WO2022001079A1 - Utilisation d'azacytidine dans la préparation de médicaments antiviraux - Google Patents

Utilisation d'azacytidine dans la préparation de médicaments antiviraux Download PDF

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Publication number
WO2022001079A1
WO2022001079A1 PCT/CN2021/070351 CN2021070351W WO2022001079A1 WO 2022001079 A1 WO2022001079 A1 WO 2022001079A1 CN 2021070351 W CN2021070351 W CN 2021070351W WO 2022001079 A1 WO2022001079 A1 WO 2022001079A1
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WIPO (PCT)
Prior art keywords
virus
drug
azacytidine
application according
antiviral
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Application number
PCT/CN2021/070351
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English (en)
Chinese (zh)
Inventor
刘�文
唐冲
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大连三博生物科技有限公司
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Publication of WO2022001079A1 publication Critical patent/WO2022001079A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • 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 relates to the field of antiviral drugs, and more particularly to the application of Azacytidine in the preparation of antiviral drugs.
  • Virus is a kind of non-cellular organism that is small in size, simple in structure, contains only one nucleic acid (DNA or RNA), and must be parasitic in living cells and reproduce by means of replication.
  • Virus is a non-cellular life form. It consists of a long nucleic acid chain and a protein shell. Viruses do not have their own metabolic mechanisms and do not have an enzyme system. Therefore, the virus leaves the host cell and becomes a chemical substance without any life activity and unable to reproduce independently. Its replication, transcription, and translation capabilities are all carried out in the host cell. When it enters the host cell, it can use the substances and energy in the cell to complete life activities and generate it according to the genetic information contained in its own nucleic acid. A new generation virus like it.
  • polioviruses that can cause polio, many viruses that can cause myocarditis, meningitis, epidemic chest myalgia, laryngotracheitis and gastroenteritis, and rhinoviruses that can cause colds and flu .
  • Foot-and-mouth disease virus can cause oral inflammation and hoof ulceration in cattle, pigs, sheep and other livestock, and often lead to large-scale deaths.
  • viruses Most of the diseases caused by viruses are the main infectious diseases of human beings. Viruses can invade different tissues and organs and cause diseases by infecting cells. Common diseases caused by viruses are:
  • Latent infection herpetic keratitis, venereal herpes virus.
  • Penetration and uncoating inhibitors DNA polymerase inhibitors, reverse transcriptase inhibitors, nucleosides, non-nucleosides, protein inhibitors, neuraminidase inhibitors, broad-spectrum antivirals: ribavirin, interfering White.
  • viruses Due to the diversity of viruses, many viruses do not have specific treatment drugs, such as the new coronary pneumonia virus that occurred at the end of 2019 and SARS that occurred in 2003.
  • the purpose of the present invention is to provide the application of a known drug in antiviral.
  • the virus is a virus with a short course of disease.
  • the virus with a short course of disease includes a Viruses that cause people to die quickly also include viruses that experience a certain incubation period without symptoms, and can cause people to die quickly after the onset of the disease.
  • the antiviral drug is a drug that inhibits virus replication.
  • the antiviral drug is a drug for reducing cytokine storm.
  • the virus is a virus that relies on RNA as a gene carrier, or RNA as an intermediate metabolite.
  • the virus is a coronavirus.
  • the coronavirus is a novel coronavirus.
  • the virus is SARS virus, MERS virus or nCoV-2019 virus.
  • Azacytidine in the preparation of a medicine for treating atypical pneumonia, where the atypical pneumonia is pneumonia caused by a virus.
  • the antiviral drug is a drug that slows down the progression of acute viral disease.
  • the dosage of the antiviral drug for human use is 1-10000 mg/m 2 .
  • Virus infection damages cells after virus infection.
  • SARS nsp1 protein can shear the RNA of cells, resulting in the degradation of cellular RNA and damage to cells; virus infection leads to an increase in IgG in the blood, and immune cells in the blood overreact to cause an immune storm , and immune storms are often the most deadly.
  • This mechanism is similar to Ebola; the virus progresses quickly, the body has no time to produce the corresponding antibodies, and the body has respiratory failure, so the rescue method is often based on a ventilator.
  • AIDS drugs can inhibit the replication of SARS in the early stage, but because AIDS is a targeted drug, how effective it is on non-targeted SARS may still need to be studied and verified.
  • Current research is that the vast majority of HIV and flu drugs are ineffective against the new crown. Glead released remdesivir as a nucleoside analog to stop SARS virus RNA synthesis, but the current results are also ineffective. The reasons are mainly divided into two points. The first RNA polymerase has fidelity, so it has a relatively strong recognition effect on nucleoside analogs, resulting in the RNA that will not be integrated into the virus, such as ribavirin. Secondly, most protease inhibitors are also targeted drugs, so the specificity of the protein structure is also very high, so it is difficult for the new crown to work.
  • cytokine storm also known as immune storm
  • glucocorticoids mainly uses glucocorticoids, and excessive use of glucocorticoids can cause serious sequelae, such as femoral head necrosis, pulmonary fibrosis, and other sequelae, in 2003 SARS Especially during a pandemic.
  • Aza Azacytidine
  • Aza is a highly similar nucleoside analog, and all current polymerases in eukaryotic cells cannot specifically reject the integration of Aza.
  • Aza can be highly efficiently integrated into cellular RNA.
  • Integrating into the RNA of the virus can effectively disrupt the high-speed translation mechanism of the virus, thereby slowing down the virus infection
  • the RNA integrated into the cell itself may also play a role in preventing the virus from cutting the host RNA, thereby protecting the cell from being destroyed.
  • this drug can also slow down the response of immune cells by integrating Aza into immune cell RNA, thereby weakening the immune storm.
  • Azacytidine can effectively inhibit the replication of the virus and reduce the damage caused by immune storms to the human body, so that the human body has enough time to produce antibodies, thereby improving the cure rate of patients.
  • FIG. 1 is the survival curve of the mice of Example 1 under immune storm.
  • FIG. 2 is the expression level of the cytokine TNF- ⁇ in Example 1.
  • FIG. 3 shows the number of virus infections in Example 2.
  • FIG. 4 is the control regression curve of Example 2.
  • Figure 5 shows the expression levels of cytokines (tumor necrosis factor, interleukin-6) under different drug concentrations in Example 3.
  • mice were injected with PDL1 to create an immune storm model, so that the mice developed a severe immune storm.
  • mice were injected with PDL1 and Azacytidine at the same time.
  • the immune storm state of the mice was significantly relieved.
  • the number of mice that died due to immune storm also decreased significantly, as shown in Figure 1, the survival curve of mice under immune storm.
  • the mice in the PD-L1-treated group died rapidly due to the immune storm.
  • the immune storm of the mice in the PD-L1 treatment group was significantly relieved, and the survival curve was significantly prolonged.
  • the immune storm indicator factor TNF-a in the lung tissue was measured. As shown in Figure 2, it was found that the concentration of the immune storm indicator factor TNF-a in the lungs of mice injected with Azacytidine was significantly reduced.
  • Azacytidine has the effect of suppressing the immune storm, which can relieve the immune storm caused by the late SARS, and will not produce sequelae such as glucocorticoids.
  • BHK21-hACE2 cells are plated, 2X104 cells per well of 96-well plate, so that the density can reach 70%-80% after 12 hours;
  • Aza (2mM) was diluted as follows: 10ul Aza (2mM) + 90ul DMEM to make the final concentration 0.2mM, take 0.2mM sample 50ul + 150ul DMEM as gradient 1, take 50ul gradient 1 + 100ul DMEM as gradient 2, in turn 3 fold dilution, a total of 8 gradients;
  • Chloroquine-NIDVD (20mM) was diluted as follows: 10ul Chloroquine-NIDVD (20mM)+990ulDMEM to make the final concentration 0.2mM, the post-dilution method was the same as that of Aza (2mM), a total of 8 gradients;
  • Mock is the blank control group (DMSO).
  • Inhibition rate (the number of blank control fluorescence - the number of fluorescence at drug concentration)/the number of blank control fluorescence (y-axis)
  • the cytotoxicity of Aza is slightly higher than that of chloroquine between 2.5 and 5, but the cytotoxicity of Aza is lower than that of chloroquine when the concentration is greater than 5, which proves that the cell viability of Aza is better than that of chloroquine and the toxicity is lower at high concentrations.
  • 293T cells were transiently transfected with S protein (S protein granules), and 24 hours later, they were digested and plated in a 24-well plate, with 2*105 cells per well. After 24h, S-CART and different concentrations of Aza drug (1 uM, 5 uM, 10 uM) were added. S protein can stimulate the corresponding S-cart to produce immune storm, and immune storm-related factors are secreted into the supernatant. The supernatant was collected after 48h. Cytokines (tumor necrosis factor, interleukin-6) in the supernatant were detected by ELISA to determine the severity of the immune storm.
  • S protein S protein granules
  • Aza drug 1 uM, 5 uM, 10 uM
  • the horizontal axis represents the drug concentration
  • the vertical axis represents the signal intensity (indicated concentration) of detected cytokines. It can be clearly seen that the cytokines IL6 and TNFa in the supernatant are significantly reduced at high concentrations above 5uM, indicating that Aza can obviously inhibit the immune storm.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'azacytidine dans la préparation de médicaments antiviraux. Les virus sont ceux présentant une évolution rapide de la maladie. L'azacytidine peut inhiber efficacement la réplication de virus et réduire les dommages provoqués sur des corps humains par un choc cytokinique, et permet en outre aux corps humains de disposer de suffisamment de temps pour générer des anticorps, ce qui permet d'améliorer le taux de guérison des patients.
PCT/CN2021/070351 2020-06-30 2021-01-05 Utilisation d'azacytidine dans la préparation de médicaments antiviraux WO2022001079A1 (fr)

Applications Claiming Priority (2)

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CN202010612522.2A CN111789863B (zh) 2020-06-30 2020-06-30 一种Azacytidine在制备抗病毒药物中的应用
CN202010612522.2 2020-06-30

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CN111789863B (zh) * 2020-06-30 2021-07-02 大连三博生物科技有限公司 一种Azacytidine在制备抗病毒药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011075656A1 (fr) * 2009-12-18 2011-06-23 The University Of British Columbia Procédés et compositions pour l'administration d'acides nucléiques
WO2014079709A1 (fr) * 2012-11-23 2014-05-30 Ab Science Utilisation d'inhibiteurs/activateurs à petite molécule en combinaison avec des analogues de (désoxy)nucléoside ou de (désoxy)nucléotide pour le traitement du cancer et de malignités hématologiques ou d'infections virales
CN111789863A (zh) * 2020-06-30 2020-10-20 大连三博生物科技有限公司 一种Azacytidine在制备抗病毒药物中的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011075656A1 (fr) * 2009-12-18 2011-06-23 The University Of British Columbia Procédés et compositions pour l'administration d'acides nucléiques
WO2014079709A1 (fr) * 2012-11-23 2014-05-30 Ab Science Utilisation d'inhibiteurs/activateurs à petite molécule en combinaison avec des analogues de (désoxy)nucléoside ou de (désoxy)nucléotide pour le traitement du cancer et de malignités hématologiques ou d'infections virales
CN111789863A (zh) * 2020-06-30 2020-10-20 大连三博生物科技有限公司 一种Azacytidine在制备抗病毒药物中的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DAPP MICHAEL J., CLOUSER CHRISTINE L., PATTERSON STEVEN, MANSKY LOUIS M.: "5-Azacytidine Can Induce Lethal Mutagenesis in Human Immunodeficiency Virus Type 1", JOURNAL OF VIROLOGY, vol. 83, no. 22, 15 November 2009 (2009-11-15), US , pages 11950 - 11958, XP055885547, ISSN: 0022-538X, DOI: 10.1128/JVI.01406-09 *
FELSENSTEIN SUSANNA; HERBERT JENNY A.; MCNAMARA PAUL S.; HEDRICH CHRISTIAN M.: "COVID-19: Immunology and treatment options", CLINICAL IMMUNOLOGY, vol. 215, 27 April 2020 (2020-04-27), AMSTERDAM, NL , pages 1 - 13, XP086176899, ISSN: 1521-6616, DOI: 10.1016/j.clim.2020.108448 *

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CN111789863B (zh) 2021-07-02
CN111789863A (zh) 2020-10-20

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