 10 μg/mouse IFN-γ was administered to the trachea every day.

2. Experimental results:

IFN-β and IFN-γ can lead to decreased blood oxygen saturation in mice (Fig. 3A), hypoxia and dyspnea, increased Rrs (respiratory system resistance), ERS (respiratory system elasticity), PV-k and Eta, etc. The level of the index reflects the damage of lung function in mice.

Then, the IDO-KYN-AhR pathway was blocked by intravenous injection of an AhR inhibitor. Under this condition, the IFN-β or IFN-γ-induced respiratory impairment in mice disappeared (Fig. 3B to Fig. 3E).

Example 4. AHR inhibitor reverses IFN-β-induced mucin upregulation and lung function impairment in mouse lung tissue

1. Experimental steps:

C57 mice were treated with unexposed intratracheal infusion. The normal group was injected with the same volume of normal saline as the treatment group at one time through the trachea, and the experimental group was injected with 5 μg of IFN-β, IFN-γ, IFN-β+CH223191 or IFN-γ modeling group+CH223191 through the trachea at one time. Immediately after injection, the animals were rotated fully upright to distribute the drug evenly in the lungs. Lung function was measured and lung tissue samples were collected after four consecutive days of dosing once a day. Lung tissue collection: After the mice were anesthetized with sodium barbital, the mice were sacrificed, and the heart was perfused. After removing the blood from the lungs, the lung tissue was taken out, and the blood stains on the surface of the lung tissue were washed with prepared normal saline. Immediately after the above procedure, the tissue was stored at –80°C. A portion of lung tissue was immediately preserved in 4% paraformaldehyde for preparation for immunohistochemical staining.

Control group (PBS): PBS was administered to the trachea every day;

Experimental group 1 (IFN-β modeling group + PBS): 5 μg/mouse IFN-β + PBS was administered to the trachea every day;

Experimental group 2 (IFN-β modeling group + CH223191): 5 μg/mouse IFN-β + 10 mg/kg CH223191 was administered to the trachea every day;

Experimental group 3 (IFN-γ modeling group + CH223191): 10 μg/mouse IFN-γ + 10 mg/kg CH223191 was administered to the trachea every day;

Experimental group 4 (IFN-γ modeling group + PBS): 10 μg/mouse IFN-γ was administered into the trachea every day.

2. Experimental results:

Immunohistochemical results showed that IFN-β and IFN-γ could induce up-regulation of mucin levels in the lungs of mice (Fig. 4A). Then, the IDO-KYN-AhR pathway was blocked by intravenous injection of an AhR inhibitor. Under these conditions, IFN-β and IFN-γ-induced mucin levels in the lungs of mice were significantly reduced (Fig. 4B).

Example 5. AHR inhibitor reverses interstitial pneumonia caused by SARS-CoV-2 infection

1. Experimental steps

Human ACE2 transgenic C57 mice were divided into the following groups:

Control group: One-time intranasal injection of the same amount of normal saline as the treatment group;

Model group: One-time intranasal administration of 10 ⁵ TCID ₅₀ of SARS-CoV-2 virus particles;

Treatment group: After intranasal administration of 10 ⁵ TCID ₅₀ SARS-CoV-2 virus particles, 10 mg/kg CH223191 was administered via tail vein, once a day, for a total of 5 times.

Five days after virus infection, the mice were anesthetized with sodium barbital, and then the lung tissue was removed, and a part of the lung tissue was immediately placed in 4% paraformaldehyde for preservation for immunohistochemical analysis.

2. Experimental results

In human ACE2 transgenic mice infected with SARS-CoV-2, the inventors found that compared with control mice (MOCK group, uninfected with virus), H&E staining results in lung tissue showed that SARS-CoV-2 infection caused The mice developed marked interstitial pneumonia, which was significantly reversed by treatment with the AHR inhibitor CH223191.

To sum up, the solution of the present application has the following effects:

1. The AhR inhibitor of the anti-respiratory viral pneumonia preparation of the present application can effectively inhibit the mucus produced by the virus-induced respiratory system of the body, effectively treat dyspnea and hypoxemia in patients with new crowns, and effectively prevent patients with new coronaviruses from becoming severely ill at an early stage. The effect of direction development can effectively reduce the mortality rate of new crown patients and effectively improve the survival rate of patients with respiratory viral pneumonia, which has a good clinical application prospect.

2. After viral infection, the body will produce a large amount of IFN-β and IFN-γ. These two cytokines are supposed to play an antiviral role, but they have other negative effects (that is, promoting the production of more mucus in the lungs). to block the virus, but affects the gas exchange in the lungs, causing the patient to suffer from respiratory distress). AhR inhibitors (IDO acts through the AhR pathway) reversed this negative effect.

3. The anti-respiratory viral pneumonia preparation of the present application can also kill the virus by enhancing the systemic immune response, and has the advantages of high safety and no toxic and side effects.

Claims (7)

1. Use of an AhR inhibitor in the preparation of a medicament, wherein: The medicine is used for any one or combination selected from the following: preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia or symptoms thereof; The virus is selected from one or a combination of the following: coronavirus, influenza A virus, influenza B virus, influenza C virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza virus, human metapneumovirus , Hendra virus, Nipah virus, Rubella virus, Rhinovirus, Adenovirus, Reovirus, Coxsackie virus, ECHO virus, and variants thereof; Preferably, the medicament is prepared in a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral dosage forms, dosage forms suitable for mucosal administration; Preferably, the AhR inhibitor is selected from one or a combination of the following: AHR antagonist 1, α-NF, CB7993113, CMLD-2166, CH223191, DMF, GNF351, PDM2, StemRegenin 1, SR1, IDO inhibitor; Preferably, the IDO inhibitor is selected from one or a combination of the following: tryptophan analogs, quinone and its derivatives, imidazole and its derivatives, triazole and its derivatives, N-hydroxyamidine and its derivatives thing; More preferably, the IDO inhibitor is selected from the following one or a combination: 1-MT, Epacadostat, DO-IN-2, NLG919, PF-06840003, INCB024360, Exiguamine A, benzimidazole; most preferably, the Said IDO is IDO1. 2. The use according to claim 1, wherein the coronavirus is selected from the group consisting of: SARS, MERS, 2019-nCoV, and variants thereof. 3. The use according to claim 1, the amount of the AhR inhibitor in a unit formulation is 10 mg to 10 g; Preferably, the amount of the IDO inhibitor in a unit formulation is 1 g to 10 g; Preferably, the amount of AhR inhibitor other than the IDO inhibitor in the unit formulation is 10 mg to 80 mg. 4. The use according to any one of claims 1 to 3, wherein: The treatment is embodied in one or a combination selected from the group consisting of improving blood oxygen saturation, improving PaO ₂ /FiO ₂ , relieving respiratory distress, reducing RRS respiratory system resistance, improving ERS, improving PV-k level, improving Eta level, Reduce airway mucus, regulate the expression level of mucin, improve survival rate and prolong survival period; The prevention refers to delaying or preventing the progression of the disease to severe or critical illness, reducing the risk of developing severe or critical illness. 5. The use according to claim 1, wherein the viral pneumonia is selected from the group consisting of: mild, common, severe, and critical. 6. A pharmaceutical composition comprising: AhR inhibitors, and Optionally, a pharmaceutically acceptable carrier: The pharmaceutical composition is used for any one or combination selected from the following: preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia or symptoms thereof; The virus is selected from one or a combination of the following: coronavirus, influenza A virus, influenza B virus, influenza C virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza virus, human metapneumovirus , Hendra virus, Nipah virus, Rubella virus, Rhinovirus, Adenovirus, Reovirus, Coxsackie virus, ECHO virus, and variants thereof; The coronavirus is selected from: SARS, MERS, 2019-nCoV, and variants thereof; The pharmaceutical composition is in a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral dosage forms, dosage forms suitable for mucosal administration; Preferably, the AhR inhibitor is selected from one or a combination of the following: AHR antagonist 1, α-NF, CB7993113, CMLD-2166, CH223191, DMF, GNF351, PDM2, StemRegenin 1, SR1, IDO inhibitor; Preferably, the IDO inhibitor is selected from one or a combination of the following: tryptophan analogs, quinone and its derivatives, imidazole and its derivatives, triazole and its derivatives, N-hydroxyamidine and its derivatives thing; More preferably, the IDO inhibitor is selected from the following one or a combination: 1-MT, Epacadostat, DO-IN-2, NLG919, PF-06840003, INCB024360, Exiguamine A, benzimidazole; The amount of the AhR inhibitor in a unit formulation is 10 mg to 10 g; Preferably, the amount of the IDO inhibitor in a unit formulation is 1 g to 10 g; Preferably, the amount of AhR inhibitor other than the IDO inhibitor in the unit formulation is 10 mg to 80 mg; Preferably, the IDO is IDO1. 7. A method of preventing or treating viral pneumonia, comprising: administering to the subject a prophylactically effective amount or a therapeutically effective amount of an AhR inhibitor; The virus is selected from one or a combination of the following: coronavirus, influenza A virus, influenza B virus, influenza C virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza virus, human metapneumovirus , Hendra virus, Nipah virus, Rubella virus, Rhinovirus, Adenovirus, Reovirus, Coxsackie virus, ECHO virus, and variants thereof; The administration is selected from: intramuscular, intravenous, subcutaneous, intradermal, oral, intranasal, respiratory, transmucosal, sublingual, parenteral; The AhR inhibitor is selected from the following one or a combination: AHR antagonist 1, α-NF, CB7993113, CMLD-2166, CH223191, DMF, GNF351, PDM2, StemRegenin 1, SR1, IDO inhibitor; Preferably, the IDO inhibitor is selected from the following one or a combination: 1-MT, Epacadostat, DO-IN-2, NLG919, PF-06840003, INCB024360, Exiguamine A, benzimidazole; The amount of the AhR inhibitor in a unit formulation is 10 mg to 10 g; Preferably, the amount of the IDO inhibitor in a unit formulation is 1 g to 10 g; Preferably, the amount of AhR inhibitor other than the IDO inhibitor in the unit formulation is 10 mg to 80 mg; Preferably, the IDO is IDO1; The prevention refers to delaying or preventing the progression of the disease to severe or critical illness, and reducing the risk of developing severe or critical illness; The treatment is embodied in one or a combination selected from the group consisting of improving blood oxygen saturation, improving PaO ₂ /FiO ₂ , relieving respiratory distress, reducing RRS respiratory system resistance, improving ERS, improving PV-k level, improving Eta level, Reduce airway mucus, regulate the expression level of mucin, improve survival rate and prolong survival time.

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