WO2022241666A1 - 脂质小分子作为3c-样蛋白酶靶向剂在抗病毒方面的用途以及广谱抗炎作用 - Google Patents

脂质小分子作为3c-样蛋白酶靶向剂在抗病毒方面的用途以及广谱抗炎作用 Download PDF

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WO2022241666A1
WO2022241666A1 PCT/CN2021/094517 CN2021094517W WO2022241666A1 WO 2022241666 A1 WO2022241666 A1 WO 2022241666A1 CN 2021094517 W CN2021094517 W CN 2021094517W WO 2022241666 A1 WO2022241666 A1 WO 2022241666A1
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virus
targeting agent
phosphatidylcholine
pharmaceutically acceptable
protease
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PCT/CN2021/094517
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French (fr)
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蒋澄宇
马一鸣
杜芯仪
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中国医学科学院基础医学研究所
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Priority to PCT/CN2021/094517 priority Critical patent/WO2022241666A1/zh
Priority to CN202180038299.8A priority patent/CN115708408A/zh
Publication of WO2022241666A1 publication Critical patent/WO2022241666A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • 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

Definitions

  • This application belongs to the field of medicinal chemistry.
  • 3C-like protease (3CLpro) of viruses such as the new coronavirus SARS-CoV-2
  • virtual screening is performed with lipids derived from traditional Chinese medicines to obtain drug lead compounds, which are verified by virus challenge experiments. .
  • 3C-like protease also known as main protease (Mpro)
  • Mpro main protease
  • 3CLpro enzymes eg, porcine epidemic diarrhea virus, coronavirus, foot-and-mouth disease virus, encephalomyocarditis virus
  • Novel coronavirus pneumonia is an acute infectious pneumonia caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus type 2
  • the main route of transmission is through air and contact, and there is the possibility of aerosol transmission and fecal-oral transmission.
  • the initial stage of patients is mostly respiratory symptoms, such as fever, cough, shortness of breath, and dyspnea. If the disease is not well controlled, in severe cases, infection can lead to severe acute respiratory syndrome, systemic sepsis and even death.
  • a Compound 3C-like protease targeting agent there is provided a Compound 3C-like protease targeting agent.
  • the 3C-like protease targeting agent is a diglyceride or a phosphatidylcholine.
  • phosphatidylcholine compound which is represented by formula I:
  • phosphatidylcholine compound which is represented by formula II:
  • phosphatidylcholine compound represented by formula IV:
  • phosphatidylcholine compound which is represented by formula V:
  • a 3C-like protease targeting agent or a pharmaceutically acceptable salt thereof selected from any of the following in the preparation of an antiviral drug:
  • a 3C-like protease targeting agent or a pharmaceutically acceptable salt thereof selected from any of the following in the preparation of a disinfectant or a disinfectant composition:
  • a 3C-like protease targeting agent or a pharmaceutically acceptable salt thereof selected from any of the following in the preparation of a virus inhibitor:
  • a 3C-like protease targeting agent selected from any of the following or a pharmaceutically acceptable salt thereof in the preparation of an anti-inflammatory drug:
  • the inflammation is inflammation caused by Gram-negative bacteria or Gram-positive bacteria.
  • the lung inflammation is selected from: inflammation caused by viruses, inflammation caused by bacteria, inflammation caused by fungi, or a combination thereof.
  • the compounds of the present application are acidic, such as compounds having carboxyl or hydroxyl groups. These compounds can form pharmaceutically acceptable salts. Examples of these salts may include sodium, potassium, calcium, aluminum. Also included are salts formed with amines such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine, and the like.
  • the compounds of the present application are basic compounds, and can also form pharmaceutically acceptable salts, such as acid addition salts.
  • examples include inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfamic acid, etc., and organic acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid, cinnamic acid, citric acid, maleic acid, adipic acid, Alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, glycolic acid, malic acid, lactic acid, malonic acid, oxalic acid, niacin, succinic acid, salicylic acid, stearic acid, tartaric acid, p-amino Salts of benzenesulfonic acid, trimethylbenzenesulfonic acid, p-toluenes
  • inorganic acids such as sulfuric acid
  • a virus suitable for use in the present application is not limited to a particular family of viruses, provided it contains the 3CLpro enzyme.
  • it can be selected from any one of the following: rhinovirus, coronavirus, adenovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, echovirus, coxsackievirus, porcine epidemic diarrhea virus, foot-and-mouth disease virus , Encephalomyocarditis virus.
  • the virus is a coronavirus selected from any of the following: SARS-CoV, SARS-CoV-2, MERS-CoV, or variants thereof .
  • the virus is SARS-CoV-2.
  • an antiviral agent (or antiviral preparation, or viral inhibitor) comprising a compound or a pharmaceutically acceptable salt thereof selected from any of the following:
  • an anti-inflammatory agent comprising a compound selected from any of the following, or a pharmaceutically acceptable salt thereof:
  • any compound of formula I to formula V or a pharmaceutically acceptable salt thereof according to the present application is used for therapeutic use.
  • any compound of formula I to formula V or a pharmaceutically acceptable salt thereof according to the present application is used for non-therapeutic use.
  • an antiviral agent refers to any virus that can inhibit (or reduce, hinder, interfere, inactivate, kill) virus activity, vitality, replication, proliferation, growth, infectivity, , or toxic compound or composition.
  • the virus is selected from any one of the following: rhinovirus, coronavirus (SARS-CoV, SARS-CoV-2, MERS-CoV, or variants thereof), adenovirus, influenza virus, parainfluenza virus, Respiratory syncytial virus, echovirus, coxsackievirus, porcine epidemic diarrhea virus, foot-and-mouth disease virus, encephalomyocarditis virus.
  • disinfectant especially refers to any virus activity, viability, replication , proliferation, growth, infectivity, or virulence compound (or composition).
  • the disinfectant (or disinfectant composition) of the present application is used to disinfect environment, area, article, sample, surface, container or food infected or polluted by virus.
  • the present invention provides a method of disinfection or antiviral method suitable for use in treating an environment, area, item, sample, surface, container, or food product exposed to or threatened by a pathogen.
  • the virus is contacted with an environmental surface, the method comprising contacting the environmental surface with an amount of the compound/composition sufficient to disinfect the surface. But disinfection does not have to result in the elimination of all pathogens.
  • any compound of formula I to formula V according to the present application or a pharmaceutically acceptable salt thereof is used as an additive to prevent harmful or undesirable Virus contamination.
  • any compound of formula I to formula V of the present application or a pharmaceutically acceptable salt thereof targets 3C-like protease, thereby exerting the effect of inhibiting viruses.
  • the drug may also include one or more pharmaceutically acceptable carriers, which include conventional diluents and excipients in the field of pharmacy , fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants or synergists, etc.
  • pharmaceutically acceptable carriers include conventional diluents and excipients in the field of pharmacy , fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants or synergists, etc.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered.
  • suitable aqueous and non-aqueous carriers include: water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol) or mixtures thereof, oils (eg olive oil, injectable organic esters).
  • suitable pharmaceutical carriers are described in Remington Pharmaceutical Sciences by E.W. Martin.
  • the medicine can be made into injections, tablets, pills, capsules, suspensions, emulsions, sprays, disinfectants, detergents, culture media form application.
  • the route of administration may be oral, transdermal, intravenous, pulmonary inhalation, nasal drops, or intramuscular injection.
  • it can be prepared as a spray, detergent, lotion.
  • a method of treating a viral infection comprising exposing a subject to a therapeutically effective amount of a compound selected from any of the following, or a pharmaceutically acceptable salt thereof:
  • a method of disinfection comprising contacting an environment, area, item, sample, surface, container, or food with an effective amount of a compound selected from any of the following, or a pharmaceutically acceptable salt thereof:
  • a method of treating inflammation comprising exposing a subject to a therapeutically effective amount of a compound selected from any of the following, or a pharmaceutically acceptable salt thereof:
  • subject refers to an organism treated with a compound of the present application. These organisms include those exposed or suspected of being exposed to the virus. Organisms include, but are not limited to, animals (eg, humans, domestic animals, wild animals) and plants.
  • an "effective amount” is an amount required or sufficient to inhibit (or reduce, impede, interfere, inactivate, kill) the activity, viability, replication, proliferation, growth, infectivity, or virulence of a virus.
  • an effective amount of a compound of the present application is an amount capable of producing a statistically significant reduction in viral replication ability in a subject.
  • an effective amount of a compound of the present application is an amount capable of producing a statistically significant reduction in viral load, viral transmissibility, or viral viability in the environment.
  • the effective amount of the compound of the present application is an amount capable of significantly reducing the expression levels of inflammatory factors in a subject.
  • the contact time between the compound of the present application and the subject (or the environment to be treated, the surface, etc.) is sufficient to inhibit (or reduce, hinder, interfere, inactivate, kill) the activity, vitality, and replication of the virus , proliferation, growth, infectivity, or virulence.
  • the effective amount level selected will depend on a variety of factors, including the activity of the particular compound of the application used, the route of administration, the time of administration, the rate of metabolism of the particular compound used, the duration of the treatment, and the combination with the particular compound used.
  • Other drugs compounds and/or materials used, age, sex, weight, condition, general health and medical history of the subject being treated, and other factors well known in the medical arts.
  • a physician or veterinarian of ordinary skill in the art can readily determine the effective amount required.
  • a suitable daily dose of a compound of the present application will be that amount of the compound effective to produce a therapeutic effect.
  • the daily dose of a compound of the present application may be administered at appropriate intervals throughout the day as two, three, four, five, six or more sub-doses administered separately; optionally, the sub-doses are Dosage in unit dosage form.
  • the pharmaceutical composition or active ingredient provided by the application can be administered according to conventional clinical treatment methods, for example, for pneumonia, it can be administered directly through nasal drops, sprays, or perfusion into the lungs; the dosage can be determined according to the dosage determined by medical workers to use.
  • compositions or active ingredients provided herein are formulated for pulmonary administration.
  • inhalable powders for pulmonary administration can be produced by conventional techniques such as jet milling, spray drying, solvent precipitation, supercritical fluid condensation, and the like.
  • dry powder inhalers dry powder inhalers, DPI
  • metered dose inhalers metered dose inhalers
  • GSK GSK
  • Astra TeurbohalerTM
  • a suitable carrier such as mannitol , sucrose or lactose
  • Solution formulations with liposomes can also be delivered to the lungs using an ultrasonic nebulizer.
  • the compounds of the present application may be administered alone, it is preferred to administer the compounds in the form of pharmaceutical compositions (or antiseptic compositions).
  • Figure 1 Cell viability assay results.
  • Fig. 2A to Fig. 2H results of cytotoxicity test (MTT).
  • Figure 4A to Figure 4F the expression of IL-1 ⁇ , IL-6, TNF- ⁇ .
  • Figure 5A to Figure 5F the expression of IL-1 ⁇ , IL-6, TNF- ⁇ .
  • Figure 6A to Figure 6E Expression of IL-1 ⁇ , IL-6, TNF- ⁇ .
  • Figures 7A-7C SPR results of binding of small lipid molecules to 3C-like proteases.
  • Figures 8A-8E IC50 binding of small lipid molecules to 3C-like proteases.
  • Embodiment 1 Establishment of Chinese medicine decoction lipid bank
  • the obtained raw data was converted into .abf format using ABF CONVERTER, imported into MS-DIAL 4.0.0 for data analysis, and Lipidblast was used to identify components to obtain a lipid small molecule library of traditional Chinese medicine soup.
  • Example 2 The 5 compounds obtained in Example 2 proved to have an inhibitory effect on SARS-COV-2 virus infection at the cellular level. According to the experiments in Figure 1, the five compounds improved the proliferation of Vero E6 cells after they were infected. According to the CPE experiment, compared with the model group, the five compounds improved the viability of infected Vero E6 cells.
  • THP-1 cells used in the experiment were purchased from the Cell Culture Center of Peking Union Medical College. ⁇ -MEM medium was purchased from HyClone Company. The cells were cultured in a 37°C, 5% CO2 incubator. The culture of THP-1 cells was based on 1640 medium, which was supplemented with 10% v/v fetal bovine serum and antibiotics (penicillin 100 U/mL and streptomycin 100 mg/mL). When the cells were cultured to the logarithmic growth phase, they were divided into 12-well plates (1 mL medium/well), incubated overnight at 37° C., and the subsequent experiments were performed after the cells grew to 80%.
  • LPS was purchased from Sigma-Aldrich, and the concentration of the stock solution was 1 mg/mL. When in use, 50 ⁇ L LPS stock solution was added to 450 ⁇ L opti-MEM, and 10 ⁇ L was added to each well.
  • Blank group refers to untreated cells, and this group serves as a blank control group.
  • Model group add LPS stimulation.
  • Small lipid molecule group preventive administration of small lipid molecules and stimulation with LPS.
  • A549 cells used in the experiment were purchased from the Cell Culture Center of Peking Union Medical College. F-12 medium was purchased from HyClone Company. The cells were cultured in a 37°C, 5% CO2 incubator. The culture of A459 cells was based on F-12 medium, which was supplemented with 10v/v% fetal calf serum and antibiotics (penicillin 100U/mL and streptomycin 100mg/mL). When the cells were cultured to the logarithmic growth phase, they were divided into 12-well plates (1mL medium/well), incubated overnight at 37°C, and subsequent experiments were performed after the cells adhered to the wall.
  • PolyI:C was purchased from Sigma-Aldrich with a storage concentration of 10mg/mL, and the configuration of the transfection system in a 12-well plate: 100 ⁇ L opti-MEM+2 ⁇ L lipo2000; 100 ⁇ L opti-MEM+0.1 ⁇ L PolyI:C, let stand for 15min, 200 ⁇ L per well .
  • Blank group refers to untreated cells, and this group serves as a blank control group.
  • Model group add PolyI:C stimulation.
  • Small lipid molecule group Preventive administration of small lipid molecules was given in advance, and PolyI:C stimulation was given.
  • Example 6 The small lipid molecule of the present application has a relieving effect on the inflammation model induced by Gram-positive bacteria lipoteichoic acid (LTA) on the U937 cell line
  • the U937 cells used in the experiment were purchased from the Cell Culture Center of Peking Union Medical College. 1640 medium was purchased from HyClone Company. The cells were cultured in a 37°C, 5% CO2 incubator. The culture of U937 cells was based on 1640 medium, which was supplemented with 10v/v% fetal calf serum and antibiotics (penicillin 100U/mL and streptomycin 100mg/mL). When the cells were cultured to the logarithmic growth phase, they were divided into 12-well plates (1 mL medium/well), incubated overnight at 37° C., and the subsequent experiments were performed after the cells grew to 80%.
  • LTA was purchased from Sigma-Aldrich with a storage concentration of 1 mg/mL. When in use, 50 ⁇ L LTA stock solution was added to 450 ⁇ L opti-MEM, and 10 ⁇ L was added to each well.
  • Blank group refers to untreated cells, and this group serves as a blank control group.
  • Model group adding LTA stimulation.
  • Small lipid molecule group Preventive administration of small lipid molecules was given in advance, and LTA stimulation was given.
  • 3C-like proteins were immobilized on carboxymethyl-5'-dextran (CM5) sensor chips using amine coupling chemistry. 3C-like proteins were immobilized in a four-channel flow cell, activated and blocked with a three-channel flow cell as a reference cell. 3C-like protein (20 ⁇ g ⁇ mL-1, 10 mm sodium acetate solution, pH 4.5) was immobilized on the surface after injection for 420 s. Remaining activated groups on the surface were blocked by 420 s injection of 1 ⁇ M ethanolamine at pH 8.5. In the above steps, the flow rate was maintained at 30 ⁇ L min-1, and 1x phosphate-buffered saline (PBS) running buffer was used during fixation. Approximately 13,000 response units (RU) of protein can be routinely captured on the CM5 chip of a four-channel flow cell.
  • PBS 1x phosphate-buffered saline
  • Example 8 Detection of the half inhibitory rate (IC 50 ) of the binding of small lipid molecules to 3C-like proteases
  • Fluorescence detection (320nm excitation, 405nm detection), once every 30s, a total of 20 measurements;

Abstract

脂质小分子作为3C-样蛋白酶靶向剂在抗病毒方面的用途以及广谱抗炎作用。具体而言，通过中药脂质分子库，针对病毒(例如SARS-CoV-2)的3C-样蛋白酶进行筛选，获得了药物先导化合物，并用病毒攻击实验验证磷脂酰胆碱和甘油二酯具有抗病毒、抗炎作用。

Description

脂质小分子作为3C-样蛋白酶靶向剂在抗病毒方面的用途以及广谱抗炎作用 技术领域
本申请属于药物化学领域，针对病毒(例如新型冠状病毒SARS-CoV-2)的3C-样蛋白酶(3CLpro)，用来源于中药的脂质进行虚拟筛选以获得药物先导化合物，并用病毒攻击实验验证。
背景技术
3C-样蛋白酶(3CLpro)又称作主蛋白酶(Mpro)，是病毒复制和感染过程中的关键水解酶。多种病毒(例如猪流行性腹泻病毒、冠状病毒、口蹄疫病毒、脑心肌炎病毒)均可编码3CLpro酶。
新型冠状病毒肺炎(COVID-19)是一种由严重急性呼吸道综合征冠状病毒2型(SARS-CoV-2)感染所致的急性感染性肺炎。主要传播途径是通过空气和接触传播，存在经气溶胶传播和粪-口途径传播的可能性。患者初期多为呼吸道症状，存在发热、咳嗽、气促和呼吸困难等，若疾病控制不佳，在重症病例中，感染可导致严重急性呼吸综合征、全身性脓毒血症甚至死亡。
目前针对COVID-19尚无特效治疗药物。因此，研究抗COVID-19靶向药物具有重大意义。在COVID-19的治疗中，中药起着不可或缺的作用。服用中药熬煮后的汤汁，是中药最常见的一种使用方式。已有文献报道，中药汤汁由化学小分子组分、脂质、蛋白和sRNA组成。其中脂质一直是中药有效成分中被忽略的一部分。
随着计算机辅助药物设计的发展，药物虚拟筛选有效的改善了传统药物研发过程中高成本、高风险的问题，已经成为一种与高通量筛选互补的技术，是发现先导化合物及其活性优化的中药方法。建立中药汤汁来源的脂质小分子库，对病毒的主要蛋白靶点进行筛选，对抑制病毒的复制和感染以及控制病毒的传播起着至关重要的作用。
发明内容
根据一些实施方案，提供一种化合物3C-样蛋白酶靶向剂。
在具体的实施方案中，所述3C-样蛋白酶靶向剂是甘油二酯或磷脂酰胆碱。
根据一些实施方案，提供一种甘油二酯化合物，其是式III所示：
Figure PCTCN2021094517-appb-000001
根据一些实施方案，提供一种磷脂酰胆碱化合物，其是式I所示：
Figure PCTCN2021094517-appb-000002
根据一些实施方案，提供一种磷脂酰胆碱化合物，其是式II所示：
Figure PCTCN2021094517-appb-000003
根据一些实施方案，提供一种磷脂酰胆碱化合物，其是式IV所示：
Figure PCTCN2021094517-appb-000004
根据一些实施方案，提供一种磷脂酰胆碱化合物，其是式V所示：
Figure PCTCN2021094517-appb-000005
Figure PCTCN2021094517-appb-000006
根据一些实施方案，提供选自以下任一项的3C-样蛋白酶靶向剂或其可药用盐在制备抗病毒药物中的用途：
Figure PCTCN2021094517-appb-000007
根据一些实施方案，提供选自以下任一项的3C-样蛋白酶靶向剂或其可药用盐在制备消毒剂或消毒组合物中的用途：
Figure PCTCN2021094517-appb-000008
根据一些实施方案，提供选自以下任一项的3C-样蛋白酶靶向剂或其可药用盐在制备病毒抑制剂中的用途：
Figure PCTCN2021094517-appb-000009
Figure PCTCN2021094517-appb-000010
根据一些实施方案，提供选自以下任一项的3C-样蛋白酶靶向剂或其可药用盐在制备抗炎症药物中的用途：
Figure PCTCN2021094517-appb-000011
Figure PCTCN2021094517-appb-000012
其中，所述炎症是革兰氏阴性菌或革兰氏阳性菌所致炎症。
根据一些实施方案，提供前述3C-样蛋白酶靶向剂或其可药用盐在制备用于治疗肺部炎症的药物中的用途。具体而言，肺部炎症选自：病毒所致炎症、细菌所致炎症、真菌所致炎症、或其组合。
当用于前述各应用时，在一些实施方案中，本申请的化合物是酸性的，如具有羧基或羟基的化合物。这些化合物可以形成药用盐。这些盐的示例可以包括钠、钾、钙、铝。也包括与胺(如氨、烷基胺、羟基烷基胺、N-甲基葡糖胺等)形成的盐。
当用于前述各应用时，在一些实施方案中，本申请的化合物是碱性化合物，也可以形成药用盐，如酸加成盐。示例包括无机酸如硫酸、硝酸、磷酸、盐酸、氢溴酸、氨基磺酸等，及有机酸如醋酸、三氟醋酸、三氯醋酸、肉桂酸、柠檬酸、马来酸、己二酸、藻酸、抗坏血酸、天冬氨酸、苯甲酸、苯磺酸、乙醇酸、苹果酸、乳酸、丙二酸、草酸、烟酸、丁二酸、水杨酸、硬脂酸、酒石酸、对氨基苯磺酸、三甲基苯磺酸、对甲基苯磺酸、扁桃酸、果胶酯酸、苦味酸、丙酸等所形成的盐。
所有这些酸盐和碱盐都为本申请范围内的可药用盐。
适用于本申请的病毒并不限于具体特定的病毒科，条件是它包含3CLpro酶。作为实例，可以选自以下的任一项：鼻病毒、冠状病毒、腺病毒、流感病毒、副流感病毒、呼吸道合胞病毒、埃可病毒、柯萨奇病毒、猪流行性腹泻病毒、口蹄疫病毒、脑心肌炎病毒。
当用于前述各应用时，在一些具体的实施方案中，所述病毒是冠状病毒，其选自以下的任一项：SARS-CoV、SARS-CoV-2、MERS-CoV、或其变体。
当用于前述各应用时，在一些具体的实施方案中，所述病毒是SARS-CoV-2。
根据一些实施方案，提供一种抗病毒剂(或抗病毒制剂、或病毒抑制剂)，其包含选自以下任一项的化合物或其可药用盐：
Figure PCTCN2021094517-appb-000013
Figure PCTCN2021094517-appb-000014
根据一些实施方案，提供一种抗炎剂，其包含选自以下任一项的化合物或其可药用盐：
Figure PCTCN2021094517-appb-000015
Figure PCTCN2021094517-appb-000016
在一些实施方案中，根据本申请式I至式V的任一化合物或其可药用盐用于治疗用途。
在另一些实施方案中，根据本申请式I至式V的任一化合物或其可药用盐用于非治疗用途。
在本申请中，抗病毒剂(或病毒抑制剂)是指任何能够在体内或体外抑制(或降低、阻碍、干扰、失活、杀灭)病毒活性、活力、复制、增殖、生长、传染性、或毒力的化合物或组合物。作为示例，所述病毒选自以下的任一项：鼻病毒、冠状病毒(SARS-CoV、SARS-CoV-2、MERS-CoV、或其变体)、腺病毒、流感病毒、副流感病毒、呼吸道合胞病毒、埃可病毒、柯萨奇病毒、猪流行性腹泻病毒、口蹄疫病毒、脑心肌炎病毒。
在本申请中，消毒剂(或消毒组合物)尤其是指任何能够在体外(例如环境中、物体表面等)抑制(或降低、阻碍、干扰、失活、杀灭)病毒活性、活力、复制、增殖、生长、传染性、或毒力的化合物(或组合物)。
本申请的消毒剂(或消毒组合物)用于消毒被病毒感染或污染的环境、区域、物品、样品、表面、容器、或食品。
在一些实施方案中，本发明提供一种消毒方法或抗病毒方法，其适合用于处理暴露于病原体或受病原体威胁的环境、区域、物品、样品、表面、容器、或食品。在示例的实施方案中，病毒与环境表面相接触，该方法包括将环境表面与足以使该表面消毒的量的化合物/组合物接触。但是消毒不必非要导致消除所有的病原体。
消除各种表面(特别是这些病毒能在相对长的一段时间内保持活性的硬质表面)、以及商业和公共环境(例如医院、门诊部、旅馆)的病毒。
在一些实施方案中，根据本申请式I至式V的任一化合物或其可药用盐作为添加剂使用，以防止环境、区域、物品、样品、表面、容器、或食品中有害或不希望的病毒污染。
在具体的实施方案中，本申请的式I至式V的任一化合物或其可药用盐靶向3C-样蛋白酶，从而发挥抑制病毒的作用。
在具体的实施方案中，所述药物(或抗病毒剂、或消毒组合物)还可包括一种或多种药学上可接受的载体，所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂或增效剂等。
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。可用于本申请药物组合物(或抑制剂、消毒剂)中的合适的水性和非水性载体的示例包括：水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇)或其混合物、油(如橄榄油、可注射的有机酯类)。适宜的药物载体描述于E.W.Martin的Remington Pharmaceutical Sciences中。
在具体的实施方案中，所述药物(或抗病毒剂、或消毒组合物)可以制成注射剂、片剂、丸剂、胶囊、悬浮剂、乳剂、喷雾剂、消毒液、洗涤剂、培养介质的形式施用。当适用于人或动物受试者时，给药途径可以为口服、经皮、静脉、肺吸入、滴鼻、或肌肉注射。当适用于环境、区域、物品、样品、表面、容器、或食品时，可以制备成喷雾剂、洗涤剂、洗剂。
根据一些实施方案，提供了一种治疗病毒感染的方法，其包括使受试者接触治疗有效量的选自以下任一项的化合物或其可药用盐：
Figure PCTCN2021094517-appb-000017
Figure PCTCN2021094517-appb-000018
根据一些实施方案，提供了一种消毒的方法，其包括使环境、区域、物品、样品、表面、容器、或食品接触有效量的选自以下任一项的化合物或其可药用盐：
Figure PCTCN2021094517-appb-000019
Figure PCTCN2021094517-appb-000020
根据一些实施方案，提供了一种治疗炎症(优选肺部炎症)的方法，其包括使受试者接触治疗有效量的选自以下任一项的化合物或其可药用盐：
Figure PCTCN2021094517-appb-000021
Figure PCTCN2021094517-appb-000022
此处所用的术语“受试者”，指的是用本申请的化合物所处理的生物。这些生物包括那些暴露于或怀疑被暴露于病毒的生物。生物包括，但不限于动物(例如人、家养动物、野生动物)和植物。
一方面，“有效量”是抑制(或降低、阻碍、干扰、失活、杀灭)病毒的活性、活力、复制、增殖、生长、传染性、或毒力所需的或者足够的量。在一个示例中，本申请化合物的有效量是在受试者中能够对病毒复制能力产生统计学上显著性降低的量。在另一个示例中，本申请化合物的有效量是能够将环境中的病毒载量、病毒传播能力、或病毒活力产生统计学上显著性降低的量。
另一方面，“有效量”也指改善炎症的症状所需的或者足够的量。在一个示例中，本申请化合物的有效量是在受试者中能够使炎症因子的表达水平显著性降低的量。
在具体的实施方案中，本申请化合物和受试者(或待处理的环境、表面等)接触的时间足以抑制(或降低、阻碍、干扰、失活、杀灭)病毒的活性、活力、复制、增殖、生长、传染性、或毒力。
所选择的有效量水平将取决于多种因素，包括所用的具体的本申请的化合物的活性、施用途径、施用时间、所用的具体化合物的代谢 速率、处理的持续时间、与所用的具体化合物组合使用的其他药物(化合物和/或材料)、所治疗的受试者的年龄、性别、体重、情况、一般健康状况和病史、以及医学领域中公知的其他因素。本领域普通技能的医师或兽医可容易地确定所需的有效量。
一般而言，本申请的化合物的合适的日剂量将是有效产生治疗作用的化合物量。
如果需要的话，本申请的化合物的日剂量可以在一天中以分开施用的二、三、四、五、六或更多个亚剂量以适宜的时间间隔施用；任选地，所述亚剂量是单位剂型的剂量。
本申请提供的药物组合物或活性成分可以按照常规临床治疗方法给药，例如对于肺炎，可以直接滴鼻、喷雾、或灌注至肺部而给药；给药剂量可按照医疗工作者确定的剂量进行使用。
在具体的实施方案中，本申请提供的药物组合物或活性成分制备成肺部施用的剂型。
作为一个示例，用于肺部施用可吸入的粉末可以通过常规的技术生产，如喷射制粉(jet milling)、喷雾干燥、溶剂沉淀、超临界流体浓缩(supercritical fluid condensation)等。用干粉吸入器(dry powder inhalers，DPI)如基于NektarTM、Vectura(GyrohalerTM)和GSK(DiscusTM)或Astra(TurbohalerTM)等生产的计量吸入器(metered dose inhalers)，在合适的载体中(如甘露醇、蔗糖或乳糖)包含本申请提供的药物组合物或活性成分，输送到末端肺泡表面。也可以使用超声波喷雾器，将有脂质体(或没有脂质体)的溶液制剂递送至肺部。
虽然本申请的化合物可以单独施用，但优选以药物组合物(或消毒组合物)的形式施用所述化合物。
除非另有说明，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。
附图说明
图1：细胞活力检测结果。
图2A至图2H：细胞毒性试验(MTT)检测结果。
图3：致细胞病变效应(CPE)结果。
图4A至图4F：IL-1β、IL-6、TNF-α的表达情况。
图5A至图5F：IL-1β、IL-6、TNF-α的表达情况。
图6A至图6E：IL-1β、IL-6、TNF-α的表达情况。
图7A至图7C：脂质小分子与3C-样蛋白酶结合的SPR结果。
图8A至图8E：脂质小分子与3C-样蛋白酶结合的IC 50。
具体实施方式
下面详细描述本申请的实施例，仅用于解释本申请，而不能理解为对本申请的限制。除非另外说明，本申请所使用的科技术语具有与本申请所属领域技术人员的通常理解相同的含义。尽管本申请的技术方案是在特定病毒株上实施的，技术人员理解其他包含3C-样蛋白酶的病毒也对本申请的化合物产生响应。
实施例1.中药汤汁脂质库建立
1.取中药100g，加500mL水，冷水浸泡30min，加热沸腾后改小火30min后改大火10min，开盖冷却至室温，得到中药汤汁。
2.向4mL所得中药汤汁中加入二氯甲烷-甲醇混合液(二氯甲烷:甲醇＝1:2，v/v)15mL，使得二氯甲烷:甲醇:水＝1:2:0.8，涡旋混匀10-15min。
3.向EP管中加入5mL二氯甲烷，涡旋混匀10min。
4.向EP管中加入5mL ddH2O，使得二氯甲烷:甲醇:水＝2:2:1.8，涡旋混匀10min。
5.除去上层液体和中间层的不溶性物质，取下层的二氯甲烷层，氮气吹干，得到脂质小分子。
6.样品分析采用ExionLC(SCIEX，USA)和TripleTOF 5600+(SCIEX，USA)仪器，在正负离子模式下检测。
7.得到的原始数据使用ABF CONVERTER转化为.abf格式，导入MS-DIAL 4.0.0进行数据分析，使用Lipidblast来鉴定组分，得到中药汤汁脂质小分子库。
实施例2.数据库的筛选
1.靶点：Mpro(PDB:6LU7)。
2.从RCSB PDB上下载Mpro蛋白与抑制剂共晶体的三维结构(PDB:6LU7)。
3.将实施例1建立的中药汤汁脂质数据库中的分子通过Build 3D数据库功能模块添加进Discovery studio 4.0，构成可用于后续筛选的小分子化合物库。
4.采用Prepare Protein模块对步骤1中下载的Mpro蛋白与抑制剂共晶的三维结构的Mpro进行蛋白文件处理，以去除蛋白多构象，补充非完整的氨基酸残基，为蛋白质加氢等，处理后以该蛋白配体晶体结构中配体的位置定义为活性口袋。
5.运用Discovery Studio的快速分子对接工具LibDock/CDOCKER进行虚拟筛选，将得分高的化合物分子构象保存下来，共5个脂质分子，结构式如下：
PC(9:0/9:0)CAS号：27869-45-0：
Figure PCTCN2021094517-appb-000023
PC(16:0e/18:1)CAS号：26853-31-6：
Figure PCTCN2021094517-appb-000024
DG(18:0/16:0)CAS号：17708-08-06：
Figure PCTCN2021094517-appb-000025
Figure PCTCN2021094517-appb-000026
LPC(14:0/0:0)CAS号：20559-16-4：
Figure PCTCN2021094517-appb-000027
LPC(16:0)CAS号：17364-16-8：
Figure PCTCN2021094517-appb-000028
6.购买化合物分子进行MTT和CPE实验验证，以及表面等离子共振试验(SPR)和酶半数抑制率(IC 50)试验验证。
实施例3.MTT实验
1.实验步骤
96孔板铺板，每孔5000个Vero E6细胞。12h后，设立8组：
未处理组、病毒组、空白对照、PC(9:0/9:0)组、PC(16:0e/18:1)组、DG(18:0/16:0)组、LPC(14:0/0:0)组、LPC(16:0)组。每组共设立6个复孔，药物处理浓度为3μM。
加药后12h，除未处理组进行攻毒(SARS-COV-2，MOI：0.1)，同时保证各组药物浓度不变。48h后进行观察拍照，后各个孔加入10μl的MTT染料。4h后选择490nm波长处，测定各孔吸光度，记录结果(图1、图2A至图2H、图3)。
2.结果
实施例2所得到的5个化合物证实对SARS-COV-2病毒感染在细胞水平上具有抑制作用。根据图1实验，5个化合物在Vero E6细胞被感染后，改善细胞的增殖。根据CPE实验可知，相比模型组，5个化合物改善了受感染Vero E6细胞的活力。
实施例4.在THP-1细胞系上对革兰氏阴性菌脂多糖(LPS)诱导的炎症模型的缓解作用
1.细胞培养
实验所用的THP-1细胞购自北京协和医学院细胞培养中心。α-MEM培养基购自HyClone公司。细胞置于37℃、5％CO2培养箱中培养。THP-1细胞的培养以1640培养基为基础培养基，其中添加有10％v/v胎牛血清和抗生素(青霉素100U/mL和链霉素100mg/mL)。细胞培养至对数生长期时，分至12孔板(1mL培养基/孔)，37℃孵育过夜，待细胞生长至80％，进行后续实验。
2.细胞的实验分组及预防性给药
待12孔板细胞生长至80％，提前12h进行脂质小分子预防性给药，每孔的量为0.03mg，然后给予LPS刺激，每孔终浓度为1μg/mL，并于12h后收集细胞上清和细胞。
LPS购自Sigma-Aldrich，储液浓度为1mg/mL，使用时取50μL LPS储液于450μL opti-MEM中，每孔加入10μL。
空白组：是指未经处理的细胞，该组作为空白对照组。
模型组：加入LPS刺激。
脂质小分子组：进行脂质小分子预防性给药，并给予LPS刺激。
3.收集细胞上清，用于ELISA试剂盒检测上清中IL-1β、IL-6、TNF-α的含量。
4.收集细胞用RNA快速试剂盒提取RNA，采用qPCR方法检测IL-1β、IL-6、TNF-αmRNA表达情况(图4A至图4F)。
实施例5.在A549细胞系上对聚肌苷酸胞苷酸(Poly I:C)诱导的炎症模型的缓解作用
1.细胞培养
实验所用的A549细胞购自北京协和医学院细胞培养中心。F-12培养基购自HyClone公司。细胞置于37℃、5％CO2培养箱中培养。A459细胞的培养以F-12培养基为基础培养基，其中添加有10v/v％胎牛血清和抗生素(青霉素100U/mL和链霉素100mg/mL)。细胞培养至对数生长期时，分至12孔板(1mL培养基/孔)，37℃孵育过夜， 待细胞贴壁后进行后续实验。
2.细胞的实验分组及预防性给药
待12孔板细胞生长至80％，提前12h进行脂质小分子预防性给药，每孔的量为0.03mg，然后给予Poly I:C刺激，每孔终浓度为1μg/mL，并于12h后收集细胞上清和细胞。
PolyI:C购自Sigma-Aldrich，储存浓度为10mg/mL，12孔板转染体系配置：100μL opti-MEM+2μL lipo2000；100μL opti-MEM+0.1μL PolyI:C，静置15min，每孔200μL。
空白组：是指未经处理的细胞，该组作为空白对照组。
模型组：加入PolyI:C刺激。
脂质小分子组：提前进行脂质小分子预防性给药，并给予PolyI:C刺激。
3.收集细胞上清，用于ELISA试剂盒检测上清中IL-1β、IL-6、TNF-α的含量。
4.收集细胞用RNA快速试剂盒提取RNA，采用qPCR方法检测IL-1β、IL-6、TNF-αmRNA表达情况(图5A至图5F)。
实施例6.本申请的脂质小分子在U937细胞系上对革兰氏阳性菌脂磷壁酸(LTA)诱导的炎症模型的缓解作用
1.细胞培养
实验所用的U937细胞购自北京协和医学院细胞培养中心。1640培养基购自HyClone公司。细胞置于37℃、5％CO2培养箱中培养。U937细胞的培养以1640培养基为基础培养基，其中添加有10v/v％胎牛血清和抗生素(青霉素100U/mL和链霉素100mg/mL)。细胞培养至对数生长期时，分至12孔板(1mL培养基/孔)，37℃孵育过夜，待细胞生长至80％，进行后续实验。
2.细胞的实验分组及预防性给药
待12孔板细胞生长至80％，提前12h进行脂质小分子预防性给药，每孔的量为0.03mg，然后给予LTA刺激，每孔终浓度为1μg/mL，并于12h后收集细胞上清和细胞。
LTA购自Sigma-Aldrich，储存浓度为1mg/mL，使用时取50μL  LTA储液于450μL opti-MEM中，每孔加入10μL。
空白组：是指未经处理的细胞，该组作为空白对照组。
模型组：加入LTA刺激。
脂质小分子组：提前进行脂质小分子预防性给药，并给予LTA刺激。
3.收集细胞上清，用于ELISA试剂盒检测上清中IL-1β，IL-6，TNF-α的含量。
4.收集细胞用RNA快速试剂盒提取RNA，采用qPCR方法检测IL-1β，IL-6，TNF-αmRNA表达情况(图6A至图6E)。
实施例7.表面等离子共振试验(SPR)验证脂质小分子与3C-样蛋白酶的结合
采用胺偶联化学方法将3C-样蛋白固定在羧甲基-5'-葡聚糖(CM5)传感器芯片上。将3C-样蛋白固定在四通道流细胞中，以三通道流细胞作为参比细胞进行激活和封闭。3C-样蛋白(20μg·mL-1，10mm乙酸钠溶液，pH值4.5)经420s的注射固定于表面。在pH值为8.5的条件下，通过420s注射1μM乙醇胺阻断表面上剩余的活化基团。在上述步骤中，流速保持在30μL·min-1，固定期间使用1倍磷酸盐缓冲盐水(PBS)运行缓冲液。大约13000个响应单位(RU)的蛋白质可以在四通道流动细胞的CM5芯片上被常规捕获。
SPR试验证明PC(9:0/9:0)、LPC(14:0)、LPC(16:0)与3C-样蛋白能够结合(图7A至图7C)。
实施例8.脂质小分子与3C-样蛋白酶结合半数抑制率(IC 50)检测
1.将化合物溶于DMSO溶液中，配制高浓度母液备用(10至100mM)；
2.将SARS-CoV-2主蛋白酶溶于孵育溶液(50mM Tris-HCl+1mM EDTA,pH7.3)，至终浓度为30nM；
3.将96孔荧光检测板中加入主蛋白酶溶液80μL，然后加入待测药物母液，至终浓度为0.01至100μM，共计10个浓度梯度；
4.酶与药物混合体系在30℃条件下孵育10min后加入底物，反应体系避光孵育；
5.加入40μL荧光底物至终浓度为20μM；
6.设置阴性对照为加入酶、底物和等药物体积DMSO溶液，3复孔；
7.荧光检测(320nm激发，405nm检测)，每30s测定一次，共计测定20次；
8.结果统计及IC 50计算(图8A至图8E)。

Claims (10)

  1. 3C-样蛋白酶靶向剂在制备抗病毒或抗炎药物中的用途，所述3C-样蛋白酶靶向剂是甘油二酯或磷脂酰胆碱，其中：
    所述甘油二酯选自以下任一项的化合物：
    Figure PCTCN2021094517-appb-100001
    所述磷脂酰胆碱选自以下任一项的化合物：
    Figure PCTCN2021094517-appb-100002
    或其可药用盐。
  2. 3C-样蛋白酶靶向剂在制备病毒抑制剂中的用途，所述3C-样蛋白酶靶向剂是甘油二酯或磷脂酰胆碱，其中：
    所述甘油二酯选自以下任一项的化合物：
    Figure PCTCN2021094517-appb-100003
    所述磷脂酰胆碱选自以下任一项的化合物：
    Figure PCTCN2021094517-appb-100004
    或其可药用盐。
  3. 3C-样蛋白酶靶向剂在制备消毒组合物中的用途，所述3C-样蛋白酶靶向剂是甘油二酯或磷脂酰胆碱，其中：
    所述甘油二酯选自以下任一项的化合物：
    Figure PCTCN2021094517-appb-100005
    所述磷脂酰胆碱选自以下任一项的化合物：
    Figure PCTCN2021094517-appb-100006
    或其可药用盐。
  4. 根据权利要求1至3中任一项所述的用途，所述化合物是式II、 式III或式IV所示的化合物或其可药用盐；优选式III所示的化合物或其可药用盐。
  5. 根据权利要求1至3中任一项所述的用途，所述病毒是包含3C-样蛋白酶的病毒；
    优选地，所述病毒选自以下的任一项：鼻病毒、冠状病毒、腺病毒、流感病毒、副流感病毒、呼吸道合胞病毒、埃可病毒、柯萨奇病毒、猪流行性腹泻病毒、口蹄疫病毒、脑心肌炎病毒；
    优选地，所述病毒是冠状病毒，所述冠状病毒选自以下的任一项：SARS-CoV、SARS-CoV-2、MERS-CoV、或其变体。
  6. 根据权利要求1至3中任一项所述的用途，所述可药用盐选自：钠盐、钾盐、钙盐、铝盐、硫酸盐、硝酸盐、磷酸盐、盐酸盐、氢溴酸盐、氨基磺酸盐、醋酸盐、三氟醋酸盐、三氯醋酸盐、肉桂酸盐、柠檬酸盐、马来酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、乙醇酸盐、苹果酸、乳酸盐、丙二酸盐、草酸盐、烟酸盐、丁二酸盐、水杨酸盐、硬脂酸盐、酒石酸盐、对氨基苯磺酸盐、三甲基苯磺酸盐、对甲基苯磺酸盐、扁桃酸盐、果胶酯酸盐、苦味酸盐、丙酸盐。
  7. 一种体外抑制病毒增殖或生长的方法，其包括使病毒接触有效量的3C-样蛋白酶靶向剂，所述3C-样蛋白酶靶向剂是甘油二酯或磷脂酰胆碱，其中：
    所述甘油二酯选自以下任一项的化合物：
    Figure PCTCN2021094517-appb-100007
    所述磷脂酰胆碱选自以下任一项的化合物：
    Figure PCTCN2021094517-appb-100008
    或其可药用盐。
  8. 根据权利要求7所述的方法，所述病毒是包含3C-样蛋白酶的病毒；
    优选地，所述病毒选自以下的任一项：鼻病毒、冠状病毒、腺病毒、流感病毒、副流感病毒、呼吸道合胞病毒、埃可病毒、柯萨奇病毒、猪流行性腹泻病毒、口蹄疫病毒、脑心肌炎病毒；
    优选地，所述病毒是冠状病毒，所述冠状病毒选自以下的任一项：SARS-CoV、SARS-CoV-2、MERS-CoV、或其变体。
  9. 根据权利要求7所述的方法，所述可药用盐选自：钠盐、钾盐、钙盐、铝盐、硫酸盐、硝酸盐、磷酸盐、盐酸盐、氢溴酸盐、氨基磺 酸盐、醋酸盐、三氟醋酸盐、三氯醋酸盐、肉桂酸盐、柠檬酸盐、马来酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、乙醇酸盐、苹果酸、乳酸盐、丙二酸盐、草酸盐、烟酸盐、丁二酸盐、水杨酸盐、硬脂酸盐、酒石酸盐、对氨基苯磺酸盐、三甲基苯磺酸盐、对甲基苯磺酸盐、扁桃酸盐、果胶酯酸盐、苦味酸盐、丙酸盐。
  10. 一种药物组合物或消毒组合物，其包含3C-样蛋白酶靶向剂，所述3C-样蛋白酶靶向剂是甘油二酯或磷脂酰胆碱，其中：
    所述甘油二酯选自以下任一项的化合物：
    Figure PCTCN2021094517-appb-100009
    所述磷脂酰胆碱选自以下任一项的化合物：
    Figure PCTCN2021094517-appb-100010
    Figure PCTCN2021094517-appb-100011
    或其可药用盐。
PCT/CN2021/094517 2021-05-19 2021-05-19 脂质小分子作为3c-样蛋白酶靶向剂在抗病毒方面的用途以及广谱抗炎作用 WO2022241666A1 (zh)

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