WO2021253647A1 - Use of small molecule inhibitor in treatment of respiratory viral pneumonia - Google Patents

Use of small molecule inhibitor in treatment of respiratory viral pneumonia Download PDF

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WO2021253647A1
WO2021253647A1 PCT/CN2020/113478 CN2020113478W WO2021253647A1 WO 2021253647 A1 WO2021253647 A1 WO 2021253647A1 CN 2020113478 W CN2020113478 W CN 2020113478W WO 2021253647 A1 WO2021253647 A1 WO 2021253647A1
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virus
ahr
inhibitor
ido
combination
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PCT/CN2020/113478
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French (fr)
Chinese (zh)
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黄波
刘玉英
佟伟民
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中国医学科学院基础医学研究所
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • This application relates to the fields of biology, medicine and clinical. Specifically, it relates to small molecule inhibitors and their use in the treatment of viral pneumonia.
  • Viral pneumonia can break out or spread. Viral pneumonia can occur at any time of the year, but it is more common in winter and spring. Initially, the above-mentioned 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, mainly with similar symptoms of respiratory diseases such as headache, fatigue, fever, and cough.
  • Respiratory tract infection is one of the leading causes of death in the world, especially patients with severe pneumonia have high mortality and serious sequelae.
  • viruses such as influenza virus and coronavirus are the main pathogens that cause regional outbreaks of severe pneumonia, which are highly infectious and have a high fatality rate.
  • an AhR (arylhydrocarbon receptor) inhibitor which can be used as a viral pneumonia preparation.
  • the viral pneumonia preparation contains an AhR inhibitor.
  • the term "inhibitor” refers to a natural compound or a synthetic compound that inhibits (or reduces or down-regulates) the expression of genes and/or proteins, and/or inhibits (or reduces or down-regulates) genes and/or The activity of the protein and/or regulate the signal transduction pathway related to the gene and/or protein.
  • the inhibitor can act on any of the following links or combinations of 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, signal transduction. Inhibitors are allowed to be competitive, non-competitive, completely antagonistic, or partially antagonistic.
  • an AhR inhibitor refers to a compound that has the following effects: inhibits (or reduces or down-regulates) the expression of the gene encoding AhR, and/or the expression of AhR, and/or the activity of AhR, and/or modulates the signal transduction pathway related to AhR (For example, but not limited to upstream of AhR-related signaling pathways).
  • an AhR inhibitor in the preparation of a medicament, wherein the medicament is used for any one or a combination selected from the following: preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia, or Its symptoms.
  • the virus is selected from one or a combination of: coronavirus, influenza A virus, influenza B virus, influenza C virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza virus, Human metapneumovirus, Hendra virus, Nipa virus, rubella virus, rhinovirus, adenovirus, reovirus, Coxsackie virus, ECHO virus, and variants thereof.
  • the drug is prepared into a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral preparations, and dosage forms suitable for mucosal administration.
  • AhR inhibitors suitable for the present disclosure include, but are not limited to, the compounds disclosed in the prior art: WO2019036657, WO2018195397, CN106860471A, WO2013034685, WO2012015914.
  • the AhR inhibitor is selected from one or a combination of the following: AhR antagonist 1, ⁇ -NF, CB7993113, CMLD-2166, CH223191, DMF, GNF351, PDM2, StemRegenin 1, SR1, IDO inhibitor.
  • an IDO (indoleamine 2,3-dioxygenase) inhibitor is provided, which can be used as a viral pneumonia preparation.
  • the viral pneumonia preparation contains an IDO inhibitor.
  • IDO is an active molecule located upstream of the AhR signaling pathway. Therefore, inhibitors acting on IDO can indirectly modulate the activity of AhR.
  • IDO inhibitors refer to compounds that have the following effects: inhibit (or reduce or down-regulate) the expression of IDO-encoding genes, and/or the expression of IDO, and/or the activity of IDO.
  • IDO inhibitors can generally be divided into the following types according to their structure:
  • An exemplary compound is the N-methyl derivative of tryptophan L1MT;
  • 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-Hydroxy amidine compounds can combine with the iron atom of heme and at the same time form a hydrogen bond with the nitrogen atom on the side amide group.
  • An exemplary compound is INCB024360.
  • IDO inhibitors suitable for the present disclosure include, but are not limited to, compounds disclosed in the prior art: CN106866648B, CN106883224B, CN107501272B, CN109438513B, CN109748838B, CN105567690B, CN107260743B, WO2015173764.
  • 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.
  • the IDO inhibitor is selected from one or a combination of the following: 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.
  • the amount of IDO inhibitor in a unit formulation is 1 g to 10 g.
  • the amount of the AhR inhibitor in the unit formulation is 10 mg to 80 mg.
  • the coronavirus is selected from: SARS, MERS, 2019-nCoV, and variants thereof.
  • treatment is embodied as one or a combination selected from:
  • the viral pneumonia is selected from: mild, normal, severe, and critical.
  • a pharmaceutical composition comprising an AhR inhibitor, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is used for any one or a combination selected from the following: preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia or its symptoms.
  • 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, Nipa 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 a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral preparations, and dosage forms suitable for mucosal administration.
  • a method of preventing or treating viral pneumonia comprising administering a prophylactically effective amount or a therapeutically effective amount of an AhR inhibitor to a subject.
  • administration routes that may be mentioned include, but are not limited to: intramuscular, intravenous, subcutaneous, intradermal, oral, intranasal, respiratory, transmucosal, sublingual, parenteral.
  • effective amount refers to the amount of the drug, compound, or pharmaceutical composition necessary to obtain any one or more beneficial or desired therapeutic results.
  • beneficial or desired results include: improving clinical results (eg, reducing morbidity, mortality, improving one or more symptoms), reducing the severity, delaying the onset of the disease (including the disease or its complications, in the course of the development of the disease) Intermediate pathological phenotypes, biochemical, histological and/or behavioral symptoms presented in).
  • the unit preparation is a preparation that satisfies the active ingredient (AhR inhibitor) required for one-time administration, such as a unit (needle) injection or the like.
  • the amount of the drug required by the patient for one administration can be conveniently obtained by calculating the product of the patient's weight and the unit weight dose required for the patient's one administration.
  • the dosage can be determined initially by the equivalent dose conversion relationship between the unit weight dose of experimental animals and humans.
  • it can be based on the guidance provided by the FDA, SFDA and other drug regulatory agencies, and you can also refer to (Huang Jihan et al., "Equivalent dose conversion between animals and between animals and humans in pharmacological trials", “Chinese Clinical Pharmacology and Therapeutics” , 2004 Sep; 9(9): 1069-1072).
  • a conversion factor of 0.0026 according to the body surface area of humans and mice can be used to convert the doses of humans and mice.
  • 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 prepared as a 5 mg/mL solution with water , Mice are given 4 mL of the solution every day).
  • a method for preventing a patient with respiratory viral pneumonia from becoming severely ill including administering the anti-respiratory viral pneumonia preparation to a patient suffering from respiratory viral pneumonia or an individual with a tendency to become severely ill. the process of.
  • the specific procedure is intravenous or oral AhR inhibitor.
  • the amount of the AhR inhibitor in the anti-respiratory viral pneumonia preparation can be controlled as needed, so as to facilitate the administration to patients with viral pneumonia at different stages.
  • interferon is the first warning of virus invasion. Its signal activates a series of antiviral genes to exert a direct antiviral effect. However, the delayed interferon response may cause the body's immunopathological changes through the recruitment and activation of innate immune cells that produce high levels of inflammatory factors.
  • the applicant’s study found that IFN- ⁇ and IFN- ⁇ up-regulated the expression of mucin in BAES-2B cells, and the mucus produced was blocked in the patient’s alveolar cavity, which resulted in dyspnea and hypoxemia of the patient, leading to death of the patient.
  • AhR inhibitors effectively block the mucus produced by the respiratory system induced by IFN- ⁇ and IFN- ⁇ , and can achieve clinical treatment and prevention of critically ill patients with respiratory viral pneumonia virus pneumonia value.
  • the patient refers to a virus carrier, especially a patient who has or may have symptoms due to the presence of the virus.
  • patients are especially patients who are at risk of developing severe or critical illness.
  • Figure 1 shows the PAS staining experiment found that there may be a large amount of mucus-like substances in the alveolar lavage fluid of patients with new coronary disease.
  • Figure 2A and Figure 2B show the humanized ACE2 transgenic mice as the animal model of SARS-CoV-2 infection. Compared with the control group (Mock group, hACE2 mice not infected with the virus), the infected group mice The up-regulated expression and nuclear localization of AhR protein in lung epithelial cells (Figure 2A), and increased IFN- ⁇ expression in lung tissue was found in the infected group ( Figure 2B).
  • Figures 3A to 3E show that after bronchial nebulization treatment of mice with IFN- ⁇ or IFN- ⁇ , the lung function of the mice was found to be damaged. After intravenous injection of AhR inhibitor, the lung function of the mice returned to normal .
  • Fig. 4B shows that after intravenous injection of AhR inhibitor, the apparent increase in mucin levels in the lungs of mice was reversed.
  • FIGs 5A to 5F show that humanized ACE2 (hACE2) transgenic mice were used as the animal model of SARS-CoV-2 infection. Compared with the control group (Mock group-uninfected hACE2 mice), In the infected group, the expression levels of IFN- ⁇ and IFN ⁇ in the lung tissue were found to increase ( Figure 5A to Figure 5D). The expression of IFN- ⁇ at different time points was measured by real-time PCR ( Figure 5E). At different time points after hACE2 transgenic mice were infected with SARS-CoV-2, the expression of IFN- ⁇ was measured by real-time PCR (Figure 5F).
  • Figures 6A to 6C show (scale bar: 50 ⁇ m): SARS-CoV-2 infected humanized ACE2 transgenic mice were used as animal models, and it was observed that the administration of AhR inhibitors reversed the pneumonia symptoms of the infected mice.
  • Fig. 6A control group Fig. 6B model group
  • Fig. 6C treatment group Fig. 6A treatment group.
  • BEAS-2B human lung epithelial cell line was purchased from CCTCC of China Collection of Types;
  • SARS-CoV-2 comes from the Institute of Medical Laboratory Animals, Chinese Academy of Medical Sciences;
  • mice Female Balb/c mice aged 6-8 weeks were purchased from the Experimental Animal Center of Peking Union Medical College, Chinese Academy of Medical Sciences;
  • IDO inhibitor (1-MT) was purchased from SIGMA, USA;
  • AhR inhibitor (CH223191) was purchased from MCE Company, USA.
  • BAL samples from SARS-CoV-2 patients.
  • BAL samples come from 22-82-year-old patients, 4 males and 4 females.
  • the oxygen saturation is ⁇ 93%
  • ICU monitoring and treatment is required.
  • Example 1 SARS-COV-2 virus infection leads to the expression of a large number of mucins in the lung tissues of patients
  • the operation method is as follows: 2 hours before the operation, intramuscular injection of atropine and phenobarbital sodium, and local anesthesia with lidocaine hydrochloride 0.1g. Patients with poor compliance and anxiety are given intravenous painless anesthesia; after the anesthesia is completed, Olympus The electronic bronchoscope was inserted through the patient’s side of the nasal cavity to the lesion and lower respiratory tract secretions, 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 Put it into a sterile sputum collection bottle and send it for inspection within 2h.
  • the specimens submitted for inspection shall be separated and identified in accordance with the corresponding requirements of the "National Clinical Laboratory Procedures".
  • the isolated bronchoalveolar lavage fluid (BAL) specimens were fixed with 10% neutral formalin, embedded in paraffin, conventional HE staining, immunohistochemistry and PAS staining, and observed under light microscope.
  • PAS staining showed a large amount of mucus in the bronchoalveolar lavage fluid (BAL) ( Figure 1), and the results showed that viral infection caused the expression of a large amount of mucin in the lung tissue of patients with new coronary pneumonia.
  • SARS-COV-2 virus stimulates the nuclear localization phenomenon of AHR in lung tissue
  • C57-humanized ACE2 transgenic mice adopt non-exposure intratracheal injection method.
  • the animal was fully upright and rotated to make the drug evenly distributed in the lungs, and waited for 1 week for modeling.
  • Lung tissue collection After the mice were anesthetized with sodium barbital, the lung tissues were taken out after the mice were sacrificed, and the blood stains on the surface of the lung tissues were washed with preparatory normal saline. After the above operations were performed as quickly as possible, the tissues were then stored in the lungs. Store at -80°C. A part of the lung tissue was immediately placed in 4% paraformaldehyde for preservation for the preparation of immunofluorescence staining.
  • Example 3 AHR inhibitor reverses IFN- ⁇ or IFN- ⁇ causing lung function damage in mice
  • mice use non-exposure intratracheal injection.
  • the normal group was injected with the same amount of normal saline through the trachea at one time, and the experimental group was injected with 5 ⁇ g/mouse IFN- ⁇ or 10 ⁇ g/mouse IFN- ⁇ through the trachea. After the injection of the medicine, immediately rotate the animal upright to make the medicine evenly distributed in the lungs. The drug was administered once a day, and after four consecutive days of administration, blood gas analysis and lung function tests in mice were performed.
  • PBS PBS is given to the trachea every day
  • mice daily tracheal administration of 10 ⁇ g/mouse IFN- ⁇ +10mg/kg CH223191;
  • IFN- ⁇ and IFN- ⁇ can reduce the blood oxygen saturation of mice (Figure 3A), hypoxia and dyspnea, increase 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.
  • Example 4 AHR inhibitor reverses IFN- ⁇ or IFN- ⁇ causing mucin up-regulation and lung function damage in mouse lung tissue
  • C57 mice use non-exposure intratracheal injection.
  • the normal group was injected with the same amount of normal saline through the trachea at one time, and the experimental group was injected with 5 ⁇ g of IFN- ⁇ , IFN- ⁇ , IFN- ⁇ +CH223191 or IFN- ⁇ model+CH223191 through the trachea.
  • the medicine is injected, immediately rotate the animal upright to make the medicine evenly distributed in the lungs.
  • the drug was administered once a day, and the lung function was measured and lung tissue samples were collected after four consecutive days of administration. Lung tissue collection: After the mouse is anesthetized with barbital sodium, the mouse is sacrificed, and the heart is perfused.
  • the lung tissue is taken out, and the blood stains on the lung tissue surface are cleaned with preparatory normal saline. Immediately after the above operation, the tissue was stored at -80°C. A part of the lung tissue was immediately stored in 4% paraformaldehyde for the preparation of immunohistochemical staining.
  • PBS PBS is given to the trachea every day
  • Experimental group 1 (IFN- ⁇ model +PBS): daily tracheal treatment with 5 ⁇ g/mouse IFN- ⁇ +PBS;
  • mice daily tracheal administration of 10 ⁇ g/mouse IFN- ⁇ +10mg/kg CH223191;
  • mice 10 ⁇ g/mouse IFN- ⁇ was given to the trachea every day.
  • Example 5 AHR inhibitor reverses interstitial pneumonia caused by SARS-CoV-2 infection
  • the human ACE2 transgenic C57 mice were divided into the following groups:
  • Control group intranasal injection of the same amount of normal saline as the treatment group;
  • Model group intranasal administration of 10 5 TCID 50 SARS-CoV-2 virus particles at a time;
  • Treatment group After intranasal administration of 10 5 TCID 50 SARS-CoV-2 virus particles, 10 mg/kg CH223191 was administered to the tail vein, once a day, for a total of 5 administrations.
  • mice Five days after the virus infection, the mice were anesthetized with sodium barbital, the lung tissue was taken out, and a part of the lung tissue was immediately placed in 4% paraformaldehyde for preservation for immunohistochemical analysis.
  • the AhR inhibitor of the anti-respiratory viral pneumonia preparation of the present application can effectively inhibit virus-induced pathological mucus produced by the respiratory system of the body, and it is expected to become a potential drug for the treatment of lung diseases caused by respiratory viral infections.
  • IFN- ⁇ and IFN- ⁇ are supposed to play an anti-viral effect, but they have other negative effects (that is, promote the production of more mucus in the lungs).
  • AhR inhibitors IDO works through the AhR pathway) reverse this negative effect.
  • the anti-respiratory viral pneumonia preparation of the present application can also enhance the systemic immune response, thereby killing the virus, and has the advantages of high safety and no toxic side effects.

Abstract

This application provides the use of small molecule inhibitors in the treatment of respiratory viral pneumonia. In particular, this application relates to new use of AhR inhibitors in the treatment or improvement of respiratory virus infection. The inhibitors for treatment of viral infection provided in the present application can effectively inhibit the pathological mucus produced by the virus-induced lung tissue, and AhR inhibitors are expected to become potential agent for the treatment of lung diseases caused by respiratory viral infection.

Description

小分子抑制剂在治疗呼吸道病毒性肺炎上的应用Application of small molecule inhibitors in the treatment of respiratory viral pneumonia
本申请要求中国专利申请202010552732.7(优先权日2020年6月17日)和中国专利申请202010701456.6(优先权日2020年7月20日)的优先权。This application claims the priority of Chinese patent application 202010552732.7 (priority date June 17, 2020) and Chinese patent application 202010701456.6 (priority date July 20, 2020).
技术领域Technical field
本申请涉及生物、医学、临床领域。具体而言，涉及小分子抑制剂及其在治疗病毒性肺炎中的用途。This application relates to the fields of biology, medicine and clinical. Specifically, it relates to small molecule inhibitors and their use in the treatment of viral pneumonia.
背景技术Background technique
病毒性肺炎可爆发，也可散发流行。病毒性肺炎可在一年中的任何时候发生，但多见于冬春季节。最初是以上呼吸道病毒感染为主，随着病毒向下蔓延至肺部引起肺炎。Viral pneumonia can break out or spread. Viral pneumonia can occur at any time of the year, but it is more common in winter and spring. Initially, the above-mentioned respiratory tract virus infection is the main cause, and as the virus spreads down to the lungs, it causes pneumonia.
病毒性肺炎可通过飞沫传染。临床表现一般较轻，以头痛、乏力、发热、咳嗽等呼吸道疾病相似症状为主。呼吸道感染是全球最主要的死亡原因之一，尤其是重症肺炎患者出现高死亡率和严重的后遗症。目前，流感病毒、冠状病毒等病毒是导致区域爆发性重症肺炎的主要病原体，具有强传染性和高病死率。Viral pneumonia can be transmitted through droplets. The clinical manifestations are generally mild, mainly with similar symptoms of respiratory diseases such as headache, fatigue, fever, and cough. Respiratory tract infection is one of the leading causes of death in the world, especially patients with severe pneumonia have high mortality and serious sequelae. At present, viruses such as influenza virus and coronavirus are the main pathogens that cause regional outbreaks of severe pneumonia, which are highly infectious and have a high fatality rate.
新型冠状病毒肺炎COVID-19，一旦进入重症阶段，其进程就会变得非常难以掌控，并很容易导致患者死亡。目前，SARS-CoV-2感染导致患者死亡的原因尚不明确。一般认为，新冠肺炎引发的不受控制的严重炎症反应可能参与了患者死亡的过程。临床上针对关键炎性细胞因子IL-6的药物已经在新型冠状病毒肺炎危重症患者中进行了试验。这种炎性细胞因子可以破坏肺泡上皮细胞和内皮细胞，导致肺部毛细血管通透性增加和肺间质纤维化，从而阻碍机体氧气和二氧化碳的交换，导致患者缺氧而死亡，其被认为是导致新型冠状病毒肺炎危重症患者死亡的关键原因。然而，缺氧的临床症状似乎出现在新型冠状病毒肺炎患者的早期阶段，而失控的炎症反应可能出现在相对较晚的阶段。临床实践发现，许多无症状的新型冠状病毒肺炎患者早期出现缺氧的临床表现，这暗示了炎性细胞因子爆发之前的其他因素也可能是 导致新型冠状病毒肺炎患者出现缺氧。尸检报告显示，新型冠状病毒肺炎患者肺泡腔内可见黏液及黏液栓形成。Once the new type of coronavirus pneumonia COVID-19 enters the severe stage, its progress will become very difficult to control and easily lead to the death of the patient. At present, the cause of death caused by SARS-CoV-2 infection is still unclear. 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 destroy 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 considered It is the key cause of death of critically ill patients with novel coronavirus pneumonia. However, the clinical symptoms of hypoxia seem to appear in the early stages of patients with new coronavirus pneumonia, and the uncontrolled inflammatory response may appear at a relatively late stage. Clinical practice has found that many asymptomatic patients with new coronavirus pneumonia have early clinical manifestations of hypoxia, which suggests that other factors before the outbreak of inflammatory cytokines may also cause hypoxia in patients with new coronavirus pneumonia. The autopsy report showed that mucus and mucus embolism were visible in the alveolar cavity of patients with new coronavirus pneumonia.
因此，如何提供可以将减少患者呼吸***黏液的产生，从而有效改善新冠患者的呼吸困难和低氧血症，成为当前有待解决的问题。Therefore, how to provide can reduce the production of mucus in the patient's respiratory system, thereby effectively improving the dyspnea and hypoxemia of patients with new coronary disease, which has become a problem to be solved at present.
发明内容Summary of the invention
根据本公开的一些实施方案，提供了一种AhR(芳烃受体，arylhydrocarbon receptor)抑制剂，其可用作病毒性肺炎制剂。所述病毒性肺炎制剂包含AhR抑制剂。According to some embodiments of the present disclosure, there is provided an AhR (arylhydrocarbon receptor) inhibitor, which can be used as a viral pneumonia preparation. The viral pneumonia preparation contains an AhR inhibitor.
在本公开中，术语“抑制剂”是指天然化合物或合成化合物，其抑制(或减小或下调)基因和/或蛋白的表达、和/或抑制(或减小或下调)基因和/或蛋白的活性、和/或调节与该基因和/或蛋白的相关信号传导通路。作为非限制性的示例，所述抑制剂可以作用于基因和/或蛋白的以下任一环节或组合：例如但不限于翻译、翻译后加工、稳定性、降解、核定位、胞质定位、转录、转录后加工、激活、失活、修饰、信号传导。抑制剂允许是竞争性的、非竞争性的、完全拮抗的、或部分拮抗的。In the present disclosure, the term "inhibitor" refers to a natural compound or a synthetic compound that inhibits (or reduces or down-regulates) the expression of genes and/or proteins, and/or inhibits (or reduces or down-regulates) genes and/or The activity of the protein and/or regulate the signal transduction pathway related to the gene and/or protein. As a non-limiting example, the inhibitor can act on any of the following links or combinations of 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, signal transduction. Inhibitors are allowed to be competitive, non-competitive, completely antagonistic, or partially antagonistic.
因此，AhR抑制剂是指具有以下作用的化合物：抑制(或减小或下调)AhR编码基因的表达、和/或AhR的表达、和/或AhR的活性、和/或调节AhR相关信号传导通路(例如，但不限于AhR相关信号传导通路的上游)。根据本公开的一些实施方案，提供了AhR抑制剂在制备药物中的用途，其中所述药物用于选自以下的任一项或组合：预防病毒性肺炎的发生或复发、治疗病毒性肺炎或其症状。Therefore, an AhR inhibitor refers to a compound that has the following effects: inhibits (or reduces or down-regulates) the expression of the gene encoding AhR, and/or the expression of AhR, and/or the activity of AhR, and/or modulates the signal transduction pathway related to AhR (For example, but not limited to upstream of AhR-related signaling pathways). According to some embodiments of the present disclosure, 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 following: preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia, or Its symptoms.
在一些实施方案中，病毒选自以下的一种或组合：冠状病毒、甲型流感病毒、乙型流感病毒、丙型流感病毒、麻疹病毒、腮腺炎病毒、呼吸道合胞病毒、副流感病毒、人偏肺病毒、亨德拉病毒、尼派病毒、风疹病毒、鼻病毒、腺病毒、呼肠病毒、柯萨奇病毒、ECHO病毒、及其变体。In some embodiments, the virus is selected from one or a combination of: coronavirus, influenza A virus, influenza B virus, influenza C virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza virus, Human metapneumovirus, Hendra virus, Nipa virus, rubella virus, rhinovirus, adenovirus, reovirus, Coxsackie virus, ECHO virus, and variants thereof.
在一些实施方案中，所述药物制备成选自以下的剂型：注射剂、喷雾剂、气雾剂、滴鼻剂、口服剂、适用于粘膜施用的剂型。In some embodiments, the drug is prepared into a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral preparations, and dosage forms suitable for mucosal administration.
适用于本公开的AhR抑制剂例如但不限于现有技术中公开的化合 物：WO2019036657、WO2018195397、CN106860471A、WO2013034685、WO2012015914。AhR inhibitors suitable for the present disclosure include, but are not limited to, the compounds disclosed in the prior art: WO2019036657, WO2018195397, CN106860471A, WO2013034685, WO2012015914.
在一些示例性实施方案中，所述AhR抑制剂选自以下的一种或组合：AhR拮抗剂1、α-NF、CB7993113、CMLD-2166、CH223191、DMF、GNF351、PDM2、StemRegenin 1、SR1、IDO抑制剂。In some exemplary embodiments, 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.
在一些实施方案中，提供了一种IDO(吲哚胺2,3-双加氧化酶，indoleamine 2,3-dioxygenase)抑制剂，其可用作病毒性肺炎制剂。所述病毒性肺炎制剂包含IDO抑制剂。In some embodiments, an IDO (indoleamine 2,3-dioxygenase) inhibitor is provided, which can be used as a viral pneumonia preparation. The viral pneumonia preparation contains an IDO inhibitor.
IDO(例如IDO1)是位于AhR信号传导通路上游的活性分子。因此，作用于IDO的抑制剂能够间接地调节AhR的活性。IDO (such as IDO1) is an active molecule located upstream of the AhR signaling pathway. Therefore, inhibitors acting on IDO can indirectly modulate the activity of AhR.
IDO抑制剂是指具有以下作用的化合物：抑制(或减小或下调)IDO编码基因的表达、和/或IDO的表达、和/或IDO的活性。IDO inhibitors refer to compounds that have the following effects: inhibit (or reduce or down-regulate) the expression of IDO-encoding genes, and/or the expression of IDO, and/or the activity of IDO.
在本领域中，IDO抑制剂按结构通常可分为以下几个类型：In this field, IDO inhibitors can generally be divided into the following types according to their structure:
-色氨酸类似物：示例性的化合物是色氨酸的N-甲基衍生物L1MT；-Tryptophan analogues: An exemplary compound is the N-methyl derivative of tryptophan L1MT;
-醌类化合物：主要从天然产物中获得；-Quinone compounds: mainly obtained from natural products;
-咪唑及三氮唑类化合物：4-苯并咪唑及其衍生物可与亚铁血红素的铁原子配位，具有较强的IDO抑制活性。示例性的化合物是NewLink Genetics公司的NLG919；-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-羟基脒类化合物：N-羟基脒类化合物可以与亚铁血红素的铁原子结合，同时和旁边酰胺基上的氮原子形成氢键。示例性的化合物是INCB024360。-N-Hydroxy amidine compounds: N-Hydroxy amidine compounds can combine with the iron atom of heme and at the same time form a hydrogen bond with the nitrogen atom on the side amide group. An exemplary compound is INCB024360.
适用于本公开的IDO抑制剂例如但不限于现有技术中公开的化合物：CN106866648B、CN106883224B、CN107501272B、CN109438513B、CN109748838B、CN105567690B、CN107260743B、WO2015173764。IDO inhibitors suitable for the present disclosure include, but are not limited to, compounds disclosed in the prior art: CN106866648B, CN106883224B, CN107501272B, CN109438513B, CN109748838B, CN105567690B, CN107260743B, WO2015173764.
在一些示例性的实施方案中，所述IDO抑制剂选自以下的一种或组合：色氨酸类似物、醌及其衍生物、咪唑及其衍生物、三氮唑及其衍生物、N-羟基脒及其衍生物。In some exemplary embodiments, 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.
在一些实施方案中，所述IDO抑制剂选自以下的一种或组合：1-MT、Epacadostat、DO-IN-2、NLG919、PF-06840003、INCB024360、Exiguamine A、苯并咪唑。In some embodiments, the IDO inhibitor is selected from one or a combination of the following: 1-MT, Epacadostat, DO-IN-2, NLG919, PF-06840003, INCB024360, Exiguamine A, benzimidazole.
在一些实施方案中，所述AhR抑制剂在单位制剂中的量是10mg至10g。可以提及10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1g、1.5g、2g、2.5g、3g、3.5g、4g、4.5g、5g、5.5g、6g、6.5g、7g、7.5g、8g、8.5g、9g、9.5g、10g或前述任意两个数值间的范围。In some embodiments, the amount of the AhR inhibitor in a unit formulation is 10 mg to 10 g. Can mention 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1g, 1.5g, 2g, 2.5g, 3g , 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.
在一些实施方案中，单位制剂中IDO抑制剂的量是1g至10g。In some embodiments, the amount of IDO inhibitor in a unit formulation is 1 g to 10 g.
在另一些实施方案中，所述AhR抑制剂在单位制剂中的量是10mg至80mg。In other embodiments, the amount of the AhR inhibitor in the unit formulation is 10 mg to 80 mg.
在一些实施方案中，所述冠状病毒选自：SARS、MERS、2019-nCoV、及其变体。In some embodiments, the coronavirus is selected from: SARS, MERS, 2019-nCoV, and variants thereof.
在一些实施方案中，治疗体现为选自以下的一项或组合：In some embodiments, treatment is embodied as one or a combination selected from:
改善血氧饱和度、改善PaO 2/FiO 2、缓解呼吸窘迫、降低RRS呼吸***阻力、改善ERS、改善PV-k水平、改善Eta水平、减少呼吸道黏液、调节黏蛋白的表达水平、延迟或阻止疾病向重症发展、提高存活率、延长生存期。 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 respiratory mucus, adjust mucin expression level, delay or prevent The disease progresses to severe, which improves the survival rate and prolongs the survival period.
在一些实施方案中，所述病毒性肺炎选自：轻型、普通型、重型、危重型。In some embodiments, the viral pneumonia is selected from: mild, normal, severe, and critical.
根据一些实施方案，提供了一种药物组合物，其包含AhR抑制剂、以及任选地可药用载体。According to some embodiments, there is provided a pharmaceutical composition comprising an AhR inhibitor, and optionally a pharmaceutically acceptable carrier.
在一些实施方案中，所述药物组合物用于选自以下的任一项或组合：预防病毒性肺炎的发生或复发、治疗病毒性肺炎或其症状。In some embodiments, the pharmaceutical composition is used for any one or a combination selected from the following: preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia or its symptoms.
在一些实施方案中，所述病毒选自以下的一种或组合：冠状病毒、甲型流感病毒、乙型流感病毒、丙型流感病毒、麻疹病毒、腮腺炎病毒、呼吸道合胞病毒、副流感病毒、人偏肺病毒、亨德拉病毒、尼派病毒、风疹病毒、鼻病毒、腺病毒、呼肠病毒、柯萨奇病毒、ECHO病毒、及其变体。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 Virus, human metapneumovirus, Hendra virus, Nipa virus, rubella virus, rhinovirus, adenovirus, reovirus, Coxsackie virus, ECHO virus, and variants thereof.
在一些实施方案中，所述冠状病毒选自：SARS、MERS、2019-nCoV、及其变体。In some embodiments, the coronavirus is selected from: SARS, MERS, 2019-nCoV, and variants thereof.
在一些实施方案中，所述药物组合物是选自以下的剂型：注射剂、喷雾剂、气雾剂、滴鼻剂、口服剂、适用于粘膜施用的剂型。In some embodiments, the pharmaceutical composition is a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral preparations, and dosage forms suitable for mucosal administration.
根据一些实施方案，提供了一种预防或治疗病毒性肺炎的方法，包括向受试者施用预防有效量或治疗有效量的AhR抑制剂。在一些实施方案中，可以提及的施用途径包括但不限于：肌内、静脉内、皮下、皮内、口服、鼻内、呼吸道、经粘膜、舌下、肠胃外。According to some embodiments, there is provided a method of preventing or treating viral pneumonia, comprising administering a prophylactically effective amount or a therapeutically effective amount of an AhR inhibitor to a subject. In some embodiments, administration routes that may be mentioned include, but are not limited to: intramuscular, intravenous, subcutaneous, intradermal, oral, intranasal, respiratory, transmucosal, sublingual, parenteral.
在根据本申请的方法的一些实施方案中，“有效量”或“有效剂量”指获得任一种或多种有益的或所需的治疗结果所必需的药物、化合物、药物组合物的量。有益的或所需的结果包括：改善临床结果(如，减少发病率、死亡率、改善一个或多个症状)、减轻严重程度、延迟病症的发作(包括病症或其并发症、在病症发展过程中呈现的中间病理表型、生物化学、组织学和/或行为症状)。In some embodiments of the method according to the present application, "effective amount" or "effective dose" refers to the amount of the drug, compound, or pharmaceutical composition necessary to obtain any one or more beneficial or desired therapeutic results. Beneficial or desired results include: improving clinical results (eg, reducing morbidity, mortality, improving one or more symptoms), reducing the severity, delaying the onset of the disease (including the disease or its complications, in the course of the development of the disease) Intermediate pathological phenotypes, biochemical, histological and/or behavioral symptoms presented in).
在一些实施方案中，所述单位制剂为满足一次给药所需有效成分(AhR抑制剂)的制剂，如一单位(针)针剂等。In some embodiments, the unit preparation is a preparation that satisfies the active ingredient (AhR inhibitor) required for one-time administration, such as a unit (needle) injection or the like.
患者一次施用所需的药物的量可以方便地通过计算患者的体重和该患者一次用药所需单位体重剂量的乘积得到。例如，在制备药物的过程中，一般认为成人体重为50-70kg，可以最初可以通过实验动物与人的单位体重剂量之间的等效剂量换算关系来确定用药量。例如，可以根据FDA、SFDA等药品管理机构提出的指导意见，也可参考(黄继汉等，“药理试验中动物间和动物与人体间的等效剂量换算”，《中国临床药理学与治疗学》，2004Sep；9(9)：1069-1072)来确定。The amount of the drug required by the patient for one administration can be conveniently obtained by calculating the product of the patient's weight and the unit weight dose required for the patient's one administration. For example, in the process of preparing drugs, it is generally considered that the weight of an adult is 50-70 kg, and the dosage can be determined initially by the equivalent dose conversion relationship between the unit weight dose of experimental animals and humans. For example, it can be based on the guidance provided by the FDA, SFDA and other drug regulatory agencies, and you can also refer to (Huang Jihan et al., "Equivalent dose conversion between animals and between animals and humans in pharmacological trials", "Chinese Clinical Pharmacology and Therapeutics" , 2004 Sep; 9(9): 1069-1072).
在本公开的实施方式中，可以使用按照人和小鼠的体表面积折算系数0.0026来换算人和小鼠的剂量。In the embodiments of the present disclosure, a conversion factor of 0.0026 according to the body surface area of humans and mice can be used to convert the doses of humans and mice.
在本公开的方案中，例如，针对体重为20g的小鼠，IDO抑制剂以1000mg/kg的量施用给小鼠(例如对于20g的小鼠，将IDO抑制剂用水配制为5mg/mL的溶液，小鼠每天灌服该溶液4mL)。In the scheme of the present disclosure, 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 prepared as a 5 mg/mL solution with water , Mice are given 4 mL of the solution every day).
根据一些实施方案，还提供了一种预防呼吸道病毒性肺炎患者转为重症的方法，包括患有呼吸道病毒性肺炎的患者或具有转为重症的发生趋势的个体施用所述抗呼吸道病毒性肺炎制剂的过程。具体过程为静脉或口服AhR抑制剂。According to some embodiments, there is also provided a method for preventing a patient with respiratory viral pneumonia from becoming severely ill, including administering the anti-respiratory viral pneumonia preparation to a patient suffering from respiratory viral pneumonia or an individual with a tendency to become severely ill. the process of. The specific procedure is intravenous or oral AhR inhibitor.
根据本公开的方案，可以根据需要控制抗呼吸道病毒性肺炎制剂中的AhR抑制剂的量，方便对不同阶段的病毒性肺炎患者的给药。According to the solution of the present disclosure, the amount of the AhR inhibitor in the anti-respiratory viral pneumonia preparation can be controlled as needed, so as to facilitate the administration to patients with viral pneumonia at different stages.
不限于任何理论束缚，干扰素是病毒入侵的第一个警报，其信号 激活一系列抗病毒基因，以发挥直接抗病毒作用。然而，延迟的干扰素反应可能通过产生高水平炎症因子的固有免疫细胞的募集和激活，引起机体免疫病理学改变。本申请人研究中发现IFN-β和IFN-γ上调BAES-2B细胞中粘蛋白的表达，这些产生的黏液堵塞在患者的肺泡腔从而导致患者的呼吸困难和低氧血症，导致患者死亡。本申请人经过大量实验研究出乎意料的发现，AhR抑制剂有效阻断IFN-β和IFN-γ诱导呼吸***产生的黏液，能够实现对治疗和预防危重症呼吸道病毒性肺炎病毒肺炎患者的临床价值。Not limited to any theoretical constraints, interferon is the first warning of virus invasion. Its signal activates a series of antiviral genes to exert a direct antiviral effect. However, the delayed interferon response may cause the body's immunopathological changes through the recruitment and activation of innate immune cells that produce high levels of inflammatory factors. The applicant’s study 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 patient’s alveolar cavity, which resulted in dyspnea and hypoxemia of the patient, leading to death of the patient. The applicant unexpectedly discovered through a large number of experimental studies that AhR inhibitors effectively block the mucus produced by the respiratory system induced by IFN-β and IFN-γ, and can achieve clinical treatment and prevention of critically ill patients with respiratory viral pneumonia virus pneumonia value.
在根据本申请的方法的一些实施方案中，患者是指病毒携带者，尤其是因病毒的存在而已经出现或可能出现症状的患者。在具体的实施方案中，患者尤其是具有发展为重症或危重症风险的患者。In some embodiments of the method according to the present application, the patient refers to a virus carrier, especially a patient who has or may have symptoms due to the presence of the virus. In specific embodiments, patients are especially patients who are at risk of developing severe or critical illness.
附图说明Description of the drawings
图1显示了经过PAS染色实验发现新冠患者的肺泡灌洗液中可能存在大量粘液样物质。Figure 1 shows the PAS staining experiment found that there may be a large amount of mucus-like substances in the alveolar lavage fluid of patients with new coronary disease.
图2A和图2B显示了将人源化ACE2转基因小鼠作为SARS-CoV-2感染的动物模型，观察到相比于对照组(Mock组，未感染病毒的hACE2小鼠)，感染组小鼠肺上皮细胞内AhR蛋白的上调表达和核定位现象(图2A)，并且在感染组中发现肺组织中IFN-β的表达量升高(图2B)。Figure 2A and Figure 2B show the humanized ACE2 transgenic mice as the animal model of SARS-CoV-2 infection. Compared with the control group (Mock group, hACE2 mice not infected with the virus), the infected group mice The up-regulated expression and nuclear localization of AhR protein in lung epithelial cells (Figure 2A), and increased IFN-β expression in lung tissue was found in the infected group (Figure 2B).
图3A至图3E显示了使用IFN-β或IFN-γ通过支气管雾化吸入处理小鼠后，发现小鼠的肺功能出现了损伤，通过静脉注射AhR抑制剂后，小鼠的肺功能恢复正常。Figures 3A to 3E show that after bronchial nebulization treatment of mice with IFN-β or IFN-γ, the lung function of the mice was found to be damaged. After intravenous injection of AhR inhibitor, the lung function of the mice returned to normal .
图4A，使用IFN-β或IFN-γ通过支气管雾化吸入处理小鼠后，免疫组化染色观察到小鼠肺脏的黏蛋白水平明显上升。Figure 4A, after treating mice with IFN-β or IFN-γ through bronchial nebulization, immunohistochemical staining showed that the mucin level in the lungs of the mice increased significantly.
图4B显示，在静脉注射AhR抑制剂后，小鼠肺脏的黏蛋白水平明显上升的现象被逆转。Fig. 4B shows that after intravenous injection of AhR inhibitor, the apparent increase in mucin levels in the lungs of mice was reversed.
图5A至图5F显示：将人源化ACE2(hACE2)转基因小鼠作为SARS-CoV-2感染的动物模型，观察到相比于对照组(Mock组-未感染病毒的hACE2小鼠)，在感染组中发现肺组织中IFN-β和IFNγ的表达量升高(图5A至图5D)。通过实时PCR测量IFN-β的表达在不同时间点的表达(图5E)。hACE2转基因小鼠感染SARS-CoV-2后不同时 间点，实时PCR测量IFN-γ的表达(图5F)。Figures 5A to 5F show that humanized ACE2 (hACE2) transgenic mice were used as the animal model of SARS-CoV-2 infection. Compared with the control group (Mock group-uninfected hACE2 mice), In the infected group, the expression levels of IFN-β and IFNγ in the lung tissue were found to increase (Figure 5A to Figure 5D). The expression of IFN-β at different time points was measured by real-time PCR (Figure 5E). At different time points after hACE2 transgenic mice were infected with SARS-CoV-2, the expression of IFN-γ was measured by real-time PCR (Figure 5F).
图6A至图6C显示(标尺：50μm)：SARS-CoV-2感染的人源化ACE2转基因小鼠作为动物模型，观察到施用AhR抑制剂后逆转了感染组小鼠的肺炎病症。图6A对照组；图6B模型组；图6C治疗组。Figures 6A to 6C show (scale bar: 50 μm): SARS-CoV-2 infected humanized ACE2 transgenic mice were used as animal models, and it was observed that the administration of AhR inhibitors reversed the pneumonia symptoms of the infected mice. Fig. 6A control group; Fig. 6B model group; Fig. 6C treatment group.
具体实施方式detailed description
1.下述实施例中使用的各种细胞系、药物及实验动物：1. Various cell lines, drugs and experimental animals used in the following examples:
BEAS-2B人肺上皮细胞系购自中国典型物保藏中心CCTCC；BEAS-2B human lung epithelial cell line was purchased from CCTCC of China Collection of Types;
SARS-CoV-2来源于中国医学科学院医学实验动物研究所；SARS-CoV-2 comes from the Institute of Medical Laboratory Animals, Chinese Academy of Medical Sciences;
6-8周龄雌性Balb/c小鼠购自中国医学科学院协和医学院实验动物中心；Female Balb/c mice aged 6-8 weeks were purchased from the Experimental Animal Center of Peking Union Medical College, Chinese Academy of Medical Sciences;
6-8周龄C57-人源化ACE2小鼠来源于中国医学科学院协和医学院实验动物研究所；C57-humanized ACE2 mice aged 6-8 weeks were from the Institute of Experimental Animals, Peking Union Medical College, Chinese Academy of Medical Sciences;
IDO抑制剂(1-MT)购自美国SIGMA公司；IDO inhibitor (1-MT) was purchased from SIGMA, USA;
AhR抑制剂(CH223191)购自美国MCE公司。AhR inhibitor (CH223191) was purchased from MCE Company, USA.
2.患者样本来源：2. Source of patient sample:
收集SARS-CoV-2患者的石蜡包埋BAL样本。BAL样本来自22-82岁患者，男性、女性各4名。Collect paraffin-embedded BAL samples from SARS-CoV-2 patients. BAL samples come from 22-82-year-old patients, 4 males and 4 females.
3.患者的肺炎临床分型分为四型：3. The clinical classification of patients with pneumonia is divided into four types:
轻型：临床症状轻微，影像学未见肺炎表现。Mild: The clinical symptoms are mild, and there is no evidence of pneumonia in imaging.
普通型：具有发热、呼吸道等症状，影像学可见肺炎表现。Common type: symptoms such as fever and respiratory tract, and pneumonia manifestations can be seen on imaging.
重型：符合下列任何一条：Heavy: Meet any of the following:
呼吸窘迫，RR≥30次/分；Respiratory distress, RR≥30 beats/min;
静息状态下，指氧饱和度≤93％；In the resting state, the oxygen saturation is ≤93%;
动脉血氧分压(PaO2)/吸氧浓度(FiO2)≤300mmHgArterial partial pressure of oxygen (PaO2)/inhaled oxygen concentration (FiO2) ≤300mmHg
(1mmHg＝0.133kPa)。(1mmHg=0.133kPa).
危重型：符合以下情况之一者：Critical: Those who meet one of the following conditions:
出现呼吸衰竭，且需要机械通气；Respiratory failure occurs and mechanical ventilation is required;
出现休克；Shock
合并其他器官功能衰竭需ICU监护治疗。Combined with other organ failure, ICU monitoring and treatment is required.
实施例1.SARS-COV-2病毒感染导致患者肺组织中大量粘蛋白的表达Example 1. SARS-COV-2 virus infection leads to the expression of a large number of mucins in the lung tissues of patients
1.实验步骤1. Experimental steps
8名感染的受试者，按照纤维支气管镜操作规范获取肺泡灌洗液并进行细菌培养。Eight infected subjects obtained alveolar lavage fluid and carried out bacterial culture in accordance with the operating specifications of fiberoptic bronchoscopy.
操作方法如下：术前2h肌肉注射阿托品、***钠，另给予盐酸利多卡因0.1g局部麻醉，其中依从性差、紧张焦虑患者给予静脉无痛麻醉；麻醉完成后，将奥林巴斯电子支气管镜经患者一侧鼻腔伸入至病灶及下呼吸道分泌物多的部位，并给予50ml无菌0.9％氯化钠溶液进行灌洗或待刷检后反复灌洗，而后收集灌洗液并放入无菌集痰瓶中并于2h内送检。The operation method is as follows: 2 hours before the operation, intramuscular injection of atropine and phenobarbital sodium, and local anesthesia with lidocaine hydrochloride 0.1g. Patients with poor compliance and anxiety are given intravenous painless anesthesia; after the anesthesia is completed, Olympus The electronic bronchoscope was inserted through the patient’s side of the nasal cavity to the lesion and lower respiratory tract secretions, 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 Put it into a sterile sputum collection bottle and send it for inspection within 2h.
送检标本按照《全国临床检验操作规程》相应要求分离鉴定。对分离的支气管肺泡灌洗液(BAL)标本，用10％的中性***固定、石蜡包埋，常规HE染色，免疫组化和PAS染色，光镜下进行观察。The specimens submitted for inspection shall be separated and identified in accordance with the corresponding requirements of the "National Clinical Laboratory Procedures". The isolated bronchoalveolar lavage fluid (BAL) specimens were fixed with 10% neutral formalin, embedded in paraffin, conventional HE staining, immunohistochemistry and PAS staining, and observed under light microscope.
2.实验结果2. Experimental results
PAS染色显示支气管肺泡灌洗液(BAL)中有大量粘液(图1)，结果表明病毒感染导致新冠肺炎患者肺组织中大量粘蛋白的表达。PAS staining showed a large amount of mucus in the bronchoalveolar lavage fluid (BAL) (Figure 1), and the results showed that viral infection caused the expression of a large amount of mucin in the lung tissue of patients with new coronary pneumonia.
实施例2.SARS-COV-2病毒刺激肺组织AHR的核定位现象Example 2. SARS-COV-2 virus stimulates the nuclear localization phenomenon of AHR in lung tissue
1.实验步骤1. Experimental steps
C57-人源化ACE2转基因小鼠采用非暴露式气管内注入法。正常组经气管一次性注入与处理组等量生理盐水，处理组经气管一次性灌肺10 5单位的SARS-CoV-2病毒颗粒。 C57-humanized ACE2 transgenic mice adopt non-exposure intratracheal injection method. Transtracheal normal-time injection and normal saline treatment group, group treated transtracheal disposable lung filling units 105 SARS-CoV-2 virus particles.
注入后，立即将动物充分直立旋转，使药物在肺内分布均匀，等待1周造模处理。肺组织的采集：将小鼠用巴比妥钠麻醉后，小鼠处死后，开胸取出肺组织，用预备生理盐水清洗掉肺组织表面的血污，尽量迅速进行上述操作后随即将组织存于–80℃保存。把一部分的肺组织立即放入4％多聚甲醛中保存，用于免疫荧光染色的制备。Immediately after injection, the animal was fully upright and rotated to make the drug evenly distributed in the lungs, and waited for 1 week for modeling. Lung tissue collection: After the mice were anesthetized with sodium barbital, the lung tissues were taken out after the mice were sacrificed, and the blood stains on the surface of the lung tissues were washed with preparatory normal saline. After the above operations were performed as quickly as possible, the tissues were then stored in the lungs. Store at -80°C. A part of the lung tissue was immediately placed in 4% paraformaldehyde for preservation for the preparation of immunofluorescence staining.
2.实验结果2. Experimental results
用SARS-CoV-2感染的人ACE2转基因小鼠的肺组织，发明人发现相比于对照组小鼠(MOCK组，未感染病毒)，免疫荧光染色的结 果显示小鼠肺组织内的AHR明显上调表达，并且出现入核定位(图2A)。In the lung tissues of human ACE2 transgenic mice infected with SARS-CoV-2, the inventors found that compared with control mice (MOCK group, not infected with virus), the results of immunofluorescence staining showed that the AHR in the lung tissues of the mice was obvious The expression was up-regulated, and nuclear localization appeared (Figure 2A).
用SARS-CoV-2感染的人ACE2转基因小鼠的肺组织，发明人发现相比于对照组小鼠，免疫组化染色的结果显示小鼠肺组织内的IFNβ和IFNγ明显上调表达(图5A和图5B，图5C和图5D)。In the lung tissues 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 tissues of the mice was significantly up-regulated (Figure 5A And Figure 5B, Figure 5C and Figure 5D).
在RNA水平上，可以发现随着时间延长，肺组织的IFNβRNA表达量越来越多，有明显的时间依赖性，在IFNγ也在病毒感染组表达明显上调(图5E和图5F)。At the RNA level, it can be found that as time goes by, the expression of IFNβRNA in lung tissue increases, which is obviously time-dependent, and the expression of IFNγ is also significantly up-regulated in the virus-infected group (Figure 5E and Figure 5F).
实施例3.AHR抑制剂逆转IFN-β或者IFN-γ导致小鼠肺功能损伤Example 3. AHR inhibitor reverses IFN-β or IFN-γ causing lung function damage in mice
1.实验步骤：1. Experimental steps:
C57小鼠采用非暴露式气管内注入法。正常组经气管一次性注入与处理组等量生理盐水，实验组经气管一次性灌肺5μg/只的IFN-β或者10μg/只鼠的IFN-γ。注药后，立即将动物充分直立旋转，使药物在肺内分布均匀。每天给药一次，连续给药四天后，进行血气分析以及小鼠肺功能测试。C57 mice use non-exposure intratracheal injection. The normal group was injected with the same amount of normal saline through the trachea at one time, and the experimental group was injected with 5μg/mouse IFN-β or 10μg/mouse IFN-γ through the trachea. After the injection of the medicine, immediately rotate the animal upright to make the medicine evenly distributed in the lungs. The drug was administered once a day, and after four consecutive days of administration, blood gas analysis and lung function tests in mice were performed.
对照组(PBS)：每天气管给予PBS处理；Control group (PBS): PBS is given to the trachea every day;
实验组1(IFN-β造模组+PBS)：每气管给予5μg/鼠IFN-β+PBS处理；Experimental group 1 (IFN-β model +PBS): each trachea was treated with 5μg/mouse IFN-β+PBS;
实验组2(IFN-β造模组+CH223191)：每天气管给予5μg/鼠IFN-β+10mg/kg CH223191；Experimental group 2 (IFN-β model+CH223191): 5μg/mouse IFN-β+10mg/kg CH223191 is given to the trachea every day;
实验组3(IFN-γ造模组+CH223191)：每天气管给予10μg/鼠IFN-γ+10mg/kg CH223191；Experimental group 3 (IFN-γ model +CH223191): daily tracheal administration of 10μg/mouse IFN-γ+10mg/kg CH223191;
实验组4(IFN-γ造模组+PBS)：每天气管给予10μg/鼠IFN-γ处理。Experimental group 4 (IFN-γ model +PBS): the trachea was treated with 10 μg/mouse IFN-γ every day.
2.实验结果：2. Experimental results:
IFN-β和IFN-γ能导致小鼠的血氧饱和度降低(图3A)，出现缺氧和呼吸困难，增加Rrs(呼吸***阻力)、ERS(呼吸***弹性)、PV-k和Eta等指标的水平，反应了小鼠肺功能的损害。IFN-β and IFN-γ can reduce the blood oxygen saturation of mice (Figure 3A), hypoxia and dyspnea, increase 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.
然后，通过静脉注射AhR抑制剂阻断IDO-KYN-AhR通路。在此 条件下，IFN-β或IFN-γ诱导的小鼠呼吸功能损害的现象消失了(图3B至图3E)。Then, the IDO-KYN-AhR pathway was blocked by intravenous injection of AhR inhibitor. Under these conditions, IFN-β or IFN-γ-induced respiratory damage in mice disappeared (Figure 3B to Figure 3E).
实施例4.AHR抑制剂逆转IFN-β或者IFN-γ导致小鼠肺组织的黏蛋白上调和肺功能损伤Example 4. AHR inhibitor reverses IFN-β or IFN-γ causing mucin up-regulation and lung function damage in mouse lung tissue
1.实验步骤：1. Experimental steps:
C57小鼠采用非暴露式气管内注入法。正常组经气管一次性注入与处理组等量生理盐水，实验组经气管一次性灌肺5μg的IFN-β、IFN-γ、IFN-β+CH223191或者IFN-γ造模组+CH223191。注药后，立即将动物充分直立旋转，使药物在肺内分布均匀。每天给药一次，连续给药四天后测定肺功能以及收集肺组织样本。肺组织的采集：将小鼠用巴比妥钠麻醉后，小鼠处死后，进行心脏灌注，清除肺部血液后，取出肺组织，用预备生理盐水清洗掉肺组织表面的血污，尽量迅速进行上述操作后随即将组织存于–80℃保存。把一部分的肺组织立即放入4％多聚甲醛中保存，用于免疫组化染色的制备。C57 mice use non-exposure intratracheal injection. The normal group was injected with the same amount of normal saline through the trachea at one time, and the experimental group was injected with 5μg of IFN-β, IFN-γ, IFN-β+CH223191 or IFN-γ model+CH223191 through the trachea. After the medicine is injected, immediately rotate the animal upright to make the medicine evenly distributed in the lungs. The drug was administered once a day, and the lung function was measured and lung tissue samples were collected after four consecutive days of administration. Lung tissue collection: After the mouse is anesthetized with barbital sodium, the mouse is sacrificed, and the heart is perfused. After the lung blood is cleared, the lung tissue is taken out, and the blood stains on the lung tissue surface are cleaned with preparatory normal saline. Immediately after the above operation, the tissue was stored at -80°C. A part of the lung tissue was immediately stored in 4% paraformaldehyde for the preparation of immunohistochemical staining.
对照组(PBS)：每天气管给予PBS处理；Control group (PBS): PBS is given to the trachea every day;
实验组1(IFN-β造模组+PBS)：每天气管给予5μg/鼠IFN-β+PBS处理；Experimental group 1 (IFN-β model +PBS): daily tracheal treatment with 5μg/mouse IFN-β+PBS;
实验组2(IFN-β造模组+CH223191)：每天气管给予5μg/鼠IFN-β+10mg/kg CH223191；Experimental group 2 (IFN-β model+CH223191): 5μg/mouse IFN-β+10mg/kg CH223191 is given to the trachea every day;
实验组3(IFN-γ造模组+CH223191)：每天气管给予10μg/鼠IFN-γ+10mg/kg CH223191；Experimental group 3 (IFN-γ model +CH223191): daily tracheal administration of 10μg/mouse IFN-γ+10mg/kg CH223191;
实验组4(IFN-γ造模组+PBS)：每天气管给予10μg/鼠IFN-γ。Experimental group 4 (IFN-γ model +PBS): 10 μg/mouse IFN-γ was given to the trachea every day.
2.实验结果：2. Experimental results:
免疫组化结果显示IFN-β和IFN-γ能诱导小鼠肺脏的黏蛋白水平上调(图4A)。然后，通过静脉注射AhR抑制剂阻断IDO-KYN-AhR通路。在此条件下，IFN-β和IFN-γ诱导的小鼠肺脏产生的黏蛋白水平明显下降(图4B)。The results of immunohistochemistry showed that IFN-β and IFN-γ can induce up-regulation of mucin levels in the lungs of mice (Figure 4A). Then, the IDO-KYN-AhR pathway was blocked by intravenous injection of AhR inhibitor. Under these conditions, IFN-β and IFN-γ-induced mucin levels in the lungs of mice decreased significantly (Figure 4B).
实施例5.AHR抑制剂逆转SARS-CoV-2感染所致的间质性肺炎Example 5. AHR inhibitor reverses interstitial pneumonia caused by SARS-CoV-2 infection
1.实验步骤1. Experimental steps
将人ACE2转基因C57小鼠分为以下组：The human ACE2 transgenic C57 mice were divided into the following groups:
对照组：鼻内一次性注入与治疗组等量的生理盐水；Control group: intranasal injection of the same amount of normal saline as the treatment group;
模型组：鼻内一次性给与10 5TCID 50的SARS-CoV-2病毒颗粒； Model group: intranasal administration of 10 5 TCID 50 SARS-CoV-2 virus particles at a time;
治疗组：鼻内给与10 5TCID 50的SARS-CoV-2病毒颗粒后，尾静脉给与10mg/kg CH223191，每天给药一次，共给药5次。 Treatment group: After intranasal administration of 10 5 TCID 50 SARS-CoV-2 virus particles, 10 mg/kg CH223191 was administered to the tail vein, once a day, for a total of 5 administrations.
病毒感染后5天，将小鼠用巴比妥钠麻醉后，取出肺组织，把一部分的肺组织立即放入4％多聚甲醛中保存，用于免疫组化分析。Five days after the virus infection, the mice were anesthetized with sodium barbital, the lung tissue was taken out, and a part of the lung tissue was immediately placed in 4% paraformaldehyde for preservation for immunohistochemical analysis.
2.实验结果2. Experimental results
用SARS-CoV-2感染的人ACE2转基因小鼠中，发明人发现相比于对照组小鼠(MOCK组，未感染病毒)，其肺组织中的H&E染色结果显示SARS-CoV-2感染导致小鼠出现明显的间质性肺炎，而AHR抑制剂CH223191治疗后明显逆转此病变。In human ACE2 transgenic mice infected with SARS-CoV-2, the inventors found that compared with control mice (MOCK group, uninfected with virus), the results of H&E staining in the lung tissue showed that SARS-CoV-2 infection caused Mice developed obvious interstitial pneumonia, and the AHR inhibitor CH223191 significantly reversed this pathology.
综上，本公开的方案具有以下效果：In summary, the solution of the present disclosure has the following effects:
1.本申请的抗呼吸道病毒性肺炎制剂AhR抑制剂，可有效抑制病毒诱导机体呼吸***产生的病理性黏液，其有望成为治疗呼吸道病毒感染引发的肺部疾病的潜在药物。1. The AhR inhibitor of the anti-respiratory viral pneumonia preparation of the present application can effectively inhibit virus-induced pathological mucus produced by the respiratory system of the body, and it is expected to become a potential drug for the treatment of lung diseases caused by respiratory viral infections.
2.病毒感染后，机体会产生大量的IFN-β以及IFN-γ，这两种细胞因子本是要发挥抗病毒的作用，然而却产生了其他负面作用(即促进肺部产生更多的粘液来阻挡病毒，但影响了肺部气体交换，导致患者呼吸窘迫)。AhR抑制剂(IDO通过AhR通路发挥作用)逆转了这种负面作用。2. After a virus infection, the body will produce a large amount of IFN-β and IFN-γ. These two cytokines are supposed to play an anti-viral effect, but they have other negative effects (that is, promote the production of more mucus in the lungs). To stop the virus, but it affects the lung gas exchange, causing the patient to suffer from respiratory distress). AhR inhibitors (IDO works through the AhR pathway) reverse this negative effect.
3.本申请的抗呼吸道病毒性肺炎制剂还可以通过增强全身免疫反应，进而杀灭病毒，具有安全性高、无毒副作用的优点。3. The anti-respiratory viral pneumonia preparation of the present application can also enhance the systemic immune response, thereby killing the virus, and has the advantages of high safety and no toxic side effects.

Claims (7)

  1. AhR抑制剂在制备药物中的用途，其中：The use of AhR inhibitors in the preparation of medicines, wherein:
    所述药物用于选自以下的任一项或组合：预防病毒性肺炎的发生或复发、治疗病毒性肺炎或其症状；The medicine is used for any one or a combination selected from the following: preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia or its symptoms;
    所述病毒选自以下的一种或组合：冠状病毒、甲型流感病毒、乙型流感病毒、丙型流感病毒、麻疹病毒、腮腺炎病毒、呼吸道合胞病毒、副流感病毒、人偏肺病毒、亨德拉病毒、尼派病毒、风疹病毒、鼻病毒、腺病毒、呼肠病毒、柯萨奇病毒、ECHO病毒、及其变体；The virus is selected from one or a combination of: coronavirus, influenza A virus, influenza B virus, influenza C virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza virus, human metapneumovirus , Hendra virus, Nipa virus, rubella virus, rhinovirus, adenovirus, reovirus, Coxsackie virus, ECHO virus, and variants thereof;
    优选地，所述药物制备成选自以下的剂型：注射剂、喷雾剂、气雾剂、滴鼻剂、口服剂、适用于粘膜施用的剂型；Preferably, the medicine is prepared into a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral preparations, and dosage forms suitable for mucosal administration;
    优选地，所述AhR抑制剂选自以下的一种或组合：AHR拮抗剂1、α-NF、CB7993113、CMLD-2166、CH223191、DMF、GNF351、PDM2、StemRegenin 1、SR1、IDO抑制剂；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;
    优选地，所述IDO抑制剂选自以下的一种或组合：色氨酸类似物、醌及其衍生物、咪唑及其衍生物、三氮唑及其衍生物、N-羟基脒及其衍生物；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
    更优选地，所述IDO抑制剂选自以下的一种或组合：1-MT、Epacadostat、DO-IN-2、NLG919、PF-06840003、INCB024360、Exiguamine A、苯并咪唑；最优选地，所述IDO是IDO1。More preferably, the IDO inhibitor is selected from one or a combination of the following: 1-MT, Epacadostat, DO-IN-2, NLG919, PF-06840003, INCB024360, Exiguamine A, benzimidazole; most preferably, the The IDO is IDO1.
  2. 根据权利要求1所述的用途，所述冠状病毒选自：SARS、MERS、2019-nCoV、及其变体。The use according to claim 1, wherein the coronavirus is selected from: SARS, MERS, 2019-nCoV, and variants thereof.
  3. 根据权利要求1所述的用途，所述AhR抑制剂在单位制剂中的量是10mg至10g；The use according to claim 1, wherein the amount of the AhR inhibitor in a unit preparation is 10 mg to 10 g;
    优选地，所述IDO抑制剂在单位制剂中的量是1g至10g；Preferably, the amount of the IDO inhibitor in a unit preparation is 1 g to 10 g;
    优选地，IDO抑制剂以外的AhR抑制剂在单位制剂中的量是10mg至80mg。Preferably, the amount of AhR inhibitors other than IDO inhibitors in a unit preparation is 10 mg to 80 mg.
  4. 根据权利要求1至3中任一项所述的用途，其中：The use according to any one of claims 1 to 3, wherein:
    所述治疗体现为选自以下的一项或组合：改善血氧饱和度、改善PaO 2/FiO 2、缓解呼吸窘迫、降低RRS呼吸***阻力、改善ERS、改善PV-k水平、改善Eta水平、减少呼吸道黏液、调节黏蛋白的表达水平、提高存活率、延长生存期； The treatment is embodied as one or a combination selected from the following: improving blood oxygen saturation, improving PaO 2 /FiO 2 , alleviating respiratory distress, reducing RRS respiratory system resistance, improving ERS, improving PV-k level, improving Eta level, Reduce respiratory mucus, regulate the expression level of mucin, improve survival rate, and prolong survival;
    所述预防是指延迟或阻止疾病向重症或危重症发展、降低发展为重症或危重症的风险。The prevention refers to delaying or preventing the development of a disease to severe or critical illness, and reducing the risk of developing severe or critical illness.
  5. 根据权利要求1所述的用途，所述病毒性肺炎选自：轻型、普通型、重型、危重型。The use according to claim 1, wherein the viral pneumonia is selected from the group consisting of mild, common, severe, and critical.
  6. 一种药物组合物，其包含：A pharmaceutical composition comprising:
    AhR抑制剂、和AhR inhibitors, and
    任选地，可药用载体：Optionally, a pharmaceutically acceptable carrier:
    所述药物组合物用于选自以下的任一项或组合：预防病毒性肺炎的发生或复发、治疗病毒性肺炎或其症状；The pharmaceutical composition is used for any one or a combination selected from the following: preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia or its symptoms;
    所述病毒选自以下的一种或组合：冠状病毒、甲型流感病毒、乙型流感病毒、丙型流感病毒、麻疹病毒、腮腺炎病毒、呼吸道合胞病毒、副流感病毒、人偏肺病毒、亨德拉病毒、尼派病毒、风疹病毒、鼻病毒、腺病毒、呼肠病毒、柯萨奇病毒、ECHO病毒、及其变体；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, Nipa virus, rubella virus, rhinovirus, adenovirus, reovirus, Coxsackie virus, ECHO virus, and variants thereof;
    所述冠状病毒选自：SARS、MERS、2019-nCoV、及其变体；The coronavirus is selected from: SARS, MERS, 2019-nCoV, and variants thereof;
    所述药物组合物是选自以下的剂型：注射剂、喷雾剂、气雾剂、滴鼻剂、口服剂、适用于粘膜施用的剂型；The pharmaceutical composition is a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral preparations, and dosage forms suitable for mucosal administration;
    优选地，所述AhR抑制剂选自以下的一种或组合：AHR拮抗剂1、α-NF、CB7993113、CMLD-2166、CH223191、DMF、GNF351、PDM2、StemRegenin 1、SR1、IDO抑制剂；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;
    优选地，所述IDO抑制剂选自以下的一种或组合：色氨酸类似物、醌及其衍生物、咪唑及其衍生物、三氮唑及其衍生物、N-羟基脒及其衍生物；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
    更优选地，所述IDO抑制剂选自以下的一种或组合：1-MT、Epacadostat、DO-IN-2、NLG919、PF-06840003、INCB024360、Exiguamine A、苯并咪唑；More preferably, the IDO inhibitor is selected from one or a combination of the following: 1-MT, Epacadostat, DO-IN-2, NLG919, PF-06840003, INCB024360, Exiguamine A, benzimidazole;
    所述AhR抑制剂在单位制剂中的量是10mg至10g；The amount of the AhR inhibitor in a unit preparation is 10 mg to 10 g;
    优选地，所述IDO抑制剂在单位制剂中的量是1g至10g；Preferably, the amount of the IDO inhibitor in a unit preparation is 1 g to 10 g;
    优选地，IDO抑制剂以外的AhR抑制剂在单位制剂中的量是10mg至80mg；Preferably, the amount of AhR inhibitors other than IDO inhibitors in a unit preparation is 10 mg to 80 mg;
    优选地，所述IDO是IDO1。Preferably, the IDO is IDO1.
  7. 一种预防或治疗病毒性肺炎的方法，包括：A method of preventing or treating viral pneumonia, including:
    向受试者施用预防有效量或治疗有效量的AhR抑制剂；Administering a prophylactically effective amount or a therapeutically effective amount of an AhR inhibitor to the subject;
    所述病毒选自以下的一种或组合：冠状病毒、甲型流感病毒、乙型流感病毒、丙型流感病毒、麻疹病毒、腮腺炎病毒、呼吸道合胞病毒、副流感病毒、人偏肺病毒、亨德拉病毒、尼派病毒、风疹病毒、鼻病毒、腺病毒、呼肠病毒、柯萨奇病毒、ECHO病毒、及其变体；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, Nipa virus, rubella virus, rhinovirus, adenovirus, reovirus, Coxsackie virus, ECHO virus, and variants thereof;
    所述施用选自：肌内、静脉内、皮下、皮内、口服、鼻内、呼吸道、经粘膜、舌下、肠胃外；The administration is selected from: intramuscular, intravenous, subcutaneous, intradermal, oral, intranasal, respiratory tract, transmucosal, sublingual, parenteral;
    所述AhR抑制剂选自以下的一种或组合：AHR拮抗剂1、α-NF、CB7993113、CMLD-2166、CH223191、DMF、GNF351、PDM2、StemRegenin 1、SR1、IDO抑制剂；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;
    优选地，所述IDO抑制剂选自以下的一种或组合：1-MT、Epacadostat、DO-IN-2、NLG919、PF-06840003、INCB024360、Exiguamine A、苯并咪唑；Preferably, the IDO inhibitor is selected from one or a combination of the following: 1-MT, Epacadostat, DO-IN-2, NLG919, PF-06840003, INCB024360, Exiguamine A, benzimidazole;
    所述AhR抑制剂在单位制剂中的量是10mg至10g；The amount of the AhR inhibitor in a unit preparation is 10 mg to 10 g;
    优选地，所述IDO抑制剂在单位制剂中的量是1g至10g；Preferably, the amount of the IDO inhibitor in a unit preparation is 1 g to 10 g;
    优选地，IDO抑制剂以外的AhR抑制剂在单位制剂中的量是10mg至80mg；Preferably, the amount of AhR inhibitors other than IDO inhibitors in a unit preparation is 10 mg to 80 mg;
    优选地，所述IDO是IDO1；Preferably, the IDO is IDO1;
    所述预防是指延迟或阻止疾病向重症或危重症发展、降低发展为重症或危重症的风险；The prevention refers to delaying or preventing the development of a disease to severe or critical illness, and reducing the risk of developing severe or critical illness;
    所述治疗体现为选自以下的一项或组合：改善血氧饱和度、改善PaO 2/FiO 2、缓解呼吸窘迫、降低RRS呼吸***阻力、改善ERS、改善PV-k水平、改善Eta水平、减少呼吸道黏液、调节黏蛋白的表达水平、提高存活率、延长生存期。 The treatment is embodied as one or a combination selected from the following: improving blood oxygen saturation, improving PaO 2 /FiO 2 , alleviating respiratory distress, reducing RRS respiratory system resistance, improving ERS, improving PV-k level, improving Eta level, Reduce respiratory mucus, regulate the expression level of mucin, improve survival rate, and prolong survival.
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