CN111420024B - Application of bacillus phthalein A in preparing medicament for preventing and treating coronavirus - Google Patents

Application of bacillus phthalein A in preparing medicament for preventing and treating coronavirus Download PDF

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CN111420024B
CN111420024B CN202010265260.7A CN202010265260A CN111420024B CN 111420024 B CN111420024 B CN 111420024B CN 202010265260 A CN202010265260 A CN 202010265260A CN 111420024 B CN111420024 B CN 111420024B
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bacillus
phthalein
coronavirus
cov
sars
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CN111420024A (en
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袁曙光
陈显翀
罗木鹏
崔文强
邹荣峰
赵金存
孙静
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Shenzhen Institute of Advanced Technology of CAS
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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

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

The invention relates to application of bacillus phthalein A in preparation of a medicine for preventing and treating coronavirus, and in particular discloses application of bacillus phthalein A in preparation of a medicine for preventing and treating coronavirus. Use of bacillus phthalein a or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester, amide or prodrug thereof for the manufacture of a medicament for the prevention and/or treatment of a disease caused by coronavirus. The coronavirus is novel coronavirus SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 and MERS-CoV. The half-effective concentration (EC 50) of bacillus phthalein A on new coronavirus (SARS-Cov-2) is 2.38 mu M, and the toxicity is low, which shows that the bacillus phthalein A has a good treatment window.

Description

Application of bacillus phthalein A in preparing medicament for preventing and treating coronavirus
Technical Field
The invention belongs to the field of antiviral drugs, and in particular relates to application of bacillus phthalein A in preparing drugs for preventing and treating coronaviruses.
Background
New coronavirus (COVID-19) is an infectious disease caused by infection of human body with novel coronavirus (SARS-Cov-2), and its symptoms mainly include fever, debilitation, dry cough, dyspnea, renal failure, etc. [ The Lancet,2020,395 (10223):507-513; the Lancet 2020,395 (10223):497-506 ]. Coronaviruses belong to the family Coronaviridae (Coronaviridae) coronaviruses (Corona viruses) on the phylogenetic classification. Coronaviruses are enveloped positive-stranded single-stranded RNA viruses, about 80-120 nm in diameter, whose genetic material is the largest of all RNA viruses, and generally only human, murine, porcine, feline, canine, avian vertebrates are infected. Coronaviruses were first isolated from chickens in 1937. The coronavirus particles are irregular in shape and have a diameter of about 60 to 220nm. The virus has an envelope structure with three proteins: spike Protein (S), small Envelope glycoprotein (E, envelope Protein) and Membrane glycoprotein (M, membrane Protein), a few of which are also hemagglutinin glycoprotein (HE Protein, haemagglutinin-esterase) [ Nederlands Tijdschrift Voor Geneeskunde,2014,158 (158): A8119-A8119].
The SARS-Cov-2 virus particle diameter is between 60-140 nm, and the envelope has 9-12 nm spike outside, which is similar to corolla. Genome sequencing showed that SARS-Cov-2 is a single stranded RNA coronavirus. By comparison with other virus sample gene sequences, SARS-Cov-2 was found to be similar to SARS-Cov (79.5%) [ Nature,2020] and bat coronavirus (96%) [ bioRxiv,2020,2020.01.22.914952 ], and it was speculated that the virus might originate from bat [ bioRxiv,2020,2020.01.24.915157; nature,2020]. SARS-Cov-2 virus belongs to the beta CoV and is the 7 th member of the HCoV family [ New England Journal of Medicine,2020] distinct from SARS-CoV and MERS-CoV, the remaining 6 members including HCoV 229E, NL, OC43, HKU1, SARS-CoV and MERS-CoV.
The novel coronavirus is a novel coronavirus which is homologous to the well-known SARS-CoV coronavirus which causes atypical pneumonia, but is of a different type in that it has a mortality rate which is much lower than that of SARS-CoV but is much more infectious than that of SARS-CoV. Global spread suggests that there is still a possibility of spread in the novel coronavirus pneumonic epidemic. Development of effective antiviral drugs and vaccines is the most urgent task at the present time. At present, the treatment of the COVID-19 mainly depends on symptomatic adjuvant treatment, and effective specific medicaments and vaccines are not available. However, the development of new drugs and the preparation of vaccines are time-consuming processes, and not only is the development period long, but also mass production after marketing approval is a time-consuming project. Finding anti-SARS-Cov-2 virus from marketed medicineThe "old medicine" of infection is an effective strategy for treating and preventing the explosive infectious disease, such as COVID-19. The anti-SARS-Cov-2 virus drugs currently under study mainly include RNA polymerase inhibitors, interferon-beta, monoclonal antibodies, vaccines and the like. However, to date, there are no exactly effective antiviral drugs and vaccines. From analysis of in vitro antiviral activity data for these drugs, antiviral ICs for most drugs 50 Between low and medium micromolar, in vivo efficacy is still under observation.
Bacillus phthalein a is a cyclic polypeptide produced by the Bacillus subtilis var organism that inhibits proliferation of gram positive bacteria by interfering with the synthesis of cell wall peptidoglycans. Bacillus phthalein a affects the biochemical processes of bacteria, including migration of metal ions, synthesis of peptidoglycans, cell membrane permeability and synthesis of induced enzymes. In addition to antibacterial activity, bacillus phthalein a has proven useful as a tool for studying lipid-protein interactions at the molecular level.
The development of effective coronavirus pneumonia therapeutic specific drugs has become the next-to-be-solved problem. In the aspect of researching and developing a novel coronavirus (SARS-Cov-2) virus drug, the invention researches the anti-SARS-Cov-2 virus effect of bacillus phthalein A.
Disclosure of Invention
The invention aims to provide application of bacillus phthalein A in preparing a medicament for preventing or treating diseases caused by coronaviruses.
Specifically, in order to solve the technical problems of the invention, the following technical scheme is adopted:
the invention provides application of bacillus phthalein A or pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs thereof in preparing medicaments for preventing and/or treating diseases caused by coronaviruses.
In the technical scheme of the invention, the coronaviruses are novel coronaviruses SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 and MERS-CoV.
In the technical scheme of the invention, the diseases caused by coronaviruses are infectious diseases or complications thereof caused by any one of SARS-Cov-2, SARS-CoV, HCoV 229E, NL, OC43, HKU1 or MERS-CoV; preferably a respiratory tract infection disease, for example, severe acute respiratory syndrome coronavirus type 2, middle east respiratory syndrome.
In the technical scheme of the invention, bacillus phthalein A is shown as a structural formula (1)
In the technical scheme of the invention, the bacillus phthalein A or pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs thereof are used as the only active ingredients in the preparation of medicaments for preventing and/or treating diseases caused by coronaviruses.
In the technical scheme of the invention, the bacillus phthalein A or pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs thereof and the composition prepared from other antiviral drugs are used as active ingredients in the preparation of medicaments for preventing and/or treating diseases caused by coronaviruses.
In the technical proposal of the invention, the device comprises a plurality of control units, other antiviral drugs are selected from ganciclovir, acyclovir, amantadine, oseltamivir, abacavir, acebanan, acyclovir sodium, adefovir, alovudine, wei Shutuo, tricyclodecylamine hydrochloride, alenopodine, aliskiren, ate Wei Dingjia sulfonate, alfudine, cidofovir, cetpentheophylline, emtricitabine, cytarabine hydrochloride, delavirdine mesylate, desiclovir, didanosine, edestin, etomivir, etanercept, valdecoloureir, valdecoxivir, clomazone hydrochloride, fexidan, fexiback, fexido sodium fosfomate, ganciclovir, iodoside, indinavir, ethoxybutanone aldehyde, lamivudine, lobucavir, lodenosine, lopinavir, mefloxine hydrochloride, thiored thiourea, nelfinavir, nevirapine, penciclovir, pirodavir, ribavirin, saquinavir mesylate, ritonavir, amantadine hydrochloride, solivudine, epicocconomycin, stavudine, tenofovir, tenuifimbrane hydrochloride, trifluoretoside, valacyclovir hydrochloride, vidarabine phosphate, sodium arathyrophosphate, telanavir, wei Luowo, zalcitabine, zidovudine, net Wei Wo.
In another aspect the present invention provides a pharmaceutical composition for the treatment or prophylaxis of a disease caused by a virus of the coronaviridae family, said pharmaceutical composition comprising bacitracin a or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester, amide or prodrug thereof.
In the technical scheme of the invention, the pharmaceutical composition also comprises pharmaceutically acceptable auxiliary materials.
In the technical scheme of the invention, the dosage form of the pharmaceutical composition is oral preparation, pulmonary inhalation preparation, mucosa administration preparation, ophthalmic preparation or injection.
In the technical scheme of the invention, the oral preparation is selected from granules, powder, pills, tablets, capsules or oral liquid.
In another aspect the invention provides the use of bacitracin a as a disinfectant against viruses of the coronaviridae family.
In another aspect the invention provides a disinfectant for the elimination of coronaviridae virus contamination, said disinfectant comprising bacitracin a.
In another aspect the invention provides a method for the treatment of a disease caused by a virus of the coronaviridae family comprising administering to a subject a therapeutically effective amount of bacitracin a or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester, amide or prodrug thereof.
In another aspect the invention provides a method for preventing infection of a subject with a virus of the coronaviridae family comprising administering to the subject a therapeutically effective amount of bacitracin a or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof prior to infection.
The invention discloses a medicine taking bacillus phthalein A as a main component and application of a pharmaceutically acceptable salt thereof in resisting novel coronavirus (SARS-Cov-2) infection of novel coronapneumonia (COVID-19). The invention discovers that the bacillus phthalein A has antiviral effect on novel coronaviruses for the first time, can block the infection of host cells by the novel coronaviruses, and can be used for treating diseases in the aspect of resisting the infection of the novel coronaviruses of the novel coronapneumonia.
Advantageous effects
Bacillus phthalein A has antiviral effect on novel coronavirus, can block infection of host cells by novel coronavirus, and can be used for treating diseases in the aspect of resisting novel coronavirus infection of novel coronapneumonia. Half-effective concentration of Bacillus phthalein A against novel coronavirus (SARS-Cov-2) (EC 50 ) 2.38 mu M, low toxicity and a good therapeutic window.
Detailed Description
The following detailed description of the embodiments of the present invention will be made in order to make the above-mentioned objects, features and advantages of the present invention more obvious, but should not be construed as limiting the scope of the present invention.
Example 1 Virus amplification
African green monkey kidney cells (VeroE 6) were isolated at 3X 10 5 Each well was inoculated into a 96-well plate, and placed at 37℃in Eagle's minimum basal medium (MEM; gibcoInvitrogen) containing 10% fetal bovine serum (FBS; gibcoInvitrogen) at 5% CO 2 Culturing until the whole layer grows. 100-fold dilution of new clinical coronavirus isolate of coronavirus is inoculated into 96-well plate full of single-layer cells, and placed at 37 ℃ and 5% CO 2 Two days of incubation (with normal control).
After two days, the pathological change degree reaches more than 75%, the obtained product is placed in an ultralow temperature refrigerator at-80 ℃ for repeated freezing and thawing for one time, virus liquid amplified by cells is collected, centrifuged for 30 minutes at 3000r/min, sediment is removed, and the obtained product is packaged in small tubes and placed in the ultralow temperature refrigerator at-80 ℃ for long-term storage.
EXAMPLE 2 evaluation of the toxicity of the bacillus phthalein A drug
Dissolving bacillus phthalein A powder with DMSO, adding culture solution, diluting to 20mg/mL, filtering with 0.22 μm filter membrane to obtain final concentration of DMSO of 1%, and storing at 4deg.C; filtering and storing at 4deg.C. About 2.5X10 per well 4 Inoculating cells to 96-well plate, removing culture solution after cells grow into single layer after 24-48 hr, adding different dilutions of medicine L00 μL/well, adding normal cell control well into L00 μL/well MEM, and adding 5% CO at 37deg.C 2 Continuously culturing for 2-5 days, adding 20 mu L of CCK8 solution (5 mg/mL) into each hole, and placing 5% CO at 37 DEG C 2 Incubation was continued for 4 hours in the incubator. The culture supernatant was aspirated, and 1.mu.L of dimethyl sulfoxide (DMSO) was added to each well, followed by shaking at low speed for 10 minutes to allow the crystals to be sufficiently thawed. The light absorption value of each well was measured on an ELISA monitor at 490nm wavelength. The toxicity evaluation shows that when the drug addition concentration reaches 400 mu M, obvious cytotoxicity is not seen, so that the cytotoxicity of the drug is low, and the drug has a good treatment window.
EXAMPLE 3 evaluation of the efficacy of Bacillus phthalein A against novel coronaviruses against New coronapneumonitis
To evaluate antiviral efficacy of drugs, veroE6 cells were grown at a density of 5×10 4 Cells/well were cultured overnight in 48-well cell culture dishes. Virus (MOI 0.05) was added to infect it for 2 hours. Then adding 2-fold gradient diluted medicines, setting 4 multiple holes for each concentration, taking 200 μm as initial concentration of the medicines, and adding 5% CO at 34 DEG C 2 Incubate in incubator for 2 days. Recording cytopathy (Cytopathogenic Effect, CPE. CPE appeared on cells were recorded according to 6-grade standard, after recording CPE, staining was performed by CCK8 method, OD value was measured, and the half-effective concentration of drug was calculated by Reed-Muench method (EC) 50 ) half-Effective Concentration (EC) of novel coronavirus (SARS-Cov-2) against new coronapneumonia 50 ) 2.38 mu M, and low half effective concentration, which shows higher antiviral effect.
Example 4 immunofluorescence assay
Immunofluorescence microscope: to detect expression of viral proteins in VeroE6 cells, the cells were fixed with 4% paraformaldehyde and permeabilized with 0.5% triton x-100. Cells were then blocked with 5% Bovine Serum Albumin (BSA) for 2 hours at room temperature. Cells were incubated with primary antibody (anti-NP, at 1:1000 dilution) for 2 hours, then with secondary antibody incubation antibody (488 AffiniPure Donkey Anti-Rabbit IgG (H+L)) nuclei were stained with Hoechst33258 dye (Beyotime, china).

Claims (2)

1. The application of bacillus phthalein A as the only active ingredient in preparing the medicine for preventing and/or treating the diseases caused by coronavirus, wherein the coronavirus is novel coronavirus SARS-Cov-2;
the bacillus phthalein A is shown as a structural formula (1)
2. The use according to claim 1, wherein the coronavirus-caused disease is an infectious disease caused by SARS-Cov-2 or a complication thereof; the infectious disease is respiratory tract infection disease.
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CN111420024B (en) * 2020-04-07 2023-10-03 中国科学院深圳先进技术研究院 Application of bacillus phthalein A in preparing medicament for preventing and treating coronavirus
WO2022088038A1 (en) * 2020-10-30 2022-05-05 中国科学院深圳先进技术研究院 Application of cay10603 in preparation of drugs for preventing and treating coronavirus-related diseases
WO2022088037A1 (en) * 2020-10-30 2022-05-05 中国科学院深圳先进技术研究院 Application of sirtinol in preparation of drug for preventing and treating coronavirus
US20240009214A1 (en) * 2020-12-02 2024-01-11 Cipla Limited Method of Treating Viral Infection
CN113350482B (en) * 2021-05-31 2022-05-27 中国食品药品检定研究院 Application of phytohemagglutinin PHA-E in preparation of medicine for treating diseases caused by coronavirus

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