WO2021203704A1 - 杆菌酞a在制备预防和治疗冠状病毒的药物中的应用 - Google Patents
杆菌酞a在制备预防和治疗冠状病毒的药物中的应用 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- the invention belongs to the field of antiviral drugs, and specifically relates to the application of Bacillus thallium A in the preparation of drugs for the prevention and treatment of anti-coronaviruses.
- New coronary pneumonia (COVID-19) is an infectious disease caused by a new type of coronavirus (SARS-Cov-2) infecting the human body. Its symptoms mainly include fever, fatigue, dry cough, dyspnea, and kidney failure. [The Lancet, 2020, 395(10223):507-513; The Lancet, 2020,395(10223):497-506]. New crown pneumonia began to report cases in December 2019, and then many countries around the world, including South Korea, Japan, Thailand, Iran, Singapore, Germany, France, and the United States, have also seen cases one after another. Coronaviruses belong to the genus Coronavirus in the family Coronaviridae (Coronaviridae).
- the virus of the genus Coronavirus is a positive-stranded single-stranded RNA virus with an envelope, with a diameter of about 80-120nm. Its genetic material is the largest among all RNA viruses, and generally only infects humans, mice, pigs, cats, and dogs. , Poultry vertebrates.
- the coronavirus was first isolated from chickens in 1937. Coronavirus particles are irregular in shape, about 60-220nm in diameter.
- the virus has an envelope structure with three proteins: Spike Protein (S, Spike Protein), Small Envelope Protein (E, Envelope Protein) and Membrane Protein (M, Membrane Protein), and a few types also have hemagglutination.
- Prime glycoprotein HE protein, Haemaglutinin-esterase
- SARS-Cov-2 virus particles The diameter of SARS-Cov-2 virus particles is between 60nm and 140nm, and there are 9-12nm spikes outside the envelope, resembling a corolla. Genome sequencing showed that SARS-Cov-2 is a single-stranded RNA coronavirus. By comparison with the gene sequences of other virus samples, it is found that SARS-Cov-2 is similar to SARS-CoV (79.5%) [Nature, 2020] and bat coronavirus (96%) [bioRxiv,2020,2020.01.22.914952], and speculates The virus may originate from bats [bioRxiv, 2020, 2020.01.24.915157; Nature, 2020].
- the SARS-Cov-2 virus belongs to ⁇ CoV, which is the seventh member of the HCoV family that is different from SARS-CoV and MERS-CoV [New England Journal of Medicine, 2020].
- the remaining 6 members include HCoV229E, NL63, OC43, HKU1, and HCoV. SARS-CoV and MERS-CoV.
- coronavirus pneumonia is caused by a new type of coronavirus. It is the same type of coronavirus as SARS-CoV, which is known to cause atypical pneumonia, but of different types. Although its fatality rate is lower than SARS-CoV, it is far more infectious. In SARS-CoV. The global spread shows that the new coronavirus pneumonia epidemic still has the possibility of spreading.
- SARS-CoV The global spread shows that the new coronavirus pneumonia epidemic still has the possibility of spreading.
- the development of effective antiviral drugs and vaccines has become the most urgent task at the moment. At present, the treatment of COVID-19 mainly relies on symptomatic adjuvant treatment, and there is still a lack of effective specific drugs and vaccines. However, the development of new drugs and the preparation of vaccines is a time-consuming process.
- the anti-SARS-Cov-2 virus drugs currently under study mainly include RNA polymerase inhibitors, beta interferon, monoclonal antibodies, and vaccines. However, so far, there are no definite and effective antiviral drugs and vaccines. From the analysis of the in vitro antiviral activity data of these drugs, the antiviral IC50 of most drugs is between low micromolar to medium micromolar, and the in vivo efficacy is still under observation.
- Bacillus phthalein A is a cyclic polypeptide produced by the organism Bacillus subtilis var. It inhibits the proliferation of Gram-positive bacteria by interfering with the synthesis of cell wall peptidoglycan.
- Bacillus phthalate A affects the biochemical process of bacteria, including the migration of metal ions, the synthesis of peptidoglycan, the permeability of cell membranes and the synthesis of induced enzymes. In addition to its antibacterial activity, Bacillus phthalate A has been shown to be a tool for studying lipid-protein interactions at the molecular level.
- the purpose of the present invention is to provide the application of Bacitalin A in the preparation of drugs for preventing or treating diseases caused by coronavirus.
- the present invention provides Bacillus phthalate A or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs in the preparation of prevention and/or treatment of coronavirus The application of drugs to the diseases caused by.
- the coronaviruses are the new coronaviruses SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 and MERS-CoV.
- the disease caused by the coronavirus is an infectious disease or its complications caused by any virus of SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 or MERS-CoV; preferably It is a respiratory infection disease, for example, severe acute respiratory syndrome, severe acute respiratory syndrome coronavirus type 2, and Middle East respiratory syndrome.
- Bacillus phthalate A is as shown in structural formula (1)
- Bacillus phthalein A or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs are used as the sole active ingredient in Application in preparing medicines for preventing and/or treating diseases caused by coronavirus.
- Bacillus phthalate A or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs, and other antiviral The application of the composition prepared by the medicine as an active ingredient in the preparation of a medicine for preventing and/or treating diseases caused by coronavirus.
- antiviral drugs are selected from the group consisting of ganciclovir, acyclovir, amantadine, rimantadine, oseltamivir, abacavir, acemontan, and acyclovir Sodium, adefovir, alovudine, avirsuto, tricyclodecylamine hydrochloride, alanordine, aridone, ateviridine mesylate, afridine, cidofovir, western Panphylline, Emtricitabine, Cytarabine Hydrochloride, Delavirdine Mesylate, Deciclovir, Didanosine, Dioxali, Edouridine, Emivirin, Etrados Citapine, Enviraden, Enviroxime, Hepatin, Famciclovir, Chlorophenhydroisoquine Hydrochloride, Fecitabine, Feauridine, Phosphatide,
- Another aspect of the present invention provides a pharmaceutical composition for the treatment or prevention of diseases caused by coronaviruses of the coronavirus family. Mixtures of isomers, tautomers, esters, amides or prodrugs.
- the pharmaceutical composition also includes pharmaceutically acceptable excipients.
- the dosage form of the pharmaceutical composition is oral preparation, pulmonary inhalation preparation, mucosal administration preparation, ophthalmic preparation or injection.
- the oral preparation is selected from granules, powders, pills, tablets, capsules or oral liquids.
- Another aspect of the present invention provides the use of Bacitalin A as a disinfectant against coronaviruses of the coronavirus family.
- a disinfectant for eliminating the contamination of coronaviruses of the coronavirus family includes Bacillus phthalate A.
- Another aspect of the present invention provides a method for treating diseases caused by viruses of the coronavirus family, comprising adding a therapeutically effective amount of Bacillus phthalate A or a pharmaceutically acceptable salt, isotope, stereoisomer, or stereoisomer.
- a mixture of conformers, tautomers, esters, amides or prodrugs is administered to the subject.
- Another aspect of the present invention provides a method for preventing a subject from being infected with coronaviruses of the coronavirus family, comprising adding a therapeutically effective amount of Bacillus phthalate A or a pharmaceutically acceptable salt, isotope, stereoisomer, stereo Administration of mixtures of isomers, tautomers, esters or prodrugs is administered to the subject prior to infection.
- the invention discloses the application of a medicine with Bacillus thallium A as the main component and a pharmaceutically acceptable salt thereof in anti-new coronary pneumonia (COVID-19) new type coronavirus (SARS-Cov-2) infection.
- the present invention finds for the first time that Bacillus phthalein A has an antiviral effect on the new coronavirus, can block the new coronavirus from infecting host cells, and can be used as a disease treatment for the treatment of the new coronavirus infection of the new coronary pneumonia.
- Bacillus phthalein A has an antiviral effect on the new coronavirus, can block the new coronavirus from infecting host cells, and can be used as a treatment for the treatment of new coronary pneumonia and new coronavirus infection.
- the half effective concentration (EC 50 ) of Bacillus phthalein A for SARS-Cov-2 is 2.38 ⁇ M, which is low in toxicity and has a good therapeutic window.
- the African green monkey kidney cells (VeroE6) were inoculated into a 96-well plate at 3 ⁇ 10 5 cells/well. ; GibcoInvitrogen), incubate at 37°C, 5% CO 2 and wait until the monolayer grows up.
- a 100-fold dilution of the novel coronavirus clinical isolates of the novel coronavirus pneumonia was inoculated into a 96-well plate full of monolayer cells, and cultured at 37°C and 5% CO 2 for two days (including the normal control group).
- the degree of disease was as high as 75%, placed in a -80°C ultra-low temperature refrigerator, repeated freezing and thawing once, collecting the amplified virus solution, centrifuged at 3000r/min for 30 minutes, removing the sediment, and placing the small tubes in the -80°C ultra-low temperature refrigerator Long-term preservation.
- VeroE6 cells were cultured overnight in a 48-well cell culture dish with a density of 5 ⁇ 10 4 cells/well.
- Virus MOI of 0.05
- Virus MOI of 0.05
- each concentration is set with 4 replicate wells, with 200 ⁇ M as the initial concentration of the drug, incubate for 2 days in a 34°C, 5% CO 2 incubator.
- CPE Cytopathogenic Effect
- the half effective concentration (EC 50 ) of the drug for new coronary pneumonia
- the half effective concentration (EC 50 ) of the novel coronavirus (SARS-Cov-2) is 2.38 ⁇ M, and the half effective concentration is low, indicating a high antiviral effect.
- Immunofluorescence microscopy In order to detect the expression of viral proteins in VeroE6 cells, the cells were fixed with 4% paraformaldehyde and permeabilized with 0.5% TritonX-100. The cells were then blocked with 5% bovine serum albumin (BSA) for 2 hours at room temperature. Incubate the cells with the primary antibody (polyclonal antibody against the nucleocapsid protein of the bat SARS-related coronavirus, anti-NP, at a dilution of 1:1000) for 2 hours, and then incubate the antibody with the secondary antibody (488 AffiniPure Donkey Anti-Rabbit) IgG (H+L).
- the primary antibody polyclonal antibody against the nucleocapsid protein of the bat SARS-related coronavirus, anti-NP, at a dilution of 1:1000
- secondary antibody 488 AffiniPure Donkey Anti-Rabbit
- the nucleus is stained with Hoechst33258 dye (Beyotime, China). Observation by fluorescence microscope shows that Bacillus phthalein A can effectively kill the virus in the cell, and has little effect on the cell, and has a good therapeutic window.
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- Animal Behavior & Ethology (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Gastroenterology & Hepatology (AREA)
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- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Communicable Diseases (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Description
Claims (10)
- 杆菌酞A或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。
- 根据权利要求1所述的用途,所述的冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。
- 根据权利要求1所述的用途,冠状病毒所致疾病为SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、HCoV-OC43、HKU1或MERS-CoV任一病毒引起的感染性疾病或其并发症;感染性疾病优选为呼吸道感染疾病。
- 根据权利要求1所述的用途,杆菌酞A或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药作为唯一活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用;或者杆菌酞A或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药,与其他抗病毒药物的组合物作为活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用;优选地,其他抗病毒药物选自更昔洛韦、阿昔洛韦、金刚烷胺、金刚乙胺、奥司他韦、阿巴卡韦、醋孟南、阿昔洛韦钠、阿德福韦、阿洛夫定、阿韦舒托、盐酸三环癸胺、阿拉诺丁、阿立酮、阿替韦啶甲磺酸酯、阿夫立定、西多福韦、西潘茶碱、恩曲他滨、盐酸阿糖胞苷、甲磺酸地拉韦啶、地昔洛韦、去羟肌苷、二噁沙利、依度尿苷、乙米韦林、依曲西他平、恩韦拉登、恩韦肟、贺普丁、泛昔洛韦、盐酸氯苯氢异喹、非西他滨、非阿尿苷、磷利酯、膦乙酸钠、甘西洛维钠、碘苷、茚地那韦、乙氧丁酮醛、拉米夫定、洛布卡韦、洛德腺苷、洛匹那韦、盐酸美莫汀、甲红硫脲、那非那韦、奈韦拉平、喷昔洛韦、吡罗达韦、利巴韦林、 甲磺酸沙奎那韦、利托那韦、盐酸索金刚胺、索立夫定、匍枝青霉菌素、司他夫定、替诺福韦、盐酸梯络龙、曲氟尿苷、盐酸伐昔洛韦、阿糖腺苷、磷酸阿糖腺苷、阿糖腺苷磷酸钠、替拉那韦、韦罗肟、扎西他滨、齐多夫定、净韦肟。
- 一种治疗或预防冠状病毒所致疾病的药物组合物,所述药物组合物中包含杆菌酞A或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药。
- 根据权利要求5所述的药物组合物,药物组合物的还包括药学上可接受的辅料。
- 根据权利要求5所述的药物组合物,药物组合物的剂型为口服制剂、肺部吸入制剂、粘膜给药制剂、眼用制剂或注射剂;优选地,口服制剂选自颗粒剂、粉末剂、丸剂、片剂、胶囊或口服液。
- 一种消除冠状病毒科病毒污染的消毒剂,所述消毒剂包括杆菌酞A。
- 一种用于治疗或预防冠状病毒科病毒所致疾病的方法,包括将治疗有效量的杆菌酞A或其药物学上可接受的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药给药于受试者。
- 根据权利要求5-7任一项所述的药物组合物或权利要求8所述的消毒剂或权利要求9所述的方法,其中冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。
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