CN103690522B - Application of nafronyloxalate in preparing medicine for treating or preventing influenza virus - Google Patents
Application of nafronyloxalate in preparing medicine for treating or preventing influenza virus Download PDFInfo
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Abstract
The invention discloses application of nafronyl oxalate in preparing a medicine for preventing or treating influenza virus. According to the application, first, the cytotoxicity of nafronyl oxalate to MDCK (madin-darby canine kidney) cells is detected, and results indicate that CC50 (50% cytotoxic concentration) of the nafronyl oxalate is 238.1mu M; secondly, nafronyl oxalate with non-cytotoxic concentration is selected to be subjected to anti-virus experiments, and results indicate that the small molecular compound has a remarkable anti-virus activity and is related to dose dependence; finally, the anti-virus activity of the nafronyl oxalate to different types and sub-type influenza viruses is detected, and results indicate that nafronyl oxalate can be used for inhibiting replication of all detected virus strains and has a dose dependent effect, and the anti-virus activity of the nafronyl oxalate has a certain broad-spectrum. Therefore, the nafronyl oxalate can be used as a novel anti-virus medicine for developing, and a novel way and means is provided to influenza treatment.
Description
Technical field
The present invention relates to the application of a kind of naftidrofuryl oxalate in preparation treatment or flu-prevention virus drugs, 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 surfaces of viral particles the identification of HA furcella and in conjunction with host cell surface contain 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.Different from other RNA viruses, copying and transcribing of influenza virus gene group all occurs in the nucleus of host cell.MRNA transfers to endochylema after synthesizing in core, the structural protein of synthesis virus and non-structural protein.Then start to assemble progeny virus, the glycoprotein of neuraminidase hydrolyzable cell 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 is popular in the mankind have propagated more than 300 year, and the several years, namely once fulminant was popular, and many decades is then once global to be very popular.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 medicine has the toxic and side effects such as neurotoxicity, and makes persister ubiquity owing to widely using, 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 is but constantly in the news.Therefore, also development of new anti-influenza virus medicament is significant in research.
Naftidrofuryl oxalate (Nafronyl oxalate), have another name called nafronyl oxalate (Nafronyl oxalate salt), chemistry alpha-(1-menaphthyl)-2-oxolane propanoic acid diethylin ethyl ester oxalates (alpha-(1-Naphthylmethyl)-2-tetrahydrofuranpropionic acid diethylaminoethyl ester oxalate) by name.Be mainly used in clinically treating ischemic cerebral vascular, peripheral blood vessel, as unexpected in acute and subacute ischemic cerebral vascular (cerebral infarction, cerebral embolism), stroke in convalescent stage, cerebral ischaemia, intermittence and chronic insufficient cerebral blood supply, alzheimer disease, and intermittent claudication, leg pain and early stage gangrenous, diabetes that peripheral angiopathy causes cause the lower limb ischemia etc. that stricture of artery causes.As a kind of 5-HT
2receptor antagonist, its pharmacological action mainly through with the 5-HT in platelet
2receptors bind, anticoagulant, improves red cell deformability, reduces blood viscosity, thus improves microcirculation; In addition, naftidrofuryl oxalate can also increase cellular metabolism effect, and ATP output is increased, for cell provides more energy to improve the aerobic metabolism of brain and blood vessel.But so far, do not find any relevant report about naftidrofuryl oxalate resisiting influenza virus.
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 naftidrofuryl oxalate in preparation treatment or flu-prevention virus drugs, thus provide the micromolecular compound that a kind of safe and efficient toxic and side effects is little for the treatment of influenza clinically.Naftidrofuryl oxalate 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.
The English of naftidrofuryl oxalate is called Nafronyl oxalate, and chemistry alpha-(1-menaphthyl)-2-oxolane propanoic acid diethylin ethyl ester oxalates by name, has the structure shown in structural formula I:
Structural formula I
In order to realize above-mentioned object, the technical solution used in the present invention is:
The application of a kind of naftidrofuryl oxalate in preparation treatment or flu-prevention virus (A type or B-mode) medicine, the steps include:
naftidrofuryl oxalate is to the toxicity test of mdck cell:mdck cell is by 8 × 10
3individual cells/well is inoculated in 96 porocyte culture plates, after cell attachment, respectively with 4.03 μMs, 8.06 μMs, 16.125 μMs, 31.25 μMs, 62.5. μM, 125.0 μMs, 250.0 μMs and 300.0 μMs naftidrofuryl oxalate process, often organize repetition two holes, be placed in 37 DEG C, 5% CO
2cultivate in incubator after 48 hours, Alamarblue method detects the survival rate of cell.Result shows, and naftidrofuryl oxalate is to the CC of MDCK
50(median lethal concentration) is about 238.1 μMs.
naftidrofuryl oxalate is to the evaluation of 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
50/ hole virus liquid (A/PuertoRico/8/34(H1N1)) infection cell, get each experimental port supernatant after adding each Concentraton gradient medicine simultaneously totally 200 μ l cell maintenance mediums (DMEM+0.3%BSA+2.5 μ g/L pancreatin) cultivating 48h in 37 DEG C of cell culture incubators and carry out neuraminidase activity detection.Result display naftidrofuryl oxalate can obviously suppress copying of influenza virus, its EC
50it is 12.5 μMs.
naftidrofuryl oxalate is analyzed resisiting influenza virus broad spectrum 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, 100TCID
50/ hole virus liquid (is respectively A/Human/Hubei/1/2009 (H1N1), A/human/Hubei/3/2005 (H3N2), A/WSN/ S31N (H1N1), A/Duck/Hubei/5/2010 (H6N6), A/Duck/Hubei/216/1983 (H7N8), A/Chicken/Jiangsu/1/2005 (H9N2), B/human/Huber/1/2007) infection cell, get each experimental port supernatant after adding each Concentraton gradient medicine simultaneously totally 200 μ l cell maintenance mediums (DMEM+0.3%BSA+2.5 μ g/L pancreatin) cultivating 48h in 37 DEG C of cell culture incubators and carry out neuraminidase activity detection.Result display naftidrofuryl oxalate obviously 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, and all has dose-dependent effect.
The present invention compared with prior art, has the following advantages and effect:
1. naftidrofuryl oxalate is micromolecular compound, its CC
50(median lethal concentration) is 238.1 μMs.Naftidrofuryl oxalate can copy by dose-dependent suppression influenza virus, its EC
50(half-inhibition concentration) is 12.5 μMs.Selection index (SI) is about 19.0.And naftidrofuryl oxalate has had the application of many decades clinically, safety is good.This illustrates that naftidrofuryl oxalate is the medicine of the efficient resisiting influenza virus of low toxicity.
2. naftidrofuryl oxalate 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, there is the antiviral activity of very wide spectrum.
3. utilize modern common drug preparation means, naftidrofuryl oxalate 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 a kind of naftidrofuryl oxalate chemical structural formula.
Fig. 2 is that a kind of naftidrofuryl oxalate cytotoxicity detects schematic diagram.
Fig. 3 is neuraminidase activity schematic diagram in a kind of naftidrofuryl oxalate process influenza infection cell culture supernatant.
Fig. 4 is that a kind of naftidrofuryl oxalate 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/WSN/S31N (H1N1));
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/Huber/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 cell culture screening method to detect naftidrofuryl oxalate infected by influenza infection mdck cell, based on the detection quantitative analysis naftidrofuryl oxalate anti-influenza virus activity to neuraminidase activity in supernatant.
Embodiment 1: the evaluation of naftidrofuryl oxalate anti-influenza virus activity
1. experiment material
1.1 cells, virus and medicine
Mdck cell purchased from ATCC, viral A/PuertoRico/8/34(H1N1) by chick embryo culture increase obtain, naftidrofuryl oxalate is purchased from Sigma company.
1.2 experimental apparatus
Multi-tester PerkinElmer, inverted microscope Costar.
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 inspection of 2.3 naftidrofuryl oxalates: mdck cell is by 8 × 10
3cells/well (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 4.03 μMs, 8.06 μMs, 16.125 μMs, 31.25 μMs, 62.5. μM, 125.0 μMs, 250.0 μMs and 300.0 μMs of totally 8 gradients preparations, the multiple hole of every gradient 2.Discard culture supernatant after cultivating 48h, in every hole, add the new DMEM culture medium that 100 μ l contain 10% Alamarblue reagent, put in cell culture incubator after continuing to cultivate 1h, 1h and measure fluorescence and light absorption value respectively with multi-tester, calculate cell survival rate.
Result display (Fig. 2) naftidrofuryl oxalate does not have cytotoxicity completely to mdck cell within the scope of 125.0 μMs, and illustrate that naftidrofuryl oxalate has the safer scope of application, namely the dosage of naftidrofuryl oxalate is 1.6 ~ 100 μMs according to cell experiment consumption.
2.4 detect the activity of naftidrofuryl oxalate anti-A/PuertoRico/8/34 (H1N1) Strain based on neuraminidase activity
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 change of fluorescence intensity, can sensitive reaction neuraminidase activity, thus can viral load in reacting cells 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 each Concentraton gradient medicine (with 100 μMs for initial concentration simultaneously, continuous 2 times of gradient dilutions 8 gradients, the multiple hole of every gradient two) get each experimental port supernatant after totally 200 μ l maintain liquid (DMEM+0.3 %BSA+2.5ug/L pancreatin) cultivate 48h in 37 DEG C of cell culture incubators and carry out neuraminidase activity detection.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, multi-tester measures fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
2.4.4. the suppressed rate of NA in each detect aperture is calculated.Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result shows: naftidrofuryl oxalate obviously inhibits influenza virus to copy, and in dose-dependence (see Fig. 3).
Embodiment 2: the evaluation of naftidrofuryl oxalate resisiting influenza virus broad spectrum activity
This experiment detects the antiviral activity of naftidrofuryl oxalate 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. experiment uses Strain to comprise: A/Human/Hubei/1/2009 (H1N1), A/human/Hubei/3/2005 (H3N2), A/WSN/S31N (H1N1), A/Duck/Hubei/5/2010 (H6N6), A/Duck/Hubei/216/1983 (H7N8), A/Chicken/Jiangsu/1/2005 (H9N2), B/human/Huber/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 each Concentraton gradient medicine (with 100 μMs for initial concentration simultaneously, continuous 2 times of gradient dilutions 6 gradients, the multiple hole of every gradient two) get each experimental port supernatant after totally 200 μ l maintain liquid (DMEM+0.3 %BSA+2.5ug/L pancreatin) cultivate 48h in 37 DEG C of cell culture incubators and carry out neuraminidase activity detection.
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 suppressed rate of NA in each detect aperture.Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100% result display: naftidrofuryl oxalate obviously inhibits various strain influenza virus to copy, and in dose-dependence (see Fig. 4).
Claims (3)
1. a naftidrofuryl oxalate and the application of alpha-(1-menaphthyl)-2-oxolane propanoic acid diethylin ethyl ester oxalates in preparation treatment or flu-prevention virus drugs; 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 alpha-(1-menaphthyl)-2-oxolane propanoic acid diethylin ethyl ester oxalates as active constituents of medicine, makes the pharmaceutically acceptable dosage form of any one.
3. application according to claim 2, is characterized in that: described dosage form is tablet, capsule, granule, oral liquid, slow releasing preparation, controlled release preparation or injection.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101394854A (en) * | 2006-03-09 | 2009-03-25 | 皮埃尔法布雷医药公司 | Novel use of antihistamine agents for the preventive or early treatment of inflammatory syndromes, in particular those triggered by togaviruses |
| WO2012032360A2 (en) * | 2010-09-10 | 2012-03-15 | Helperby Therapeutics Limited | Novel use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101394854A (en) * | 2006-03-09 | 2009-03-25 | 皮埃尔法布雷医药公司 | Novel use of antihistamine agents for the preventive or early treatment of inflammatory syndromes, in particular those triggered by togaviruses |
| WO2012032360A2 (en) * | 2010-09-10 | 2012-03-15 | Helperby Therapeutics Limited | Novel use |
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