CN103893162B - The application of proadifen in preparation treatment or flu-prevention virus infective medicament - Google Patents
The application of proadifen in preparation treatment or flu-prevention virus infective medicament Download PDFInfo
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Abstract
The present invention relates to medical art, specifically disclose the application of a kind of proadifen in preparation treatment or flu-prevention virus infective medicament.First the present invention have detected the toxicity of proadifen to mdck cell, and the maximal non-toxic concentration of result display proadifen is 50.0 μMs; Secondly, in the concentration range of totally nontoxic, determine the antiviral activity of proadifen, result shows this micromolecular compound and has significant antiviral activity, and antivirus action is dose-dependent effect; Finally, have detected the antiviral activity of proadifen to the influenza virus of different subtype, result display proadifen can suppress copying of all detected strains of influenza viruses in dose-dependant ground, shows that the anti-influenza virus activity of proadifen has broad spectrum activity.Therefore, it is a kind of New-type wide-spectrum anti-influenza virus medicament that the present invention discloses proadifen first, may be used for the medicine preparing prevention or treatment influenza infection.
Description
Technical field
The present invention relates to medical art, be specifically related to the application of a kind of proadifen in preparation treatment or flu-prevention virus infective medicament.
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 is about 13.6kb, 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 really constantly there is report about oseltamivir persister in recent years.Therefore, also development of new anti-influenza virus medicament is significant in research.
Proadifen (Proadifen), or proadifen hydrochloride, have another name called Proadifen hydrochloride.English another name SKF-525AHydrochloride.As cell chromatograph P450 enzyme inhibitor, metabolic pathway can be competed and cause drug metabolism enzyme suppressed.The use that absorbs the drug is helped clinically as one.So far, any relevant report about proadifen resisiting influenza virus is not found.
Summary of the invention
The object of the invention is to make up the deficiencies in the prior art, the application of a kind of micromolecular compound proadifen in preparation treatment or flu-prevention virus infective medicament is provided, thus provides one micromolecular compound safely and effectively for the treatment of influenza clinically.Proadifen 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 prove the feasibility of proadifen in preparation treatment or flu-prevention virus infective medicament, this invention takes following experiment and verifying:
Proadifen 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, processes with 250.0 μMs of proadifens amounting to 8 gradients according to 2 gradient dilutions for maximum concentration, often organizes repetition two holes, is placed in 37 DEG C, 5%CO
2cultivate in incubator after 48 hours, Alamarblue method detects the survival rate of cell.Result shows, and proadifen is to the CC of MDCK
50(median lethal concentration) is about 107.4 μMs.
The evaluation of proadifen anti-influenza virus activity: by mdck cell according to 1.5 × 10
4cells/well is inoculated in 96 porocyte culture plates, 37 DEG C, 5%CO
2cultivate in cell culture incubator.After 18-24h, use 100TCID
50virus liquid (A/PuertoRico/8/34(H1N1)) infection cell, add variable concentrations gradient medicine simultaneously.Cell is got each experimental port supernatant and is carried out neuraminidase activity detection cultivate 48h in 37 DEG C of cell culture incubators after.Result display proadifen can obviously suppress copying of influenza virus, its IC
50it is 15.4 μMs.
Proadifen resisiting influenza virus broad spectrum activity is analyzed: by mdck cell according to 1.5 × 10
4cells/well is inoculated in 96 Tissue Culture Plates, 37 DEG C, 5%CO
2cultivate in cell culture incubator.After 18-24, use 100TCID
50virus liquid (being respectively A/human/Hubei/3/2005 (H3N2), A/WSN/S31N (H1N1), A/Duck/Hubei/5/2010 (H6N6), A/Duck/Hubei/216/1983 (H7N8)) infection cell, adds each Concentraton gradient medicine simultaneously.Cell is got each experimental port supernatant and is carried out neuraminidase activity detection cultivate 48h in 37 DEG C of cell culture incubators after.Result display proadifen obviously can suppress 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, and all has dose-dependent effect.
The present invention compared with prior art, has the following advantages and effect:
1. proadifen is micromolecular compound, its CC
50(median lethal concentration) is 107.4 μMs.Proadifen can suppress influenza virus to be copied in dose-dependant ground, its IC
50(half-inhibition concentration) is 15.4 μMs.Selection index (SI) is about 7.0.And proadifen has had the application of many decades clinically, safety is good.This illustrates that proadifen is the medicine of the efficient resisiting influenza virus of low toxicity.
2. proadifen can suppress 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 in dose-dependant ground, and the anti-influenza A virus with very wide spectrum is active.
3. utilize modern common drug preparation means, proadifen 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 that a kind of proadifen cytotoxicity detects schematic diagram.
Fig. 2 is a kind of proadifen process influenza virus levels of replication schematic diagram.
Fig. 3 is that a kind of proadifen anti-influenza virus activity broad spectrum activity detects schematic diagram, wherein:
Fig. 3 A is subtypes of influenza A virus H3N2 strain (A/human/Hubei/3/2005 (H3N2));
Fig. 3 B is subtypes of influenza A virus H1N1 amantadine persister (A/WSN/S31N (H1N1));
Fig. 3 C is subtypes of influenza A virus H6N6 strain (A/Duck/Hubei/5/2010 (H6N6));
Fig. 3 D is subtypes of influenza A virus H7N8 strain (A/Duck/Hubei/216/1983 (H7N8)).
Detailed description of the invention
In order to set forth content of the present invention better, below applicant will be described in further detail content of the present invention in conjunction with specific embodiments, but request of the present invention protection scope be 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 proadifen 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 proadifen.
Embodiment 1: the evaluation of proadifen 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: proadifen (CAS:302-33-0) 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, 3000rpm4 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 proadifens detects: 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), medicine is processed for maximum concentration amounts to 8 gradients according to 2 gradient dilutions with 250.0 μMs, 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. 1) proadifen does not have cytotoxicity completely to mdck cell within the scope of 50.0 μMs, and illustrate that proadifen has the safer scope of application, namely the dosage of proadifen is 0.0 ~ 50.0 μM according to cell experiment consumption.
The antiviral activity evaluation of 2.4 proadifen 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 adds 100TCID after cleaning twice
50virus liquid (100 μ l) and variable concentrations medicine (100 μ l) are cultivated in 37 DEG C of cell culture incubators.Medicine is with 50.0 μMs for initial concentration, and continuous 2 times of gradient dilutions 6 gradients, every gradient arranges two multiple holes.Get each experimental port supernatant after cultivating 48h 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/LMES, pH6.5,4mmol/LCaCl are added in the micro plate of black 96 hole
2) the substrate 20umol/LMUNANA 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. each detect aperture Chinese medicine is calculated to the suppression ratio of neuraminidase.
Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result shows: along with the increase of proadifen drug level, the suppression ratio that medicine infected by influenza copies raises gradually, presents dosage dependent effect clearly, reaches close to 100% suppression ratio when 50.0 μMs of concentration.(see Fig. 2).
Embodiment 2: the evaluation of proadifen resisiting influenza virus effect broad spectrum activity
On the basis of embodiment 1, the present embodiment have detected the antiviral activity of proadifen to 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 further.
1. experiment uses Strain to comprise: A/human/Hubei/3/2005 (H3N2), A/WSN/S31N (H1N1), A/Duck/Hubei/5/2010 (H6N6), A/Duck/Hubei/216/1983 (H7N8)
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 adds 100TCID after cleaning twice
50virus liquid (100 μ l) and variable concentrations medicine (100 μ l) are cultivated in 37 DEG C of cell culture incubators.Medicine is with 50.0 μMs for initial concentration, and continuous 2 times of gradient dilutions 6 gradients, every gradient arranges two multiple holes.Get each experimental port supernatant after cultivating 48h and carry out neuraminidase activity detection.
3. in the micro plate of black 96 hole, add 40 μ l buffer (32.5mmol/LMES, pH6.5,4mmol/LCaCl
2) the substrate 20umol/LMUNANA 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 neuraminidase in each detect aperture.
Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result shows: proadifen obviously inhibits copying of various Influenza virus strain within the scope of drug level, and in dose-dependence (see Fig. 3).It is to the half-inhibition concentration (IC of influenza A virus H3N2, subtypes of influenza A virus H1N1 amantadine persister, influenza A virus H6N6 and influenza A virus H7N8
50) being respectively 18.9 μMs, 8.7 μMs, 12.5 μMs and 26.3 μMs, corresponding selection index is respectively 5.7,12.3,8.6 and 4.1.Show that proadifen is the antiviral drugs of a wide spectrum.
Claims (6)
1. the application of proadifen in preparation treatment or flu-prevention virus infective medicament;
Described influenza virus is influenza A virus.
2. apply as claimed in claim 1, it is characterized in that: described medicine is using proadifen or its various salt form as active constituents of medicine.
3. apply as claimed in claim 1, it is characterized in that: described medicine is oral administered dosage form, injecting medicine-feeding form, mucosa delivery dosage form or transdermal dosage form.
4. apply as claimed in claim 1, it is characterized in that: described medicine is the pharmaceutically acceptable dosage form of any one.
5. apply as claimed in claim 4, it is characterized in that: described medicine is tablet, capsule, granule, oral liquid or injection.
6. apply as claimed in claim 4, it is characterized in that: described medicine is slow releasing preparation, controlled release preparation or nanometer formulation.
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| US6121299A (en) * | 1998-03-30 | 2000-09-19 | Lovelace Respiratory Research Institute | Modulating inflammation with cytochrome P-450 activators and inhibitors |
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| US6121299A (en) * | 1998-03-30 | 2000-09-19 | Lovelace Respiratory Research Institute | Modulating inflammation with cytochrome P-450 activators and inhibitors |
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| Title |
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| Determining anti-betanodavirus compounds through a GF-1 cell-based screening platform;Yi-Cheng Huang等;《antiviral research》;20140228;第47-53页 * |
| 流感病毒神经氨酸酶抑制剂药物耐药现状及机制研究进展;黄兰等;《病毒学报》;20120930;第28卷(第5期);第572-576页 * |
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