CN106074506A - The application that arbidol hydrochloride prevents in preparation and treats in the medicine of anti-Middle East respiratory system syndrome coronavirus - Google Patents

The application that arbidol hydrochloride prevents in preparation and treats in the medicine of anti-Middle East respiratory system syndrome coronavirus Download PDF

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Publication number
CN106074506A
CN106074506A CN201610421259.2A CN201610421259A CN106074506A CN 106074506 A CN106074506 A CN 106074506A CN 201610421259 A CN201610421259 A CN 201610421259A CN 106074506 A CN106074506 A CN 106074506A
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China
Prior art keywords
middle east
medicine
respiratory system
arbidol hydrochloride
arbidol
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CN201610421259.2A
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Chinese (zh)
Inventor
杨子峰
胡文辉
李润峰
赵金存
赵昕
钟南山
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Guangzhou Institute Of Respiratory Disease
Guangzhou Institute of Biomedicine and Health of CAS
First Affiliated Hospital of Guangzhou Medical University
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Guangzhou Institute Of Respiratory Disease
Guangzhou Institute of Biomedicine and Health of CAS
First Affiliated Hospital of Guangzhou Medical University
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Priority to CN201610421259.2A priority Critical patent/CN106074506A/en
Publication of CN106074506A publication Critical patent/CN106074506A/en
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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
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses the application in terms of the respiratory system syndrome coronavirus infection of the anti-Middle East of the medicine with arbidol as main component and the most acceptable salt thereof.Present invention firstly discovers that arbidol hydrochloride has antivirus action to Middle East Respirovirus, Middle East respiratory system syndrome coronavirus infection host cell can be blocked, can be used as treating the disease treatment in terms of the respiratory system syndrome coronavirus infection of the anti-Middle East.

Description

Arbidol hydrochloride is in preparation prevention and to treat anti-Middle East respiratory system syndrome crown Application in the medicine of virus
Technical field
The present invention is about arbidol hydrochloride application in terms of the respiratory system syndrome coronavirus infection of the anti-Middle East, Belong to pharmaceutical technology field.
Background technology
Middle East respiration syndrome (Middle East Respiratory Syndrome, MERS), also known as new sarsaparilla, 2012 Year finds in London first, and named No. 1 novel coronavirus [Lodon1 novel CoV 2012], its structure and SARS Virus similar, come from the Middle East.On May 23rd, 2013, novel coronavirus is infected that named " Middle East is exhaled by World Health Organization (WHO) Inhale syndrome ".Coronavirus belongs to coronaviridae (Coronaviridae) coronavirus genus in system classification (Coronavirus).The virus of coronavirus genus is the normal chain single-stranded RNA virus of tool outer embrane (envelope), diameter about 80 ～120nm, its hereditary material is maximum in all RNA viruses, only infects people, Mus, pig, cat, dog, birds vertebrates.Hat One mutation of shape virus is the pathogen causing atypical pneumonia, belongs to RNA viruses.Coronavirus is that nineteen thirty-seven is from chicken at first Separating with it, the diameter 60-200nm of virion, average diameter is 100nm, spherical in shape or oval, has multiform Property.Virus has peplos, and peplos exists spinous process, and whole virus has obvious difference as corona, the spinous process of different coronavirus. At intracellular inclusion body [the Nederlands Tijdschrift Voor that sometimes can see tubulose of coronavirus infection Geneeskunde,2014,158(158):A8119-A8119]。
Middle East respiratory system syndrome coronavirus (MERS-CoV) is similar with other coronavirus, and its morphosis is circle Shape or oval, virion diameter about 60～220nm, core is single-stranded positive RNA, includes sugar outside the capsid of virus The structure of furcella sample of albumen composition, makes whole virion under Electronic Speculum because it covers surface such as the shape of crown spline, Thus coronavirus of gaining the name.The host of Middle East respiratory system syndrome coronavirus comes from Middle East dromedary camel, its full-length genome Size is about 301Kb, including at least there being 10 open reading frame (open reading frame, ORF), is separately encoded one greatly Replicative enzyme polyprotein, surface spikes glycoprotein, little envelope protein, outer membrane protein, nucleocapsid protein and 5 non-structural proteins White etc..The replicative enzyme polyprotein wherein encoded by ORF1a/ORF1b comprises two polyprotein pp1a and pp1ab, then by Proteolytic cleavage is 15 or 16 non-structural protein product NSP1-NSP16, and NSP12 is the RNA polymerase that RNA relies on [New England Journal of Medicine,2013,369(5):407-416]。
From the second half year in 2012, Saudi Arabia started sporadicly occur suffering from acute respiratory syndrome also at first With the patient of renal failure, pathogen detection shows that these patients are all infected with a kind of new virus.It is non-with widely known Allusion quotation virus belongs to coronavirus together, but type is different, and its infectiousness is weaker than SARS virus, but case fatality rate is higher than SARS, reaches 40%.This After, Jordan, Qatar, the United Arab Emirates, Tunisia or even France, Germany, Britain, the U.S. successively find this disease confirmed cases.The world Health organization is by named for this novel coronavirus " Middle East respiratory system syndrome coronavirus ".It is worth special concern It is, vaccine that this disease is not the most available and drug treatment.For east respiratory system syndrome coronavirus (MERS-CoV) virus drugs research and development aspect, what we soundd out goes to study arbidol hydrochloride anti-MERS-CoV virus function.
Arbidol hydrochloride, it is verified that have antiviral broad-spectrum action [Arbidol:a broad-to multiple virus spectrum antiviral compound that blocks viral fusion.Curr Med Chem.2008,15 (10):997-1005].The mechanism of action of its broad spectrum activity comes from it and there is film fusion inhibitory action [Membrane fusion.Nature Structural&Molecular Biology.2008,15(7):658-64].Effect machine based on him System, it will be assumed that he still has Antiviral mechanism to Middle East respiratory system syndrome coronavirus.So we carry out salt Acid arbidol is at the action oriented research of Middle East respiratory system syndrome coronavirus antiviral drug effect.
Summary of the invention
It is an object of the invention to provide arbidol hydrochloride and in preparation prevention or treat anti-Middle East respiratory system syndrome Application in the medicine of coronavirus.
Specifically, the technical problem of the present invention for solving, adopt the following technical scheme that
The invention provides the arbidol hydrochloride as shown in structure formula (I) and in preparation prevention and treat anti-Middle East breathing system Application in the medicine of system syndrome coronavirus.
Described medicine is the medicine using the arbidol hydrochloride shown in structure formula (I) as effective ingredient.
In above-mentioned application, described medicine is using the arbidol hydrochloride shown in structure formula (I) as effective ingredient Monomeric compound
Described medicine is the arbidol hydrochloride shown in structure formula (I) and pharmaceutically acceptable carrier or excipient.
The dosage form of described medicine is pill, tablet, capsule or oral liquid.
The external half Cytotoxic evaluation model of the compound of the present invention is that the Cytotoxic detection of mtt assay half is evaluated Model.
Mtt assay half Cytotoxic evaluation model of the present invention refers to that use MTT stain can be with living cells line grain Body combines, and detection by quantitative can go out the half cytotoxic concentration (TC50) of cell.
The outer antiviral of the compounds of this invention is administered model and is respectively prevention and is administered model, and therapeutic administratp model and prevention with Treatment mixed model.
Prevention of the present invention covers with 24 holes of monolayer with the medicine that treatment mixed model is doubling dilution with 200 μ L Plate cell plates effect 24 hours.Rear removal medicine, adding 200 μ L virus titers is 100TCID50It is little that the virus liquid of/0.1mL adsorbs two Time, venom of preventing or cure a disease, changes the maintenance culture medium of the medicine of the doubling dilution of 200 μ L, after 48 hours, observation of cell pathological changes, collects disease Venom, tests the TCID of each group50Virus titer, evaluates Drug inhibition rate.
The present invention, by using external three kinds of antiviral drug effect evaluation models, evaluates arbidol hydrochloride compound to the Middle East Respiratory system syndrome coronavirus inhibitory action, finds that Middle East Respirovirus is had antiviral to make by arbidol hydrochloride first With, Middle East respiratory system syndrome coronavirus infection host cell can be blocked, can be used as treating anti-Middle East respiratory system comprehensive Levy the disease treatment in terms of coronavirus infection.
Accompanying drawing explanation
Fig. 1 is arbidol hydrochloride anti-Middle East respiratory system syndrome coronavirus infection model.Cover with monolayer VERO thin The 24 porocyte Slabs of born of the same parents, black hole represents containing hatching virus and medicine effect group, and colourless hole represents without medicine pharmaceutically-active Virus control group, shade string holes represents containing the virus-free drug toxicity group hatched.
Detailed description of the invention
Embodiment 1. drug evaluation principle
Virus amplification
African green monkey kidney cell (VERO) is pressed 3X105Individual/hole, is seeded in 96 orifice plates, puts 37 DEG C, 5%CO2Cultivate, treat Cover with monolayer.The Middle East 100 times of dilutions of respiratory system syndrome coronavirus clinical separation strain are inoculated into and cover with cell monolayer In 96 orifice plates, put 37 DEG C, 5%CO2Cultivate two days (containing Normal group).
Two days later, lesion degree is up to more than 75%, puts-80 DEG C of ultra cold storage freezers, and multigelation once, is collected cell and expanded The virus liquid increased, 3000r/min is centrifuged 30 minutes, goes precipitate, subpackage tubule to put-80 DEG C of ultra cold storage freezers and preserve for a long time.
Middle East respiratory system syndrome coronavirus median lethal titre (TCID50) measure
African green monkey kidney cell (VERO) is pressed 3X105Individual/hole, is seeded in 96 orifice plates, puts 37 DEG C, 5%CO2Cultivate, treat Cover with monolayer.Add the MERS-CoV virus liquid of ten times of doubling dilutions, 100 μ L/ holes, hatch 2 hours or 3000 for 37 DEG C and leave the heart 1 Hour；Supernatant discarded, adds fresh medium, 100 μ L/ holes, observed result after 2 days, records CPE.And count with Reed-Muench Calculate virus median lethal titre (TCID50)[Reed LJ,Muench H.A simple method of estimating fifty percent endpoints.Am J Hyg,1938,27(3):493-497]。
Arbidol hydrochloride anti-Middle East respiratory system syndrome coronavirus evaluating drug effect
96 orifice plate cell monolayers wash 1 time with PBS, add containing about 100TCID50Viral dilution liquid 100 μ L/ hole, 37 DEG C, 5%CO2Hatching in incubator 2 hours, discard virus liquid, add the medicine of 2 times of gradient dilutions, each concentration arranges 4 multiple holes, With maximal non-toxic concentration for medicine initial concentration, at 34 DEG C, 5%CO2Incubator is hatched 2 days.Record cytopathy (Cytopathogenic Effect, CPE).There is CPE by 6 grade standard records (table 1) in cell.After record CPE, contaminate with MTT Color, carries out OD pH-value determination pH.Medicine medium effective concentration (IC is calculated by Reed-Muench method50), calculate therapeutic index (Selective Index, SI): SI=TC50/IC50).[with reference to " pharmacological experimental methodology, Xu Shuyun edits ", therapeutic index (SI) > 1 represents effectively].
Arbidol hydrochloride drug toxicity is evaluated
After arbidol hydrochloride powder dissolves with DMSO, add culture fluid and be diluted to 20mg/mL, DMSO final concentration of 1%, Through the rearmounted 4 DEG C of preservations of 0.22 μm membrane filtration；Filter rearmounted 4 DEG C of preservations.By every hole about 2.5 × 104Cell is inoculated into 96 orifice plates, After 24～48h after cell grows up to monolayer, discard culture fluid, add different dilution medicine 100 μ L/ hole, normal cell pair 100 μ L/ hole MEM, 37 DEG C of 5%CO are added according to hole2Continuing to cultivate 2～5 days, every hole adds MTT solution (5mg/mL) 20 μ L, puts 37 DEG C, 5%CO2Incubator continues hatch 4 hours.Culture supernatant is abandoned in suction, and every hole adds 100 μ L dimethyl sulfoxide (DMSO), low speed Vibrate 10 minutes, make crystal fully melt.Select 490nm wavelength, enzyme linked immunological monitor measures each hole absorbance value. Calculate suppression ratio according to the following formula, and use Reed-Muench method[2]Calculating 50% toxic concentration is the poisonous concentration of medicine half (TC50).Calculate suppression ratio=(normal group-administration group)/normal group × 100%
Arbidol hydrochloride evaluating drug effect
The 24 orifice plate cell plates effect 24 hours of monolayer is covered with the medicine of the doubling dilution of 200 μ L.Rear removal medicine, adds 200 μ L virus titers are 100TCID50The virus liquid of/0.1mL adsorbs two hours, and venom of preventing or cure a disease changes the doubling dilution of 200 μ L The maintenance culture medium of medicine, after 48 hours, observation of cell pathological changes, collect virus liquid, test the TCID of each group50Virus titer, comments Valency Drug inhibition rate.
The experimental result of embodiment 2. arbidol hydrochloride antiviral model
Arbidol hydrochloride drug toxicity is evaluated
After arbidol hydrochloride dissolves with DMSO, it is completely dissolved, achromaticity and clarification, after adding culture fluid filtration, has a little white Color separates out, concussion homogeneous solution clarification.Arbidol hydrochloride is at the half poisonous concentration (TC of African green monkey kidney cell (VERO)50) For (61.3 ± 0.02) μM, maximal non-toxic concentration is 48.25 μMs.
Middle East respiratory system syndrome coronavirus median lethal titre (TCID50) measure
By Reed-Muench methodology, detect that the Middle East respiratory system syndrome coronavirus of amplification is 105.25TCID50/0.1mL。
Arbidol hydrochloride anti-Middle East respiratory system syndrome coronavirus evaluating drug effect
By mdck cell pathological changes suppression method and mtt assay, arbidol hydrochloride is carried out evaluating drug effect, system is breathed in the Middle East The medium effective concentration IC50 of system syndrome coronavirus (MERS-CoV) is respectively 12.82 ± 1.12 μMs, 16.27 ± 1.08 μ M, therapeutic index is 4.78,3.77 respectively, effectively (being shown in Table 1)
Table 1.MDCK cytopathic-effect inhibition assay and mtt assay carry out evaluating drug effect to arbidol
Arbidol hydrochloride anti-Middle East respiratory system syndrome activity of coronavirus is evaluated
Prevention and treatment mixed model, LOGTCID50/ 30 μ L results show, the arbidol hydrochloride of 45.12 μMs of concentration The MERS-CoV virus of supernatant is 0, completely inhibits, and the supernatant of the arbidol hydrochloride of 22.56 μMs, 11.28 μMs concentration is clear The MERS-CoV virus of liquid is respectively 1.38 ± 0.01,3.6 ± 0.02, illustrates that arbidol hydrochloride blocks Middle East respiratory system and combines Simulator sickness coronavirus infection activity, is specifically shown in Table 2.
Table 2 arbidol hydrochloride blocks Middle East respiratory system syndrome coronavirus infection activity

Claims (6)

1. the arbidol hydrochloride as shown in structural formula (1) in preparation prevention and treats the anti-Middle East crown disease of respiratory system syndrome Application in the medicine of poison,
Wherein: wherein HO-representation hydroxy, Br-represents bromine.
Application the most according to claim 1, it is characterised in that described medicine is many with the hydrochloric acid Ah's ratio shown in structure formula (I) You are as the medicine of effective ingredient,
Application the most according to claim 1, it is characterised in that described medicine is that arbidol hydrochloride and pharmacy thereof can be acceptable Salt and pharmaceutically acceptable carrier or excipient.
4. one kind for prevent and treat anti-Middle East breathing syndrome coronavirus pharmaceutical composition, it is characterised in that institute The pharmaceutical composition stated contains the arbidol hydrochloride as shown in formula (I),
Pharmaceutical composition the most according to claim 4, it is characterised in that described pharmaceutical composition is with shown in formula (I) Arbidol hydrochloride as active ingredient,
Pharmaceutical composition the most according to claim 4, it is characterised in that described pharmaceutical composition contains with formula (I) institute The arbidol hydrochloride shown and pharmacy thereof can acceptable salt and pharmaceutically acceptable carrier or excipient.
CN201610421259.2A 2016-06-13 2016-06-13 The application that arbidol hydrochloride prevents in preparation and treats in the medicine of anti-Middle East respiratory system syndrome coronavirus Pending CN106074506A (en)

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CN111387223A (en) * 2020-04-03 2020-07-10 四川知本生物工程有限公司 Arbidol disinfection liquid or gel and preparation method and application thereof
CN113456817A (en) * 2020-03-30 2021-10-01 华东理工大学 DHODH inhibitor of anti-RNA virus medicine and application thereof
CN113769121A (en) * 2020-09-18 2021-12-10 中国原子能科学研究院 Radiotherapeutic medicine for diseases caused by coronavirus or influenza virus and preparation method thereof

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113456817A (en) * 2020-03-30 2021-10-01 华东理工大学 DHODH inhibitor of anti-RNA virus medicine and application thereof
CN113456817B (en) * 2020-03-30 2024-05-10 华东理工大学 DHODH inhibitor of anti-RNA virus drug and application thereof
CN111387223A (en) * 2020-04-03 2020-07-10 四川知本生物工程有限公司 Arbidol disinfection liquid or gel and preparation method and application thereof
CN113769121A (en) * 2020-09-18 2021-12-10 中国原子能科学研究院 Radiotherapeutic medicine for diseases caused by coronavirus or influenza virus and preparation method thereof
CN113769121B (en) * 2020-09-18 2022-10-28 中国原子能科学研究院 Radiotherapeutic medicine for diseases caused by coronavirus or influenza virus and preparation method thereof

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Application publication date: 20161109