WO2022088037A1 - Application du sirtinol dans la préparation d'un médicament destiné à prévenir et à traiter un coronavirus - Google Patents

Application du sirtinol dans la préparation d'un médicament destiné à prévenir et à traiter un coronavirus Download PDF

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Publication number
WO2022088037A1
WO2022088037A1 PCT/CN2020/125258 CN2020125258W WO2022088037A1 WO 2022088037 A1 WO2022088037 A1 WO 2022088037A1 CN 2020125258 W CN2020125258 W CN 2020125258W WO 2022088037 A1 WO2022088037 A1 WO 2022088037A1
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hydrochloride
sirtinol
cov
coronavirus
sars
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PCT/CN2020/125258
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English (en)
Chinese (zh)
Inventor
袁曙光
李红昌
陈显翀
李红春
崔文强
邹荣峰
刘科
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中国科学院深圳先进技术研究院
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Priority to PCT/CN2020/125258 priority Critical patent/WO2022088037A1/fr
Publication of WO2022088037A1 publication Critical patent/WO2022088037A1/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
    • A61K31/33—Heterocyclic compounds
    • 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 belongs to the field of medicine, and specifically relates to the application of SIRTINOL in the preparation of medicines for preventing and treating coronavirus.
  • the new coronavirus pneumonia (Corona Virus Disease 2019) is an infectious disease caused by the infection of the human body by the new coronavirus (SARS-Cov-2). Its symptoms mainly include fever, fatigue, dry cough, dyspnea and renal failure [The Lancet , 2020, 395(10223): 507-513; The Lancet, 2020, 395(10223): 497-506].
  • the coronavirus belongs to the genus Coronavirus in the family Coronaviridae.
  • the virus of the genus Coronavirus is a positive-stranded single-stranded RNA virus with an envelope, with a diameter of about 80-120 nm.
  • RNA viruses Its genetic material is the largest among all RNA viruses, and generally only infects humans, mice, pigs, cats, and dogs. , avian vertebrates.
  • the coronavirus was first isolated from chickens in 1937. The shape of coronavirus particles is irregular, with a diameter of about 60-220nm.
  • the virus has an envelope structure with three proteins on it: spike glycoprotein (S, Spike Protein), small envelope glycoprotein (E, Envelope Protein) and membrane glycoprotein (M, Membrane Protein), and a few species also have hemagglutination.
  • S spike glycoprotein
  • E small envelope glycoprotein
  • M membrane glycoprotein
  • Glucoprotein HE protein, Haemaglutinin-esterase
  • SARS-Cov-2 virus particles The diameter of SARS-Cov-2 virus particles is between 60 and 140 nm, and there are spikes of 9 to 12 nm outside the envelope, which are shaped like a corolla.
  • Genome sequencing revealed that SARS-Cov-2 is a single-stranded RNA coronavirus. By comparing the gene sequences of other virus samples, it was found that SARS-Cov-2 was similar to SARS-CoV (79.5%) [Nature, 2020] and bat coronavirus (96%) [bioRxiv, 2020, 2020.01.22.914952], and speculated that The virus may have originated from bats [bioRxiv, 2020, 2020.01.24.915157; Nature, 2020].
  • the 2019-nCoV virus belongs to ⁇ CoV and is the seventh member of the HCoV family that is different from SARS-CoV and MERS-CoV [New England Journal of Medicine, 2020], and the remaining six members include HCoV 229E, NL63, OC43, HKU1, SARS -CoV and MERS-CoV.
  • the novel coronavirus pneumonia is caused by a new type of coronavirus. It is the same coronavirus as the well-known SARS-CoV that causes atypical pneumonia, but the type is different. Although its fatality rate is lower than that of SARS-CoV, it is far more infectious. to SARS-CoV.
  • SIRTINOL is an inhibitor of sirtuin (SIRT) with IC50 values of 48 ⁇ M, 57.7 ⁇ M and 131 ⁇ M for ySir2, hSIRT2 and hSIRT2, respectively.
  • the purpose of the present invention is to provide the application of SIRTINOL in the preparation of medicines for preventing or treating the novel coronavirus of new coronary pneumonia.
  • the present invention provides SIRTINOL or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs in the preparation of preventing and/or treating coronavirus The use of medicines for diseases.
  • Another aspect of the present invention provides SIRTINOL or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs in the preparation of a method for preventing the entry of coronavirus into cells application in medicine.
  • the coronaviruses are novel 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.
  • SIRTINOL is represented by structural formula (1)
  • SIRTINOL or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs are used as the only active ingredients in the preparation of prophylactic and/or use in medicines for the treatment of diseases caused by coronavirus.
  • SIRTINOL or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs and other antiviral drugs are prepared Application of the composition as an active ingredient in the preparation of a medicament for preventing and/or treating diseases caused by coronavirus.
  • antiviral drugs are selected from ganciclovir, acyclovir, amantadine, rimantadine, oseltamivir, abacavir, acemannan, acyclovir Sodium, Adefovir, Alovudine, Avesuto, Tricyclodecamine Hydrochloride, Alanodine, Aridone, Ateviridine Mesylate, Afrilidine, Cidofovir, Silicate panthefylline, emtricitabine, cytarabine hydrochloride, delavirdine mesylate, desilovir, didanosine, dioxalisine, eduridine, emivirine, eltra Sitapine, Enviraden, Enviroxime, Heptin, Famciclovir, Chlorphenhydramine Hydrochloride, Noncitabine, Nonauridine, Phosphorate, Foscarnet Sodium, Phos
  • Another aspect of the present invention provides a pharmaceutical composition for treating or preventing diseases caused by coronaviruses of the family Coronaviridae, comprising SIRTINOL or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, Variant, ester, amide or prodrug.
  • the pharmaceutical composition further includes pharmaceutically acceptable excipients.
  • the dosage form of the pharmaceutical composition is an oral preparation, a pulmonary inhalation preparation, a mucosal administration preparation, an ophthalmic preparation or an 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 SIRTINOL as a disinfectant against Coronaviridae.
  • Another aspect of the present invention provides a method for treating diseases caused by coronaviruses, comprising adding a therapeutically effective amount of SIRTINOL or a pharmaceutically acceptable salt, isotope, stereoisomer, stereoisomer thereof A mixture, tautomer, ester or prodrug is administered to a subject.
  • Another aspect of the present invention provides a method for preventing a subject from being infected with a coronavirus of the family Coronaviridae, comprising adding a therapeutically effective amount of SIRTINOL or a pharmaceutically acceptable salt, isotope, stereoisomer, stereoisomer thereof Mixtures of isomers, tautomers, esters or prodrugs are administered to subjects prior to infection.
  • the present invention proves for the first time that SIRTINOL has a high therapeutic index and a low half effective concentration on the novel coronavirus of novel coronavirus pneumonia; and administering SIRTINOL before infection can effectively increase the anti-virus effect.
  • SIRTINOL is used as an effective drug in the treatment of novel coronavirus infection.
  • Figure 1 shows the production and verification of SARS-2-S pseudotype particles.
  • SARS-2-S protein can be successfully expressed in mammalian cells.
  • SARS-2-S pseudovirion has S protein modification.
  • C The SARS-2-S pseudovirion can successfully infect host cells and integrate the reporter gene.
  • D SARS-2-S pseudovirions enter susceptible cells by recognizing ACE2 receptors.
  • E SARS-2-S pseudovirions were able to infect human 293T cells expressing ACE2-GFP, but not into 293T cells without ACE2 expression. ACE2-GFP, green; Flag tag, red, showing S protein;
  • SARS-2-S pseudoviral particles are able to bind to ACE2 receptors with co-localized signals at different intracellular locations (membrane and cytoplasm).
  • G Time-dependent entry of SARS-2-S pseudovirions into ACE2-GFP/293T cells.
  • Figure 2 shows that SIRTINOL effectively inhibits pseudovirion infection.
  • Immunofluorescence staining was used to determine the inhibitory effect of the screened clinical drugs on the infection of host cells by SARS-2-S pseudovirus particles. After the pseudovirus particles infect ACE2-GFP expressing 293T cells, the intracellular localization of pseudovirus particles was observed by fixed staining. Blue, DAPI; red, Flag antibody labeled S protein; green, ACE2-GFP signal.
  • treatment refers to reversing, alleviating, inhibiting the progression of, or preventing the diseases or conditions to which the term applies, or one or more symptoms of these diseases or conditions, or the One or more symptoms of a disorder.
  • terapéuticaally effective amount is the amount of Compound 1, or a pharmaceutically acceptable salt thereof, present in the compositions described herein that, when such compositions are administered by the chosen route of administration, at The desired level of drug is provided in the secretions and tissues of the airways and lungs, or alternatively in the bloodstream of the subject to be treated, to produce the desired physiological response or desired biological effect.
  • the precise amount will depend on many factors, such as the specific activity of the composition, the delivery device used, the physical properties of the composition, its intended use, and animal considerations such as the severity of the disease state, etc., and can be determined by one of skill in the art based on The information provided herein makes it easy to determine the exact amount.
  • the active ingredients of the present invention are administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It will be appreciated that the preferred route may vary depending, for example, on the condition of the recipient.
  • An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.
  • the effective dose of the active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, delivery method and pharmaceutical formulation, and will be determined by the clinician using routine dose escalation studies.
  • SIRTINOL or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs and other antiviral drugs are prepared
  • the application of the composition as an active ingredient in the preparation of a medicament for preventing and/or treating diseases caused by coronavirus, for the above-mentioned two or more active ingredients in a unit dosage form combination is administered to a patient simultaneously or sequentially.
  • Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
  • the cell is any cell, such as eukaryotic or prokaryotic cells, especially refers to a host cell that can be used as a coronavirus, especially a cell containing an ACE2 receptor.
  • the DNA sequence of SARS-2-S protein was modified without changing its amino acid sequence by codon optimization method, which facilitated the abundant expression of SARS-2-S in 293T cells (Fig. 1A).
  • the three-plasmid expression system was transfected in 293T cells, and SARS-2-S was modified on the outer membrane of the pseudovirion to form SARS-2 -S pseudovirion. It can be judged by immunoblotting that this pseudoviral particle removed the original VSV-G envelope glycoprotein and replaced it with SARS-2-S, the envelope glycoprotein of the new coronavirus ( Figure 1B).
  • the pseudovirion carrying the Luciferase reporter gene was used to infect host cells 293T or ACE2/293T cells.
  • the Luciferase cell activity assay showed that the SARS-2-S pseudovirus particles had high infectivity to ACE2/293T cells, and the infection efficiency was about 100 times higher than that of 293T cells ( Figure 1C).
  • pseudovirus particles were also used to infect monkey kidney epithelial Vero-E6 cells with endogenous ACE2 expression, and immunofluorescence staining showed that SARS-2-S pseudovirus particles could well enter Vero-E6 cells; Knockdown of the endogenous ACE2 receptor greatly reduced the infection efficiency of pseudovirions (Fig.
  • SARS-2-S pseudovirus particles were not only localized on the cell membrane, but also could enter cells with ACE2 receptors and transported to the perinuclear cells of cells perinuclear area (Fig. 1F).
  • the entry of SARS-2-S pseudovirions into host cells was also time-dependent, reaching a saturation phase after approximately 2 h (Fig. 1G).
  • SARS-2-S pseudovirus particle in vitro infection model constructed in Example 1 (Luciferase reporter system and immunofluorescence staining localization system)
  • SIRTINOL in vitro cell biology verification was carried out.
  • ACE2-GFP stably transfected 293T cells were inoculated in 96-well plates, and cells were pretreated with different concentrations of SIRTINOL for 2 hours, then SARS-2-S pseudovirus particles were added to infect for 3 hours, and then the supernatant was removed and replaced with fresh complete medium. After 40 hours of infection, the cells were lysed by the Luciferase Assay System (Promega) and the reaction substrate was added, and the luminescence intensity of luciferase was measured by Glomax 96. The bioluminescence intensity was proportional to the infection efficiency of virus particles.
  • Luciferase activity assay showed that SIRTINOL had an obvious concentration-dependent effect and could effectively inhibit the infection efficiency of SARS-2-S pseudovirus particles.
  • the EC50 concentration of SIRTINOL was approximately 82.9 ⁇ 61.1 ⁇ M.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne une application de sirtinol dans la préparation d'un médicament destiné à prévenir et traiter un coronavirus. Plus particulièrement, une application du sirtinol ou d'un sel pharmaceutiquement acceptable, d'un isotope, d'un stéréoisomère, d'un mélange de stéréoisomères, d'un tautomère, d'un ester, d'un amide ou d'un promédicament dans la préparation d'un médicament destiné à prévenir et/ou traiter des maladies provoquées par un coronavirus est divulguée. Ledit coronavirus désigne le SARS-Cov-2, le SARS-CoV, le HCoV 229E, le NL63, l'OC43, le HKU1 et le MERS-CoV. La maladie provoquée par le coronavirus est une pneumonie ou une complication de celle-ci provoquée par l'un quelconque du SARS-Cov-2, du SARS-CoV, du HCoV 229E, du NL63, de l'OC43, du HKU1 ou du MERS-CoV. L'invention confirme, pour la première fois, l'effet Inhibiteur de sirtinol sur le SARS-Cov-2, ce qui provoque la Covid-19 et présente une faible concentration effective à semi-maximale et présente ainsi un excellent potentiel.
PCT/CN2020/125258 2020-10-30 2020-10-30 Application du sirtinol dans la préparation d'un médicament destiné à prévenir et à traiter un coronavirus WO2022088037A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117695281A (zh) * 2023-12-26 2024-03-15 广州医科大学 四氢喹啉酮-酰胺-噻唑类化合物的应用

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CN111467363A (zh) * 2020-04-07 2020-07-31 中国科学院深圳先进技术研究院 索非布韦在制备预防和治疗冠状病毒的药物中的应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117695281A (zh) * 2023-12-26 2024-03-15 广州医科大学 四氢喹啉酮-酰胺-噻唑类化合物的应用

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