WO2021203702A1 - Utilisation d'acide pyroglutamique dans la préparation de médicaments pour la prévention et le traitement du nouveau coronavirus responsable de la pneumonie à nouveau coronavirus - Google Patents
Utilisation d'acide pyroglutamique dans la préparation de médicaments pour la prévention et le traitement du nouveau coronavirus responsable de la pneumonie à nouveau coronavirus Download PDFInfo
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- WO2021203702A1 WO2021203702A1 PCT/CN2020/129184 CN2020129184W WO2021203702A1 WO 2021203702 A1 WO2021203702 A1 WO 2021203702A1 CN 2020129184 W CN2020129184 W CN 2020129184W WO 2021203702 A1 WO2021203702 A1 WO 2021203702A1
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- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- INAAIJLSXJJHOZ-UHFFFAOYSA-N pibenzimol Chemical compound C1CN(C)CCN1C1=CC=C(N=C(N2)C=3C=C4NC(=NC4=CC=3)C=3C=CC(O)=CC=3)C2=C1 INAAIJLSXJJHOZ-UHFFFAOYSA-N 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 235000013594 poultry meat Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229950009279 sorivudine Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
Classifications
-
- 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
- A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- 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
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
Definitions
- the invention belongs to the field of antiviral drugs, and specifically relates to the application of pyroglutamic acid in the preparation of drugs for the prevention and treatment of new coronaviruses against new coronary pneumonia.
- Coronavirus pneumonia (Corona Virus Disease 2019) is an infectious disease caused by a new coronavirus (SARS-Cov-2) infecting the human body. Its symptoms mainly include fever, fatigue, dry cough, difficulty breathing, and kidney failure. [The Lancet ,2020,395(10223):507-513; The Lancet,2020,395(10223):497-506]. New coronary pneumonia cases were reported in December 2019, followed by cases in many countries around the world, including South Korea, Japan, Thailand, Iran, Singapore, Germany, France and the United States. 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.
- 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 2019-nCoV 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 HCoV 229E, NL63, OC43, HKU1, SARS -CoV and MERS-CoV.
- the new type of 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. Since then, South Korea, Japan, Thailand, Iran, Singapore, Germany, France, and the United States have all seen confirmed cases of the disease, indicating that the new coronavirus pneumonia epidemic may still spread. But so far, there is still no specific medicine that can cure the new type of coronavirus pneumonia. Most of the current treatment methods are symptomatic treatment, especially for some critically ill patients.
- the purpose of the present invention is to provide the application of L-pyroglutamic acid in the preparation of drugs for the prevention or treatment of new coronaviruses against new coronary pneumonia.
- the present invention provides pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs in the preparation of prevention and/or treatment of coronary Application in medicines for diseases caused by viruses.
- pyroglutamic acid is L-pyroglutamic acid, D-pyroglutamic acid or a mixture thereof.
- 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 pneumonia or its complications caused by any virus of SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 or MERS-CoV.
- L-pyroglutamic acid is represented by structural formula (1)
- pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs are used as the sole active ingredient Application in the preparation of medicines for preventing and/or treating diseases caused by coronaviruses.
- pyroglutamic acid 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, which comprises pyroglutamic acid or its pharmaceutically acceptable salts, isotopes, stereoisomers, and stereoisomers. Mixtures, 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 pyroglutamic acid as a disinfectant against coronaviruses of the coronavirus family.
- 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 pyroglutamic acid or a pharmaceutically acceptable salt, isotope, stereoisomer, stereo A mixture of isomers, tautomers, esters 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, which comprises adding a therapeutically effective amount of pyroglutamic acid or a pharmaceutically acceptable salt, isotope, stereoisomer, Administration of mixtures of stereoisomers, tautomers, esters or prodrugs is administered to the subject prior to infection.
- the present invention proves for the first time that pyroglutamic acid has a high therapeutic index and a low half effective concentration; the pyroglutamic acid can effectively increase the antivirus effect before being infected.
- Pyroglutamate is used as an effective drug in the treatment of new coronavirus infections caused by new coronary pneumonia.
- the African green monkey kidney cells (VeroE6) were inoculated into 96-well plates 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 clinical isolates of the new coronavirus pneumonia new type coronavirus was inoculated into a 96-well plate full of monolayer cells, and incubated 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
- MOI MOI of 0.05
- each concentration is set to 4 replicate wells, with the maximum non-toxic concentration as the initial concentration of the drug, incubate for 2 days in a 34°C, 5% CO 2 incubator.
- CPE Cytopathogenic Effect
- L- pyroglutamic new crown anti-pneumonia novel coronavirus efficacy evaluation efficacy evaluation of L- pyroglutamic CCK8 by law the median effective concentration for the new crown pneumonia novel coronavirus (SARS-Cov-2) of (EC 50 ) Is 9.34 ⁇ M, the half effective concentration is low, indicating that the antiviral effect is good.
- Immunofluorescence microscope 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 nucleus is stained with Hoechst33258 dye (Beyotime, China). Observation by fluorescence microscope shows that pyroglutamate can effectively kill the virus in the cell, and has a small effect on the cell, which has a good therapeutic window.
- BSA bovine serum albumin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne l'utilisation d'acide pyroglutamique dans la préparation de médicaments pour la prévention et le traitement du nouveau coronavirus responsable de la pneumonie à nouveau coronavirus et l'utilisation d'acide pyroglutamique ou de sels pharmaceutiquement acceptables, d'isotypes, de stéréo-isomères, de mélanges de stéréo-isomères, de tautomères, d'esters, d'amides ou de promédicaments associés dans la préparation de médicaments pour la prévention et/ou le traitement de maladies provoquées par des coronavirus. Les coronavirus sont les nouveaux coronavirus SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 et MERS-CoV. La concentration efficace médiane de l'acide pyroglutamique pour le nouveau coronavirus responsable de la pneumonie à nouveau coronavirus est de 9,34 μΜ. La concentration effective médiane est faible, et l'effet antiviral est bon.
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| CN202010266183.7 | 2020-04-07 | ||
| CN202010266183.7A CN111467338B (zh) | 2020-04-07 | 2020-04-07 | 焦谷氨酸在制备预防和治疗抗新冠肺炎新型冠状病毒的药物中的应用 |
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| PCT/CN2020/129184 WO2021203702A1 (fr) | 2020-04-07 | 2020-11-16 | Utilisation d'acide pyroglutamique dans la préparation de médicaments pour la prévention et le traitement du nouveau coronavirus responsable de la pneumonie à nouveau coronavirus |
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| CN111467338B (zh) * | 2020-04-07 | 2021-04-23 | 中国科学院深圳先进技术研究院 | 焦谷氨酸在制备预防和治疗抗新冠肺炎新型冠状病毒的药物中的应用 |
| WO2022088037A1 (fr) * | 2020-10-30 | 2022-05-05 | 中国科学院深圳先进技术研究院 | Application du sirtinol dans la préparation d'un médicament destiné à prévenir et à traiter un coronavirus |
| WO2022088038A1 (fr) * | 2020-10-30 | 2022-05-05 | 中国科学院深圳先进技术研究院 | Application de cay10603 dans la préparation de médicaments pour la prévention et le traitement de maladies liées aux coronavirus |
| CN113350482B (zh) * | 2021-05-31 | 2022-05-27 | 中国食品药品检定研究院 | 植物凝集素pha-e在制备治疗冠状病毒所致疾病的药物中的应用 |
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| CN1411372A (zh) * | 1999-10-19 | 2003-04-16 | 宝洁公司 | 含焦谷氨酸和金属盐的抗微生物组合物 |
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| US20090215854A1 (en) * | 2003-06-20 | 2009-08-27 | The Procter & Gamble Company | Antimicrobial compositions, products and methods employing same |
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| CN111467338A (zh) * | 2020-04-07 | 2020-07-31 | 中国科学院深圳先进技术研究院 | 焦谷氨酸在制备预防和治疗抗新冠肺炎新型冠状病毒的药物中的应用 |
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| US20040234457A1 (en) * | 1999-10-19 | 2004-11-25 | The Procter & Gamble Company | Methods of preventing and treating SARS using low pH respiratory tract compositions |
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| CN1411372A (zh) * | 1999-10-19 | 2003-04-16 | 宝洁公司 | 含焦谷氨酸和金属盐的抗微生物组合物 |
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