CN103720687B - The application of dicoumarol in the medicine preparing treatment or flu-prevention viral infection - Google Patents
The application of dicoumarol in the medicine preparing treatment or flu-prevention viral infection Download PDFInfo
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- CN103720687B CN103720687B CN201310666890.5A CN201310666890A CN103720687B CN 103720687 B CN103720687 B CN 103720687B CN 201310666890 A CN201310666890 A CN 201310666890A CN 103720687 B CN103720687 B CN 103720687B
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Abstract
The invention discloses dicoumarol (Dicoumarol) prevent in preparation or treat the application in the medicine of influenza infection.First have detected the toxicity of dicoumarol to mdck cell, the maximal non-toxic concentration of result display dicoumarol is 50.0 μMs.Secondly, in the concentration range of totally nontoxic, determine the antiviral activity of dicoumarol, result shows this micromolecular compound and has significant antiviral activity, and antivirus action is dose-dependent effect.Finally, have detected the antiviral activity of dicoumarol to the influenza virus of different shaped and hypotype, result display dicoumarol can suppress copying of all detected strains of influenza viruses in dose-dependant ground, shows that the anti-influenza virus activity of dicoumarol has broad spectrum activity.Therefore, the present invention discloses dicoumarol is a kind of New-type wide-spectrum anti-influenza virus medicament, may be used for the medicine preparing prevention or treatment influenza infection.
Description
Technical field
The present invention relates to the application of dicoumarol in the medicine preparing treatment or flu-prevention viral infection, belong to medical art.
Background technology
Influenza virus belongs to orthomyxoviridae family (Orthomyxoviridae), Influenza Virus.According to virion nucleoprotein (NP) and the antigenic characteristic of stromatin (M) and the difference of genetic characteristics, influenza virus is divided into A, B, C tri-type, also claims first, second, the third three types.Influenza A full-length genome is made up of the sub-thread strand RNA that 8 differ in size, and names respectively with sections 1 to sections 8.Full length viral genome about 13.6 kb, encode 10 kinds of structural protein (PB2, PB1, PA, HA, NP, NA, M1, M2, PB1-F2 and NS2/NEP) and non-structural protein (NS1).According to the difference of virion surface glycoprotein hemagglutinin (HA) and neuraminidase (NA), influenza A can be further divided into 17 H (H1-H17) and 10 N (N1-N10) hypotypes.Human influenza virus is H1, H2 and H3 hypotype mainly.And endanger serious high pathogenic avian influenza at present and mostly be H5, H7 and H9 hypotype, wherein the highest with the fatality rate of H5N1 hypotype.Type B influenza virus often causes influenza localized epidemics, does not cause worldwide influenza great outburst, only finds in people and sea dog.C type influenza virus exists mainly with being dispersed in form, and primary attack infant, does not generally cause influenza pandemic, can infect the mankind and pig.
The whole biocycle of influenza virus needs to complete in Cytoplasm and nucleus.Infect initial be the furcella HA of surfaces of viral particles identify and in conjunction with host cell surface containing sialic receptor.The connecting key of sialic acid and time terminal galactose, determine the host specificity of virus, this connecting key is α (2-3) in birds, is α (2-6) in the mankind.After virus absorption onto cell, cell takes in virus by the receptor-mediated pinocytosis of clathrin.In cell, clathrin molecular dissociation, virus and endosome merge and form phagosome, make the pH value around virion drop to about 5.0.Under this pH condition, the conformation of viral HA protein changes, and the fusogenic peptide being positioned at light chain (HA2) N end is exposed, thus causes virus envelope and cell membrane fusion.Low pH environment also causes a large amount of H
+enter virion inside via M2 ion channel, cause dissociating of M1 albumen and vRNPs.Both common results cause the vRNPs of virion to be discharged into the endochylema of infected cell.VRNPs forwards to subsequently in nucleus and carries out genomicly copying and transcribing, when copying virus first with self RNA for templated synthesis complementary RNA (cRNA), be then template resynthesis vRNA with cRNA.The mRNA transcribing generation transfers to endochylema by core, translates structural protein and the non-structural protein of virus.Part synthetic proteins is assembled into vRNP as NP needs again to transfer to vRNA in core with newly-generated, start to be assembled into new virion with remaining virus protein after vRNP goes out core, newly-generated progeny virus is by the glycoprotein on neuraminidase (NA) hydrolyzed cellular surface, release N-acetyl-neuraminate, impels virion to discharge from site of sprouting.The final step of virus maturation is that HA is cracked into HA1 and HA2 polypeptide under the effect of host protein enzyme, and such virion just has infectivity, thus starts copying of new round virus.
Influenza virus has been caused in the world and is very popular for five times since 20 beginnings of the century found, within about 10 years, can produce an outbreak of epidemic, cause huge loss in the world.Influenza pandemic can cause 250,000 ~ 500,000 examples dead every year, 3,000,000 ~ 5,000,000 severe disease examples, the whole world about have 5 ~ 15% people infected.Vaccination and use antiviral drugs to be the important means of reply flu outbreak, however due to influenza antigen variation ability strong, substantially can not large-scale production vaccine before being very popular.At present, the anti-influenza virus medicament ratifying official listing through food and drug administration (FDA) has two classes: the M2 ion channel blocking agent that (1) is representative with amantadine and rimantadine.This type of medicine only has preventive and therapeutic action to influenza A virus, and research shows that this type of medicine has the toxic and side effects such as neurotoxicity, and due to the ubiquity of persister, so CDC advises that this type of medicine is not used further to flu-prevention viral infection.(2) neuraminidase inhibitor, the representative of this type of medicine is oseltamivir and Zha La meter Wei.This type of medicine to all known human influenza viruses and high pathogenic avian influenza virus all effective.But the persister in recent years about oseltamivir but constantly has report.Therefore, also development of new anti-influenza virus medicament is significant in research.
Dicoumarol, English by name Dicoumarol or dicumarol, domestic goods are called dicoumarin, are Coumarins anticoagulant, clinically generally normal together with heparin for deep venous thrombosis.Chemical constitution and the vitamin K of dicoumarol are similar, and by the utilization of competitive inhibition liver to vitamin K, and then interference liver is to the normal synthesis of thrombin, and plays blood coagulation resisting function.Often use as reductase inhibitor in biochemical test.At present, dicoumarol causes disease report at resisiting influenza virus and treatment influenza infection is not seen.The structural formula of dicoumarol is as follows:
Summary of the invention
The object of the invention is to make up the deficiencies in the prior art, be there are provided the application of a kind of micromolecular compound dicoumarol in preparation treatment or flu-prevention virus infective medicament, thus provide one micromolecular compound safely and effectively for the treatment of influenza clinically.Dicoumarol can effectively suppress copying of influenza virus within the scope of avirulence, can be developed as the medicine for the treatment of or flu-prevention virus infection further, be with a wide range of applications.
In order to realize above-mentioned object, the technical solution used in the present invention is:
The application of dicoumarol in the medicine that preparation is treated or flu-prevention virus (A type or B-mode) infects, the steps include:
dicoumarol is to the toxicity test of mdck cell:madin-Darby canine kidney(cell line) (MDCK) is by 8 × 10
3individual cells/well is inoculated in 96 porocyte culture plates, after cell attachment, process with the dicoumarol of 1.6 μMs, 3.125 μMs, 6.25 μMs, 12.5 μMs, 25.0 μMs, 50.0 μMs, 100.0 μMs and 150.0 μMs respectively, often organize repetition two holes, be placed in 37 DEG C, 5% CO
2cultivate in incubator after 48 hours, Alamarblue detects the survival rate of cell.Result shows, and dicoumarol is to the CC of MDCK
50(median lethal concentration) is 150.7 μMs.
the evaluation of dicoumarol anti-influenza virus activity:by mdck cell according to 1.5 × 10
4cells/well is inoculated in 96 Tissue Culture Plates, 37 DEG C, 5% CO
2cultivating 18-24h in cell culture incubator grows up to after monolayer until cell, uses 100TCID
50the influenza virus liquid (A/PuertoRico/8/34(H1N1) in/hole) infection cell, the medicine simultaneously adding each gradient concentration, in the cell maintenance medium (DMEM+0.3%BSA+2.5 μ g/L pancreatin) of cumulative volume totally 200 μ l, gets detection that each experimental port supernatant carry out neuraminidase expression after cultivating 48h in cell culture incubator in 37 DEG C.Result display dicoumarol can suppress copying of influenza virus, its EC in dose-dependant ground
50(medium effective concentration) is 12.4 μMs.
the broad spectrum activity analysis of dicoumarol resisiting influenza virus effect:by mdck cell according to 1.5 × 10
4cells/well is inoculated in 96 Tissue Culture Plates, 37 DEG C, 5% CO
2cultivate 18-24h in cell culture incubator and after growing up to monolayer, use 100TCID
50the influenza virus liquid in/hole (is respectively A/Human/Hubei/1/2009 (H1N1), A/human/Hubei/3/2005 (H3N2), A/human/WSN/33/ (H1N1, S31N), A/Duck/Hubei/5/2010 (H6N6), A/Duck/Hubei/216/1983 (H7N8), A/Chicken/Jiangsu/1/2005 (H9N2), B/human/Hubei/1/2007) infection cell, the medicine simultaneously adding each gradient concentration is in the cell maintenance medium (DMEM+0.3%BSA+2.5 μ g/L pancreatin) of cumulative volume totally 200 μ l, the detection that each experimental port supernatant carries out neuraminidase expression is got cultivate 48h in 37 DEG C in cell culture incubator after.Result display dicoumarol can dose-dependent suppression influenza A subtype H1N1 strain, subtypes of influenza A virus H3N2 strain, subtypes of influenza A virus H1N1 amantadine persister, subtypes of influenza A virus H6N6 strain, subtypes of influenza A virus H7N8 strain, the copying of subtypes of influenza A virus H9N2 strain and Influenza B virus.
The present invention compared with prior art, has the following advantages and effect:
1. dicoumarol is micromolecular compound, its CC
50(median lethal concentration) is 150.7 μMs.Dicoumarol can copy by dose-dependent suppression influenza virus, its EC
50(medium effective concentration) is 12.4 μMs.Selection index (SI) is about 12.2.And dicoumarol has had the application of many decades clinically, safety is good.This illustrates that dicoumarol is the medicine of resisiting influenza virus safely and effectively.
2. dicoumarol can suppress influenza A subtype H1N1 strain, subtypes of influenza A virus H3N2 strain, subtypes of influenza A virus H1N1 amantadine persister, subtypes of influenza A virus H6N6 strain, subtypes of influenza A virus H7N8 strain, the copying of subtypes of influenza A virus H9N2 strain and Influenza B virus in dose-dependant ground, has the anti-influenza virus activity of very wide spectrum.
3. utilize modern common drug preparation means, dicoumarol can be made the pharmaceutically acceptable dosage forms of any one such as tablet, capsule, granule, oral liquid, slow releasing preparation, controlled release preparation, nanometer formulation or injection as active component.
Accompanying drawing explanation
Fig. 1 is dicoumarol chemical structural formula.
Fig. 2 is that dicoumarol cytotoxicity detects schematic diagram.
Fig. 3 is that dicoumarol dose-dependant suppresses influenza virus levels of replication schematic diagram.
Fig. 4 is that dicoumarol anti-influenza virus activity broad spectrum activity detects schematic diagram:
Fig. 4 A is subtypes of influenza A virus H1N1 strain (A/Human/Hubei/1/2009 (H1N1));
Fig. 4 B is subtypes of influenza A virus H3N2 strain (A/human/Hubei/3/2005 (H3N2));
Fig. 4 C is subtypes of influenza A virus H1N1 amantadine persister (A/human/WSN/33/ (H1N1, S31N));
Fig. 4 D is subtypes of influenza A virus H6N6 strain (A/Duck/Hubei/5/2010 (H6N6));
Fig. 4 E is subtypes of influenza A virus H7N8 strain (A/Duck/Hubei/216/1983 (H7N8));
Fig. 4 F is subtypes of influenza A virus H9N2 strain (A/Chicken/Jiangsu/1/2005 (H9N2));
Fig. 4 G is Influenza B virus (B/human/Hubei/1/2007).
Specific embodiments
In order to understand content of the present invention better, below in conjunction with specific implementation method, content of the present invention is described further, but protection content of the present invention is not limited to following examples.
At present, anti-influenza virus medicament in-vitro screening model is divided into the cell free system screening model of cell culture model and viral enzyme.Enzyme reaction screening model has high-throughout feature, but the compound of screening still needs to carry out more cytology, histology and toxicity in vivo, effect experiment etc. to determine its effect.Cell culture model is the most frequently used screening model, its advantage is: the cell that a large amount of hereditary character can be provided identical is object of study, easy to operate, can eliminate the impact of other extraneous factor, and can the valid density of detection of drugs and therapeutic index, for later stage study mechanism provides more how basis.The present invention adopts mdck cell to cultivate screening method and detects the impact that dicoumarol infected by influenza infects, based on to the detection of neuraminidase expression representing influenza virus levels of replication in supernatant, and the anti-influenza virus activity of quantitative analysis dicoumarol.
Embodiment 1: the evaluation of dicoumarol anti-influenza virus activity
1. experiment material
1.1 cells, virus and medicine
Mdck cell purchased from American Type DSMZ (ATCC); Strain: A/PuertoRico/8/34(H1N1); Medicine: dicoumarol is purchased from Sigma company.
1.2 experimental apparatus
Multiple labeling microtiter plate reader (Perkin Elmer).
2. experimental technique and result
2.1 cell culture: 37 DEG C, 5% CO
2cultivate in humidified incubator.Use containing the penicillin of 10%FBS, 100U/mL and the DMEM culture medium of streptomycin.Go down to posterity after cell to 90% degree of converging, the ratio that goes down to posterity 1/3 – 1/4.
2.2 Virus culture: get 9 ~ 11 age in days SPF Embryo Gallus domesticus, use Egg checker inspection before virus inoculation, and at the position mark away from embryo, sterilize and punch rear by 0.2ml/ piece of inoculation 2-
4the virus liquid of hemagglutinative titer, with nial polish sealing, puts 37 DEG C of calorstats and hatches 48h(and inoculate Embryo Gallus domesticus dead after 24h to be generally misoperation lethal, abandon it).Take out Embryo Gallus domesticus and put 4 DEG C of cold embryo 12h.75% alcohol disinfecting chick embryo air sac, sterile working cuts off air chamber shell, and capillary pipette draws chick embryo allantoic liquid and amniotic fluid, 3000rpm 4 DEG C of centrifugal 30min, and detect hemagglutinative titer, 200 μ l/ pipe subpackage juxtapositions-70 DEG C are frozen for subsequent use.
The cytotoxicity of 2.3 dicoumarols detects: mdck cell is by 8 × 10
3cells/well (volume 100 μ l) is inoculated in 96 porocyte culture plates, for subsequent use after cell attachment; With cell maintenance medium (DMEM+2% serum) by medicine according to 1.6 μMs, 3.125 μMs, 6.25 μMs, 12.5 μMs, 25.0 μMs, 50.0 μMs, 100.0 μMs and 150.0 μMs totally 8 gradient concentrations preparations, each gradient concentration establishes 2 multiple holes.Culture supernatant is discarded after cultivating 48h, the new DMEM culture medium that 100 μ l contain 10% Alamarblue reagent is added in every hole, put in cell culture incubator after continuing to cultivate 1h, 1h and measure fluorescence intensity and light absorption value respectively with microtiter plate reader, calculate cell survival rate.
Result (Fig. 2) shows in the concentration range of dicoumarol below 50.0 μMs does not have cytotoxicity completely to mdck cell.In the present embodiment, the dosage scope of dicoumarol cellular level Antiviral breeding is 0.4 ~ 50.0 μM, is in safety non-toxic concentration range completely.
The antiviral activity of 2.4 dicoumarol infected by influenza strains A/PuertoRico/8/34 (H1N1)
2.4.1. experimental principle: MUNANA(4-methylumbelliferyl-α-N-acetyl-neuraminate) be the specific substrate of influenza neuraminidase, the catalysate produced under neuraminidase effect is under 355nm excitation light irradiation, 460nm fluorescence can be produced, the power of fluorescence intensity represents the number of neuraminidase expression, reflects the virus quantity in cultured cell supernatant.
2.4.2. mdck cell is pressed 1.5 × 10
4cells/well is inoculated in 96 porocyte culture plates, after cultivating 14 ~ 18h, grows up to after monolayer for subsequent use until cell in 37 DEG C of cell culture incubators.Culture medium in orifice plate discarded, PBS liquid washes twice, adds 100TCID
50/ hole (100 μ l) virus liquid infection cell, add the medicine of each gradient concentration (with 50.0 μMs for initial concentration simultaneously, continuous 2 times of gradient dilutions 6 gradients, every gradient two is hole again) be in the cell maintenance culture solution (DMEM+0.3 %BSA+2.5ug/L pancreatin) of 200 μ l to cumulative volume, in cell culture incubator, get the detection that each experimental port supernatant carries out neuraminidase expression after 37 DEG C of cultivation 48h.Setup Experiments blank group, positive controls (ribavirin), negative control group (without drug treating after viral infection) and Experimental agents group.
2.4.3. 40 μ l buffer (32.5mmol/L MES, pH 6.5,4mmol/L CaCl is added in the micro plate of black 96 hole
2) the substrate 20umol/L MUNANA for preparing, add each experimental port culture supernatant 20 μ l again, 37 DEG C of lucifuges hatch 60min, add reaction terminating liquid (0.014 μM of NaOH, 83% ethanol) 100 μ l/ holes, micropore is read plate instrument to measure fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
2.4.4. the suppression ratio that each detect aperture Chinese medicine infected by influenza copies is calculated
Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result shows: dicoumarol obviously inhibits influenza virus to copy, and in dose-dependence (see Fig. 3).
Embodiment 2: the evaluation of dicoumarol resisiting influenza virus effect broad spectrum activity
This experiment detects the antiviral activity of dicoumarol to influenza A subtype H1N1 strain, subtypes of influenza A virus H3N2 strain, subtypes of influenza A virus H1N1 amantadine persister, subtypes of influenza A virus H6N6 strain, subtypes of influenza A virus H7N8 strain, subtypes of influenza A virus H9N2 strain and Influenza B virus.
1. the Strain that experiment uses comprises: A/Human/Hubei/1/2009 (H1N1), A/human/Hubei/3/2005 (H3N2), A/human/WSN/33/ (H1N1, S31N), A/Duck/Hubei/5/2010 (H6N6), A/Duck/Hubei/216/1983 (H7N8), A/Chicken/Jiangsu/1/2005 (H9N2), B/human/Hubei/1/2007.
2. mdck cell is pressed 1.5 × 10
4cells/well is inoculated in 96 porocyte culture plates, after cultivating 14 ~ 18h, grows up to after monolayer for subsequent use until cell in 37 DEG C of cell culture incubators.Culture medium in orifice plate discarded, PBS liquid washes twice, adds 100TCID
50/ hole (100 μ l) virus liquid infection cell, add the medicine of each gradient concentration (with 50.0 μMs for initial concentration simultaneously, continuous 2 times of gradient dilutions 6 gradients, the multiple hole of every gradient two) to cumulative volume be in 200 μ l maintain liquid (DMEM+0.3 %BSA+2.5ug/L pancreatin), in cell culture incubator 37 DEG C cultivate 48h after get the detection that each experimental port supernatant carries out neuraminidase expression.
3. in the micro plate of black 96 hole, add 40 μ l buffer (32.5mmol/L MES, pH 6.5,4mmol/L CaCl
2) the substrate 20umol/L MUNANA for preparing, add each experimental port culture supernatant 20 μ l again, 37 DEG C of lucifuges hatch 60min, add reaction terminating liquid (0.014 μM of NaOH, 83% ethanol) 100 μ l/ holes, multi-tester measures fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
4. calculate the suppression efficiency that each detect aperture Chinese medicine infected by influenza copies
Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result show: dicoumarol be dose-dependant inhibit copying (see Fig. 4) of various Influenza virus strain.
Claims (3)
1. the application of dicoumarol in preparation treatment or flu-prevention virus infective medicament; Described influenza virus is influenza A virus or Influenza B virus.
2. apply as claimed in claim 1, it is characterized in that: described medicine is using dicoumarol as active constituents of medicine, make the pharmaceutically acceptable dosage form of any one.
3. apply as claimed in claim 2, it is characterized in that: described dosage form is tablet, capsule, granule, oral liquid or injection.
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| Hui-Chen Hung, et al.Development of an Anti-Influenza Drug Screening Assay Targeting Nucleoproteins with Tryptophan Fluorescence Quenching.《Analytical Chemistry》.2012,6391-6399. * |
| 凌云,等.双香豆素类化合物的合成及表征.《化学通报》.2004,(第5 期),355-358. * |
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