WO2024040593A1 - Anti-pneumonia drug, preparation method therefor, and use thereof - Google Patents
Anti-pneumonia drug, preparation method therefor, and use thereof Download PDFInfo
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- WO2024040593A1 WO2024040593A1 PCT/CN2022/115234 CN2022115234W WO2024040593A1 WO 2024040593 A1 WO2024040593 A1 WO 2024040593A1 CN 2022115234 W CN2022115234 W CN 2022115234W WO 2024040593 A1 WO2024040593 A1 WO 2024040593A1
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- 239000003814 drug Substances 0.000 title claims abstract description 32
- 229940079593 drug Drugs 0.000 title claims abstract description 31
- 206010035664 Pneumonia Diseases 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 239000003112 inhibitor Substances 0.000 claims abstract description 28
- 108010072220 Cyclophilin A Proteins 0.000 claims abstract description 20
- 101710141454 Nucleoprotein Proteins 0.000 claims abstract description 20
- 102100034539 Peptidyl-prolyl cis-trans isomerase A Human genes 0.000 claims abstract description 20
- 239000003580 lung surfactant Substances 0.000 claims abstract description 17
- 239000002245 particle Substances 0.000 claims abstract description 16
- 230000000903 blocking effect Effects 0.000 claims abstract description 8
- 239000011664 nicotinic acid Substances 0.000 claims abstract description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 36
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 28
- 235000012000 cholesterol Nutrition 0.000 claims description 18
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 claims description 16
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 108010036949 Cyclosporine Proteins 0.000 claims description 6
- 150000003904 phospholipids Chemical class 0.000 claims description 6
- 238000001125 extrusion Methods 0.000 claims description 5
- 239000002502 liposome Substances 0.000 claims description 5
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 4
- 229960001231 choline Drugs 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- 210000000941 bile Anatomy 0.000 claims description 3
- 239000006185 dispersion Substances 0.000 claims description 3
- -1 palmitoyl phospholipid Chemical class 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- AQHMBDAHQGYLIU-XNFHFXFQSA-N (3s,6s,9s,12r,15s,18s,21s,24s,27r,30s,33s)-27-[2-(dimethylamino)ethylsulfanyl]-30-ethyl-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-24-(2-hydroxy-2-methylpropyl)-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18-tris(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10, Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)(C)O)N(C)C(=O)[C@@H](SCCN(C)C)N(C)C1=O AQHMBDAHQGYLIU-XNFHFXFQSA-N 0.000 claims description 2
- 108010030583 (melle-4)cyclosporin Proteins 0.000 claims description 2
- OLROWHGDTNFZBH-XEMWPYQTSA-N Alisporivir Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(CC)C(=O)[C@@H](C)N(C)C1=O OLROWHGDTNFZBH-XEMWPYQTSA-N 0.000 claims description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 2
- 229930105110 Cyclosporin A Natural products 0.000 claims description 2
- KBARHGHBFILILC-NGIJKBHDSA-N N-[(7R,8R)-8-[(2S,5S,8R,11S,14S,17S,20S,23R,26S,29S,32S)-5-ethyl-1,7,8,10,16,20,23,25,28,31-decamethyl-11,17,26,29-tetrakis(2-methylpropyl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-14,32-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacont-2-yl]-8-hydroxy-7-methyloctyl]acetamide Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)CCCCCCNC(C)=O)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)N(C)C1=O)C(C)C KBARHGHBFILILC-NGIJKBHDSA-N 0.000 claims description 2
- 108010090287 SCY-635 Proteins 0.000 claims description 2
- 108010088573 STG-175 Proteins 0.000 claims description 2
- 108010058359 alisporivir Proteins 0.000 claims description 2
- 229960001265 ciclosporin Drugs 0.000 claims description 2
- RPJPZDVUUKWPGT-FOIHOXPVSA-N nim811 Chemical compound CC[C@H](C)[C@@H]1N(C)C(=O)CN(C)C(=O)[C@H](CC)NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC1=O RPJPZDVUUKWPGT-FOIHOXPVSA-N 0.000 claims description 2
- 230000003592 biomimetic effect Effects 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 229940066294 lung surfactant Drugs 0.000 claims 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 241000711573 Coronaviridae Species 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 210000004072 lung Anatomy 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 4
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- 238000003125 immunofluorescent labeling Methods 0.000 description 3
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- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- 101001067833 Homo sapiens Peptidyl-prolyl cis-trans isomerase A Proteins 0.000 description 1
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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Abstract
The present invention provides an anti-pneumonia drug, a preparation method therefor, and use thereof. The anti-pneumonia drug of the present invention comprises a carrier loaded with an inhibitor. The inhibitor is an inhibitor capable of blocking the binding of N protein and cyclophilin A; the carrier is a bionic particle of a pulmonary surfactant, and can block the binding of the N protein and the cyclophilin A to treat pneumonia diseases caused by coronaviruses.
Description
本发明涉及医药领域，尤其涉及抗肺炎药物及其制备方法和应用。The present invention relates to the field of medicine, and in particular to anti-pneumonia drugs and their preparation methods and applications.
有研究发现，冠状病毒SARS-CoV的核衣壳蛋白与人体中的人亲环素A有相互作用，对病毒的成熟、病毒的复制和新病毒颗粒的形成起重要作用。Studies have found that the nucleocapsid protein of the coronavirus SARS-CoV interacts with human cyclophilin A in the human body and plays an important role in virus maturation, virus replication and the formation of new virus particles.
因此，有必要开发新型的抗肺炎药物来治疗CoV感染。Therefore, it is necessary to develop novel anti-pneumonia drugs to treat CoV infection.
发明概要Summary of the invention
本发明提供了一种抗肺炎药物及其制备方法和应用，以利于治疗冠状病毒引起的肺炎疾病。The invention provides an anti-pneumonia drug and its preparation method and application to facilitate the treatment of pneumonia diseases caused by coronavirus.
为实现上述目的，本发明的所述抗肺炎药物包括负载有抑制剂的载体；其中，所述抑制剂为能够阻断N蛋白和亲环素A结合的抑制剂；所述载体为肺表面活性物质的仿生颗粒，能够通过阻断N蛋白和亲环素A的结合治疗冠状病毒引起的肺炎疾病。In order to achieve the above object, the anti-pneumonia drug of the present invention includes a carrier loaded with an inhibitor; wherein the inhibitor is an inhibitor capable of blocking the binding of N protein and cyclophilin A; the carrier is pulmonary surfactant The bionic particles can treat pneumonia caused by coronavirus by blocking the combination of N protein and cyclophilin A.
优选的，所述载体的质量为所述抑制剂质量的10-20倍。Preferably, the mass of the carrier is 10-20 times the mass of the inhibitor.
优选的，所述肺表面活性物质的仿生颗粒包括肺表面活性物质的磷脂成分、肺表面活性物质中所含蛋白质的模拟成分和胆固醇成分。Preferably, the bionic particles of pulmonary surfactant include phospholipid components of pulmonary surfactant, simulated components of proteins contained in pulmonary surfactant, and cholesterol components.
优选的，所述肺表面活性物质的磷脂成分的质量为所述胆固醇成分质量的10-20倍。Preferably, the mass of the phospholipid component of the pulmonary surfactant is 10-20 times the mass of the cholesterol component.
优选的，所述肺表面活性物质中所含蛋白质的模拟成分与所述胆固醇成分具有相同的含量。Preferably, the protein-mimicking component contained in the pulmonary surfactant has the same content as the cholesterol component.
优选的，所述肺表面活性物质的磷脂成分为棕榈胆磷和二棕榈酰磷脂酰甘油的至少一种。Preferably, the phospholipid component of the pulmonary surfactant is at least one of palmitchophospholipid and dipalmitoylphosphatidylglycerol.
优选的，所述肺表面活性物质中所含蛋白质的模拟成分为二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000。Preferably, the simulated component of the protein contained in the pulmonary surfactant is dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000.
优选的，所述抑制剂为Debio-025、环孢多肽A、NIM811、SCY-635、STG-175、MM284和CPI-431-32中的至少一种。Preferably, the inhibitor is at least one of Debio-025, Cyclosporin A, NIM811, SCY-635, STG-175, MM284 and CPI-431-32.
优选的，所述载体的平均粒径为130-140纳米，分散性指数小于0.2。Preferably, the average particle size of the carrier is 130-140 nanometers, and the dispersion index is less than 0.2.
本发明所述抗肺炎药物的制备方法包括：The preparation method of the anti-pneumonia drug of the present invention includes:
S0：提供能够阻断N蛋白和亲环素A结合的抑制剂、棕榈胆磷、二棕榈酰磷脂酰甘油、二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和胆固醇；S0: Provides inhibitors that can block the binding of N protein and cyclophilin A, palmitoyl phospholipid, dipalmitoylphosphatidylglycerol, dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and cholesterol;
S1：将所述棕榈胆磷、所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇分散在有机溶剂中，再加入所述能够阻断N蛋白和亲环素A结合的抑制剂，得到包含载药颗粒的悬浮液，所述有机溶剂为所述能够阻断N蛋白和亲环素A结合的抑制剂的良溶剂；S1: Disperse the palm choline, the dipalmitoylphosphatidylglycerol, the dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and the cholesterol in an organic solvent, and then add the An inhibitor that blocks the binding of N protein and cyclophilin A is obtained to obtain a suspension containing drug-loaded particles, and the organic solvent is a good solvent for the inhibitor that can block the binding of N protein and cyclophilin A;
S2：对所述包含载药颗粒的悬浮液在40-60摄氏度下进行脂质体挤出工艺，得到负载有所述能够阻断N蛋白和亲环素A结合的抑制剂的载体。S2: Perform a liposome extrusion process on the suspension containing drug-loaded particles at 40-60 degrees Celsius to obtain a carrier loaded with the inhibitor capable of blocking the binding of N protein and cyclophilin A.
优选的，所述步骤S1中，将所述棕榈胆磷、所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇分散在有机溶剂中的步骤包括：Preferably, in the step S1, the palm choline, the dipalmitoylphosphatidylglycerol, the dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and the cholesterol are dispersed in an organic solvent. The steps include:
控制所述棕榈胆磷的质量为所述二棕榈酰磷脂酰甘油质量的10-20倍；Control the quality of the palm bile phosphorus to be 10-20 times the quality of the dipalmitoylphosphatidylglycerol;
控制所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇具有相同的质量。It is controlled that the dipalmitoylphosphatidylglycerol, the dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and the cholesterol have the same quality.
本发明的所述抗肺炎药物应用于抗SARS-CoV-2的治疗。The anti-pneumonia drug of the present invention is used in the treatment of anti-SARS-CoV-2.
本发明所述抗肺炎药物经鼻腔给药、口服给药或注射给药。The anti-pneumonia drug of the present invention is administered through the nasal cavity, oral administration or injection.
图1为本发明实施例的小鼠活体和离体肺部器官的成像照片；Figure 1 is an imaging photograph of the lung organs of mice in vivo and in vitro according to an embodiment of the present invention;
图2为本发明实施例的小鼠肺部组织免疫荧光染色照片。Figure 2 is a photo of immunofluorescence staining of mouse lung tissue according to an embodiment of the present invention.
发明内容Contents of the invention
本发明实施例提供了一种抗肺炎药物及其制备方法和应用，以利于治疗冠状病毒引起的肺炎疾病。The embodiments of the present invention provide an anti-pneumonia drug and its preparation method and application to facilitate the treatment of pneumonia caused by coronavirus.
实施例1Example 1
实施例1提供了一种抗肺炎药物的制备方法，包括：Embodiment 1 provides a method for preparing an anti-pneumonia drug, including:
S0：提供能够阻断N蛋白和亲环素A结合的抑制剂、棕榈胆磷、二棕榈酰磷脂酰甘油、二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和胆固醇；S0: Provides inhibitors that can block the binding of N protein and cyclophilin A, palmitoyl phospholipid, dipalmitoylphosphatidylglycerol, dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and cholesterol;
S1：将所述棕榈胆磷、所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇分散在有机溶剂中，再加入所述能够阻断N蛋白和亲环素A结合的抑制剂，得到包含载药颗粒的悬浮液，所述有机溶剂为所述能够阻断N蛋白和亲环素A结合的抑制剂的良溶剂；S1: Disperse the palm choline, the dipalmitoylphosphatidylglycerol, the dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and the cholesterol in an organic solvent, and then add the An inhibitor that blocks the binding of N protein and cyclophilin A is obtained to obtain a suspension containing drug-loaded particles, and the organic solvent is a good solvent for the inhibitor that can block the binding of N protein and cyclophilin A;
S2：对所述包含载药颗粒的悬浮液在40-60摄氏度下进行脂质体挤出工艺，得到负载有所述能够阻断N蛋白和亲环素A结合的抑制剂的载体。S2: Perform a liposome extrusion process on the suspension containing drug-loaded particles at 40-60 degrees Celsius to obtain a carrier loaded with the inhibitor capable of blocking the binding of N protein and cyclophilin A.
本实施例的所述步骤S0中，能够阻断N蛋白和亲环素A结合的抑制剂为环孢多肽A。In step S0 of this embodiment, the inhibitor that can block the binding between N protein and cyclophilin A is cyclosporine polypeptide A.
本实施例的所述步骤S1具体为：The step S1 of this embodiment is specifically:
控制棕榈胆磷、二棕榈酰磷脂酰甘油、二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和胆固醇的质量比为10：1：1：1，将棕榈胆磷、二棕榈酰磷脂酰甘油、二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和胆固醇分散在氯仿中，再加入环孢多肽A直至溶解，得到载药悬液。其中，控制加入的环孢多肽A的质量与加入的二棕榈酰磷脂酰甘油的质量相当。Control the mass ratio of palm bile phosphorus, dipalmitoyl phosphatidylglycerol, dipalmitoyl phosphatidylethanolamine-methoxypolyethylene glycol 2000 and cholesterol to 10:1:1:1. Acylglycerol, dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and cholesterol were dispersed in chloroform, and then cyclosporine polypeptide A was added until dissolved to obtain a drug-loaded suspension. Among them, the mass of the added cyclosporine polypeptide A is controlled to be equivalent to the mass of the added dipalmitoylphosphatidylglycerol.
将载药悬液温度控制为50摄氏度，使载药悬液顺次通过400纳米聚碳酸酯滤膜和200纳米聚碳酸酯滤膜以进行脂质体挤出工艺，得到负载环孢多肽A的纳米颗粒(简记为P-CsA)。所述脂质体挤出工艺的具体操作步骤为本领域技术人员的常规技术手段。The temperature of the drug-loaded suspension is controlled to 50 degrees Celsius, and the drug-loaded suspension is sequentially passed through a 400 nanometer polycarbonate filter membrane and a 200 nanometer polycarbonate filter membrane to perform a liposome extrusion process to obtain cyclosporine polypeptide A-loaded Nanoparticles (abbreviated as P-CsA). The specific operating steps of the liposome extrusion process are routine technical means for those skilled in the art.
本实施例通过Zetasizer测量得到的三组P-CsA的粒径和ζ电势，得到平均 粒径为135.6±3.8纳米，分散性指数为0.148±0.056,ζ电势为0.258±0.736mV.In this example, the particle size and zeta potential of three groups of P-CsA were measured by Zetasizer, and the average particle size was 135.6±3.8 nanometers, the dispersion index was 0.148±0.056, and the zeta potential was 0.258±0.736mV.
实施例2Example 2
实施例2提供了实施例1的P-CsA在抗SARS-CoV-2治疗方面的应用，具体为：Example 2 provides the application of P-CsA of Example 1 in anti-SARS-CoV-2 treatment, specifically:
采用近红外II区荧光探针BPBBT(Ex/Em＝808nm/1050nm)和红光荧光探针DiD(Ex/Em＝644nm/665nm)标记P-CsA得到共同标记P-CsA，将共同标记P-CsA经小鼠鼻腔内滴入给药，24小时后使用近红外二区分别对小鼠活体和离体肺部器官进行成像，此外对小鼠肺部组织进行免疫荧光染色分析，得到图1所示的小鼠活体和离体肺部器官的成像照片，以及图2所示的小鼠肺部组织免疫荧光染色照片。从图1和图2可以看到，P-CsA能够迅速高效地到达肺部。The near-infrared II region fluorescent probe BPBBT (Ex/Em=808nm/1050nm) and the red light fluorescent probe DiD (Ex/Em=644nm/665nm) are used to label P-CsA to obtain co-labeled P-CsA, which will co-label P-CsA. CsA was administered intranasally to mice. After 24 hours, the near-infrared zone was used to image the living and isolated lung organs of the mice respectively. In addition, immunofluorescence staining analysis was performed on the lung tissues of the mice, and the results shown in Figure 1 were obtained. The imaging photos of mouse lung organs in vivo and in vitro are shown, as well as the immunofluorescence staining photos of mouse lung tissue shown in Figure 2. As can be seen from Figures 1 and 2, P-CsA can reach the lungs quickly and efficiently.
Claims (10)
- 一种抗肺炎药物，其特征在于，包括负载有抑制剂的载体；An anti-pneumonia drug, characterized by comprising a carrier loaded with an inhibitor;所述抑制剂为能够阻断N蛋白和亲环素A结合的抑制剂；The inhibitor is an inhibitor that can block the binding of N protein and cyclophilin A;所述载体为肺表面活性物质的仿生颗粒。The carrier is biomimetic particles of lung surfactant.
- 根据权利要求1所述的抗肺炎药物，其特征在于，所述载体的质量为所述抑制剂质量的10-20倍。The anti-pneumonia drug according to claim 1, characterized in that the mass of the carrier is 10-20 times the mass of the inhibitor.
- 根据权利要求1所述的抗肺炎药物，其特征在于，所述肺表面活性物质的仿生颗粒包括肺表面活性物质的磷脂成分、肺表面活性物质中所含蛋白质的模拟成分和胆固醇成分；The anti-pneumonia drug according to claim 1, wherein the bionic particles of pulmonary surfactant include phospholipid components of pulmonary surfactant, simulated components of proteins contained in pulmonary surfactant, and cholesterol components;所述肺表面活性物质的磷脂成分的质量为所述胆固醇成分质量的10-20倍；The mass of the phospholipid component of the pulmonary surfactant is 10-20 times the mass of the cholesterol component;所述肺表面活性物质中所含蛋白质的模拟成分与所述胆固醇成分具有相同的含量。The protein-mimicking component contained in the pulmonary surfactant has the same content as the cholesterol component.
- 根据权利要求3所述的抗肺炎药物，其特征在于，所述肺表面活性物质的磷脂成分为棕榈胆磷和二棕榈酰磷脂酰甘油的至少一种，所述肺表面活性物质中所含蛋白质的模拟成分为二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000。The anti-pneumonia drug according to claim 3, wherein the phospholipid component of the pulmonary surfactant is at least one of palmitole and dipalmitoylphosphatidylglycerol, and the protein contained in the pulmonary surfactant is The simulated ingredient is dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000.
- 根据权利要求1所述的抗肺炎药物，其特征在于，所述抑制剂为Debio-025、环孢多肽A、NIM811、SCY-635、STG-175、MM284和CPI-431-32中的至少一种。The anti-pneumonia drug according to claim 1, characterized in that the inhibitor is at least one of Debio-025, Cyclosporin A, NIM811, SCY-635, STG-175, MM284 and CPI-431-32. kind.
- 根据权利要求1所述的抗肺炎药物，其特征在于，所述载体的平均粒径为130-140纳米，分散性指数小于0.2。The anti-pneumonia drug according to claim 1, characterized in that the average particle size of the carrier is 130-140 nanometers, and the dispersion index is less than 0.2.
- 一种抗肺炎药物的制备方法，其特征在于，包括：A method for preparing anti-pneumonia drugs, which is characterized by including:S0：提供能够阻断N蛋白和亲环素A结合的抑制剂、棕榈胆磷、二棕榈酰磷脂酰甘油、二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和胆固 醇；S0: Provides inhibitors that can block the binding of N protein and cyclophilin A, palmitoyl phospholipid, dipalmitoylphosphatidylglycerol, dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and cholesterol;S1：将所述棕榈胆磷、所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇分散在有机溶剂中，再加入所述能够阻断N蛋白和亲环素A结合的抑制剂，得到包含载药颗粒的悬浮液，所述有机溶剂为所述能够阻断N蛋白和亲环素A结合的抑制剂的良溶剂；S1: Disperse the palm choline, the dipalmitoylphosphatidylglycerol, the dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and the cholesterol in an organic solvent, and then add the An inhibitor that blocks the binding of N protein and cyclophilin A is obtained to obtain a suspension containing drug-loaded particles, and the organic solvent is a good solvent for the inhibitor that can block the binding of N protein and cyclophilin A;S2：对所述包含载药颗粒的悬浮液在40-60摄氏度下进行脂质体挤出工艺，得到负载有所述能够阻断N蛋白和亲环素A结合的抑制剂的载体。S2: Perform a liposome extrusion process on the suspension containing drug-loaded particles at 40-60 degrees Celsius to obtain a carrier loaded with the inhibitor capable of blocking the binding of N protein and cyclophilin A.
- 根据权利要求7所述的抗肺炎药物的制备方法，其特征在于，所述步骤S1中，将所述棕榈胆磷、所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇分散在有机溶剂中的步骤包括：The preparation method of anti-pneumonia drugs according to claim 7, characterized in that, in the step S1, the palmitoyl phosphatidylphosphatidylglycerol, the dipalmitoylphosphatidylethanolamine-methyl The steps of dispersing oxypolyethylene glycol 2000 and the cholesterol in an organic solvent include:控制所述棕榈胆磷的质量为所述二棕榈酰磷脂酰甘油质量的10-20倍；Control the quality of the palm bile phosphorus to be 10-20 times the quality of the dipalmitoylphosphatidylglycerol;控制所述二棕榈酰磷脂酰甘油、所述二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇2000和所述胆固醇具有相同的质量。It is controlled that the dipalmitoylphosphatidylglycerol, the dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 and the cholesterol have the same quality.
- 根据权利要求8所述的抗肺炎药物的制备方法，其特征在于，所述步骤S1中，再加入所述能够阻断N蛋白和亲环素A结合的抑制剂的步骤包括：The method for preparing anti-pneumonia drugs according to claim 8, wherein in step S1, the step of adding the inhibitor capable of blocking the binding of N protein and cyclophilin A includes:控制所述能够阻断N蛋白和亲环素A结合的抑制剂的质量与所述二棕榈酰磷脂酰甘油的质量相当。The quality of the inhibitor capable of blocking the binding of N protein and cyclophilin A is controlled to be equivalent to the quality of dipalmitoylphosphatidylglycerol.
- 一种抗肺炎药物的应用，其特征在于，应用于抗SARS-CoV-2的治疗。The application of an anti-pneumonia drug is characterized in that it is used in the treatment of anti-SARS-CoV-2.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101053660A (en) * | 2006-04-13 | 2007-10-17 | 复旦大学 | Protein and peptide medicine carrier and its preparation method and application |
| US20160082074A1 (en) * | 2014-03-11 | 2016-03-24 | Ludwig-Maximilians-Universitaet Muenchen | Compositions and methods for treating coronavirus infection |
| CN111074572A (en) * | 2019-12-27 | 2020-04-28 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method of fiber for resisting respiratory system viral diseases |
| CN112472791A (en) * | 2020-11-16 | 2021-03-12 | 复旦大学 | Application of CsA liposome in preparation of anti-SARS-CoV-2 medicine |
| CN113663073A (en) * | 2021-08-19 | 2021-11-19 | 山东大学 | Application of targeted S protein palmitoylation polypeptide in preparation of broad-spectrum anti-coronavirus drugs |
-
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- 2022-08-26 WO PCT/CN2022/115234 patent/WO2024040593A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101053660A (en) * | 2006-04-13 | 2007-10-17 | 复旦大学 | Protein and peptide medicine carrier and its preparation method and application |
| US20160082074A1 (en) * | 2014-03-11 | 2016-03-24 | Ludwig-Maximilians-Universitaet Muenchen | Compositions and methods for treating coronavirus infection |
| CN111074572A (en) * | 2019-12-27 | 2020-04-28 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method of fiber for resisting respiratory system viral diseases |
| CN112472791A (en) * | 2020-11-16 | 2021-03-12 | 复旦大学 | Application of CsA liposome in preparation of anti-SARS-CoV-2 medicine |
| CN113663073A (en) * | 2021-08-19 | 2021-11-19 | 山东大学 | Application of targeted S protein palmitoylation polypeptide in preparation of broad-spectrum anti-coronavirus drugs |
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