CN103251576B - Application of diphenhydramine hydrochloride in preparation of medicines for treating or preventing influenza viruses - Google Patents
Application of diphenhydramine hydrochloride in preparation of medicines for treating or preventing influenza viruses Download PDFInfo
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- CN103251576B CN103251576B CN201310175162.4A CN201310175162A CN103251576B CN 103251576 B CN103251576 B CN 103251576B CN 201310175162 A CN201310175162 A CN 201310175162A CN 103251576 B CN103251576 B CN 103251576B
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Abstract
The invention discloses an application of diphenhydramine hydrochloride in preparation of medicines for treating or preventing influenza viruses. Firstly, diphenhydramine hydrochloride with completely nontoxic concentration is selected for an antiviral test, and the result shows that the small molecular compound has remarkable antiviral activity and is in dose-dependent association; then, the action period of diphenhydramine hydrochloride which resists influenza viruses is analyzed, and the result shows that diphenhydramine hydrochloride mainly inhibits events in early stage of virus infection such as virus absorption and entrance; and finally, the antiviral activity of diphenhydramine hydrochloride to different types and sub-types of influenza viruses is detected, and the result shows that diphenhydramine hydrochloride can inhibit replication of all detection viral strains and has the dose-dependent effect, thereby representing that diphenhydramine hydrochloride is of certain broad spectrum to anti-influenza virus activity. The diphenhydramine hydrochloride disclosed by the invention can be developed as a novel anti-influenza virus medicine and provides a novel path and means for treating influenza.
Description
Technical field
The invention belongs to medical technical field, more specifically relate to the application of a kind of diphhydramine hydrochloride in preparation treatment or flu-prevention virus drugs.
Background technology
Influenza virus (influenza virus) has a strong impact on human health, can cause grippal pathogen.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-types, also claims first, second, the third three types.All there is significant difference in the aspects such as the genome structure of these three kinds of veriform viruses, polypeptide form, infectious and pathogenic.The full genome of A type influenza virus is comprised of 8 sub-thread strand RNAs that differ in size, and names respectively with sections 1 to sections 8.The about 13.6kb of viral genome total length, encode respectively 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), A type influenza virus can be further divided into 16 H (H1-H16) and 9 N (N1-N9) hypotype.Human influenza virus is mainly H1, H2 and H3 hypotype, and endanger at present serious high pathogenic avian influenza, mostly is 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, and in other animal except people, does not find its existence so far.C type influenza virus exists mainly with the form that is dispersed in, and mainly attacks infant, does not generally cause influenza pandemic, can infect the mankind and pig.
Influenza virus is in viral taxonomy Shang Shu orthomyxoviridae family (Orthomyxoviridae), Influenza Virus.Influenza virus is segmented minus-stranded rna virus, so viral RNA does not have infectivity, each RNA sections must just have activity in conjunction with rear formation vRNPs with RNA polymerase (PB2, PB1 and PA) and nucleoprotein (NP).Infect initial be the HA furcella identification on virion surface and in conjunction with host cell surface containing sialic receptor.The connecting key of sialic acid and time terminal galactose, has determined viral host specificity, and this connecting key is α (2-3) in birds, is α (2-6) in the mankind.In influenza virus HA protein molecular, indivedual amino acid whose replacements and the different glycosylation modified specificitys that can change its receptors bind.After virus absorption onto cell, cell is taken in virus by the receptor-mediated pinocytosis of clathrin.In cell, clathrin molecular dissociation, virus merges and forms phagosome with endosome, makes virion pH value around drop to 5.0 left and right.Under this pH condition, the conformation of viral HA albumen changes, and the fusogenic peptide that is positioned at light chain (HA2) N end is exposed, thereby causes that virus envelope and cell membrane merge.Low pH environment also causes a large amount of H
+via M2 ion channel, enter virion inside, 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, the copying and transcribe in the nucleus that all occurs in host cell of influenza virus gene group.After mRNA is synthetic in core, transfer to endochylema, synthetic viral structural protein and non-structural protein.Then start to assemble progeny virus, the glycoprotein of neuraminidase hydrolyzable cell surface, discharges N-acetyl-neuraminate, impels virion to discharge from the 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, thereby starts copying of new round virus.
Influenza virus is popular propagation more than 300 year in the mankind, and the several years i.e. outbreak of epidemic once, and global flu outbreak many decades breaks out once.Influenza pandemic can cause 250,000～500,000 examples dead every year, 3,000,000～5,000,000 severe disease examples, and it is infected that the whole world approximately has 5～15% people.For Global Influenza is very popular, " in epidemic period, vaccine and antiviral drugs are to reduce the most important counter-measure of M & M ".But the current whole world can produce every year, 300,000,000 person-portion trivalent influenza vaccines-this only reaches the use of Hesperian influenza prevention, and can not meet the pandemic demand of Global Influenza, and because the antigenic variation ability of influenza virus is strong, before occurring, novel strain can not develop vaccine.The extensive research and development of a common vaccine and manufacture at least need six months, even till that time, because worldwide production is limited in one's ability and production facility concentrates on developed country, many do not have the country of production facility will use less than vaccine at the 1st ripple epidemic period.So the protective rate that current vaccine can provide is not high.Anti-influenza virus medicament not only comes out more late, and quick-acting, effective medicine is also less clinically, belongs to the little kind in anti-infection drug.At present, the anti-influenza virus medicament through food and drug administration (FDA) approval official listing has two classes: (1) take the M2 ion channel blocking agent that amantadine and rimantadine are representative.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 being widely used, 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 is all effective to all known human influenza viruses and high pathogenic avian influenza virus.But the persister about oseltamivir but constantly has report in recent years.
Diphhydramine hydrochloride is histamine I class inhibitor, is the micromolecular compound of synthetic, can eliminate various allergic symptoms, and its central inhibitory action is remarkable, has calmness, anti-cinetosis and antiemetic effect, also has cholinolytic effect, can alleviate bronchial muscular spasm.For various allergic skin diseases, as urticaria, insect bite disease; Also for motion sickness, feel sick, vomit.Diphhydramine hydrochloride can be used for the treatment of rhinitis, does not have at present diphhydramine hydrochloride to be directly used in the application of resisiting influenza virus aspect.
Summary of the invention
The object of the invention is to make up the deficiencies in the prior art, be to be to provide the application of a kind of micromolecular compound diphhydramine hydrochloride in preparation treatment or flu-prevention medicine, thereby provide a kind of safe and efficient toxic and side effects little micromolecular compound for the treatment of influenza clinically.Diphhydramine hydrochloride can effectively suppress entering of influenza virus within the scope of avirulence, can further be developed as the medicine for the treatment of influenza infection disease, is with a wide range of applications.
The English diphenhydramine hydrochloride by name of diphhydramine hydrochloride, chemical formula is N, N-dimethyl-2-(diphenyl methoxy base) ethylamine hydrochloride (N-(2-Diphenylmethoxyethyl)-N, N-dimethylamine hydrochloride), there is the structural formula shown in structure formula I:
Structure formula I
In order to realize above-mentioned object, the present invention by the following technical solutions:
The application of diphhydramine hydrochloride in preparation treatment or flu-prevention virus (A type or B-mode) medicine, the steps include:
A. the cytotoxicity experiment of diphhydramine hydrochloride to mdck cell: mdck cell is inoculated in 96 porocyte culture plates by 5000 cells/well (100 μ l), after cell attachment, with cell maintenance medium (DMEM+2% serum), medicine be take to 1mM as 6 gradients of the continuous 2 times of gradient dilutions of initial concentration, 2 multiple holes of every gradient, are placed in 37 ℃, 5%CO
2in incubator, cultivate after 48 hours, with 3-(4,5-dimethylthiazole-2)-2, (tetrazolium bromide, MTT) method detects the survival rate of cell to 5-diphenyl tetrazole bromine salt.Result shows the CC50(median lethal concentration of diphhydramine hydrochloride to mdck cell) be 699.7 μ M.
B. the evaluation of diphhydramine hydrochloride anti-influenza virus activity: mdck cell is pressed to 2*10
4cells/well is inoculated in 96 porocyte culture plates, cultivates 14～18h and treat that cell grows up to monolayer in 37 ℃ of cell culture incubators, then adds 100TCID
50/ hole virus liquid infection cell, gets each experimental port supernatant after adding each Concentraton gradient medicine simultaneously totally 200 μ l maintain liquid (DMEM+0.3%BSA+2.5ug/L pancreatin) being cultivated 48h in 37 ℃ of cell culture incubators and carries out the detection of neuraminic acid enzymatic activity.Result shows: diphhydramine hydrochloride has obviously suppressed influenza virus to be copied, and its EC50 is 14.67 μ M.
C. the diphhydramine hydrochloride resisiting influenza virus action period is analyzed: cell is pressed 5*10
4be inoculated in 24 porocyte culture plates, after cell attachment is monolayer, respectively at viral infection-2～0h, 0～2h, 2～4h, 4～6h gives same concentrations medicine and cultivates, and 6h fixed cell after infection, by indirect immunofluorescene assay virus N P protein expression.Result shows: diphhydramine hydrochloride administration in 0～2h can suppress viral infection, mainly suppresses viruses adsorption and enters.
D. diphhydramine hydrochloride anti-influenza virus activity broad spectrum activity is analyzed: mdck cell is pressed to 2*10
4cells/well is inoculated in 96 porocyte culture plates, cultivates 14～18h and treat that cell grows up to monolayer in 37 ℃ of cell culture incubators, then adds 100TCID
50/ hole virus liquid (A/human/Hubei/1/2009(H1N1), A/human/Hubei/3/2005(H3N2), Influenza B virus) infection cell, gets each experimental port supernatant after adding each Concentraton gradient medicine simultaneously totally 200 μ l maintain liquid (DMEM+0.3%BSA+2.5ug/L pancreatin) being cultivated 48h in 37 ℃ of cell culture incubators
Carry out the detection of neuraminic acid enzymatic activity.Result shows: diphhydramine hydrochloride can obviously suppress copying of subtypes of influenza A virus H1N1 strain, influenza A virus H3N2 strain and influenza B virus strain, and has dose-dependent effect.
The present invention compared with prior art has the following advantages and effect:
1. diphhydramine hydrochloride is micromolecular compound, and its CC50 is 699.7 μ M.Diphhydramine hydrochloride dosage relies on ground inhibition influenza virus and copies, and its EC50 is 14.67 μ M, and therapeutic index is about 48.This explanation diphhydramine hydrochloride is the medicine of the efficient resisiting influenza virus of low toxicity.
2. diphhydramine hydrochloride acts on influenza virus and copies in early days, the early stage event such as mainly suppress viruses adsorption and enter.
3. diphhydramine hydrochloride can suppress copying of subtypes of influenza A virus H1N1 strain, influenza A virus H3N2 strain and influenza B virus strain, has the antiviral activity of wide spectrum.
4. utilize modern common drug preparation means, diphhydramine hydrochloride can be able to be made to active component and make any pharmaceutically acceptable dosage forms such as tablet, capsule, granule, oral liquid, slow releasing preparation, controlled release preparation, nanometer formulation, injection.
Accompanying drawing explanation
Fig. 1 is a kind of diphhydramine hydrochloride chemical structural formula.
Fig. 2 is that a kind of cytotoxicity of diphhydramine hydrochloride detects schematic diagram.
Fig. 3 is that a kind of diphhydramine hydrochloride is processed neuraminidase in the culture fluid supernatant of the influenza infection cell schematic diagram of living.
Fig. 4 is a kind of the affect result schematic diagram of diphhydramine hydrochloride on viral single-wheel replicative cycle different phase that detect.
Fig. 5 is that a kind of detection diphhydramine hydrochloride anti-influenza virus activity broad spectrum activity detects schematic diagram.
Fig. 5 A figure is subtypes of influenza A virus H1N1 strain (A/human/Hubei/1/2009(H1N1);
Fig. 5 B figure is influenza A virus H3N2 strain (A/human/Hubei/3/2005(H3N2);
Fig. 5 C figure is influenza B virus strain (Influenza B virus).
The specific embodiment
In order to understand better content of the present invention, 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: can provide the identical cell of a large amount of hereditary characters to be object of study, and easy to operate, can eliminate the impact of other extraneous factor, and valid density and therapeutic index that can detection of drugs, for more how later stage mechanism research provide basis.The present invention adopts cell culture screening method to detect diphhydramine hydrochloride infected by influenza infection mdck cell, detects the content of virion in viral supernatant, quantitative analysis diphhydramine hydrochloride anti-influenza virus activity.
Embodiment 1: the evaluation of diphhydramine hydrochloride anti-influenza virus activity
1. experiment material and method
1.1 cells, virus and medicine
Mdck cell is purchased from ATCC, and viral A/PR8/34H1N1 cultivates amplification by Embryo Gallus domesticus and obtains, and diphhydramine hydrochloride is purchased from Sigma company;
1.2 experimental apparatus
Multi-tester PerkinElmer, inverted microscope Costar
2. experimental technique:
2.1 cell culture:
37 ℃, 5%(volume ratio, below identical) CO
2in humidification incubator, cultivate.Use contains 10%(volume ratio, below identical) penicillin of FBS, 100U/mL and the DMEM culture medium of streptomycin.After cell to 90% degree of converging, go down to posterity, 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, before virus inoculation, use Egg checker inspection, and at the position mark away from embryo, after sterilizing and punching, by 0.2ml/ piece, inoculate 2
4the virus liquid of hemagglutinative titer, with nial polish sealing, puts 37 ℃ of calorstats and hatches after 48h(inoculation 24h dead Embryo Gallus domesticus to be generally misoperation lethal, abandons it).Take out Embryo Gallus domesticus and put 4 ℃ of cold embryo 12h.75% alcohol disinfecting chick embryo air sac, sterile working cuts off air chamber shell, and capillary pipette is drawn chick embryo allantoic liquid and amniotic fluid, and 3000rpm4 ℃ of centrifugal 30min detects hemagglutinative titer, and 200 μ l/ pipe subpackage juxtaposition-70 are ℃ frozen standby.
(1) drug cell toxicity detects:
1.MDCK cell is inoculated in 96 porocyte culture plates by 5000 cells/well (100 μ l), standby after cell attachment;
2. with cell maintenance medium (DMEM+2% serum), medicine be take to 1mM as 6 gradients of the continuous 2 times of gradient dilutions of initial concentration, 2 multiple holes of every gradient.After cultivating 48h, in every hole, add 5mg/ml MTT20 μ l, put in cell culture incubator and continue to cultivate;
3. cultivate after 4h, abandon culture fluid supernatant, every hole adds 100 μ l/ hole three lysates, and (lysate is by SDS10g, isobutanol 5ml, 10M HCl0.1ml, dissolves and is made into 100ml with distilled water), in 37 ℃ of incubators, dissolve 4h above or spend the night after enzyme connection detector detect 570nm wavelength place light absorption value, tuning wavelength is 630nm, and calculates each drug level cell survival rate, the results are shown in Figure 2.
Result shows: diphhydramine hydrochloride does not have obvious cytotoxicity to mdck cell within the scope of concentration <250 μ M, illustrates that diphhydramine hydrochloride has the safer scope of application.
(2) activity of the anti-A/PR8/34 H1N1 virus of diphhydramine hydrochloride strain detects:
A. based on neuraminic acid enzymatic activity, detect the effect of diphhydramine hydrochloride resisiting influenza virus:
1. experimental principle: MUNANA(4-methylumbelliferyl-α-N-acetyl-neuraminate) be the specific substrate of influenza neuraminidase, the catalysate producing under neuraminidase effect is under 355nm excitation light irradiation, can produce 460nm fluorescence, the variation of fluorescence intensity, can sensitive reaction neuraminic acid enzymatic activity, thus viral load in can reacting cells supernatant.
2. mdck cell is pressed to 2*10
4cells/well is inoculated in 96 porocyte culture plates, in 37 ℃ of cell culture incubators, cultivates after 14～18h, standby after cell grows up to monolayer.Culture medium in orifice plate is discarded, PBS liquid is washed twice, add 100TCID50/ hole virus liquid infection cell, add each Concentraton gradient (the 200 μ M of take are initial concentration simultaneously, 7 gradients of continuous 2 times of gradient dilutions, multiple holes of 2 of every gradients) medicine is got each experimental port supernatant after totally 200 μ l maintain liquid (DMEM+0.3%BSA+2.5ug/L pancreatin) are cultivated 48h in 37 ℃ of cell culture incubators and is carried out the detection of neuraminic acid enzymatic activity.
3. (32.5mmol/L MES, pH 6.5,4mmol/L CaCl in black 96 hole micro plates, to add 40 μ l buffer
2) preparation substrate 20umol/L MUNANA, add again each experimental port culture supernatant 20 μ l, 37 ℃ of lucifuges are hatched 30min, add reaction terminating liquid (0.014 μ M NaOH, 83% ethanol) 100 μ l/ holes, on multi-tester, measure fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
4. calculate the suppressed rate of NA in hole that respectively detects.Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%.
Result shows: diphhydramine hydrochloride has obviously suppressed influenza virus to be copied, and is dose-dependence (see figure 3)
Variable concentrations diphhydramine hydrochloride infected by influenza inhibition of DNA replication rate is as follows:
| Concentration (μ M) | Suppression ratio (%) |
| 200 | 98.53±1.46 |
| 100 | 101.93±2.99 |
| 50 | 81.65±5.77 |
| 25 | 62.45±10.47 |
| 12.5 | 43.54±15.19 |
| 6.25 | 27.25±8.81 |
| 3.125 | 14.41±8.56 |
Embodiment 2: the inhibitory action of diphhydramine hydrochloride to virus replication cycle different phase
1. cell is pressed 5*10
4be inoculated in 24 porocyte culture plates, standby after cell attachment is monolayer.The about 6h of influenza virus biocycle, so we are respectively at viral infection-2～0h, 0～2h, 2～4h, 4～6h gives the medicine of 50 μ M and cultivates, and 6h fixed cell after infection carries out the expression of virus protein after indirect immunofluorescene assay drug treating according to the following step.
2. abandon culture fluid supernatant, with fixative by cell at the fixing 15-20min of room temperature; With PBS, wash 3 times each 5min; With confining liquid room temperature sealing 1h; Abandon confining liquid, add primary antibodie (Mus source NP monoclonal antibody) the incubated at room 1h in conjunction with liquid dilution; With PBS, wash 3 times each 5min; Add the fluorescently-labeled two anti-and DAPI dye liquor incubated at room 1h in conjunction with liquid dilution; With PBS, wash 3 times each 5min; Under inverted fluorescence microscope, observe.
Test solution used: fixative: 4%(mass volume ratio) paraformaldehyde is dissolved in PBS (pH7.4); In conjunction with liquid: 3%(mass volume ratio) BSA, 0.3%(mass volume ratio) TritonX-100 is dissolved in PBS (pH7.4); Confining liquid: containing the combination liquid of 10%FCS.
Result shows: diphhydramine hydrochloride administration in 0～2h can suppress viral infection, infers mainly to suppress viruses adsorption and the early stage event (see figure 4) of viral infection such as enter.
Embodiment 3: the research of diphhydramine hydrochloride anti-influenza virus activity broad spectrum activity
This experiment detects the antiviral activity of diphhydramine hydrochloride to subtypes of influenza A virus H1N1 strain, influenza A virus H3N2 strain and influenza B virus strain.
1. experiment is used Strain to comprise: A/human/Hubei/1/2009(H1N1), A/human/Hubei/3/2005(H3N2), Influenza B virus
2. mdck cell is pressed to 2*10
4cells/well is inoculated in 96 porocyte culture plates, in 37 ℃ of cell culture incubators, cultivates after 14～18h, standby after cell grows up to monolayer.Culture medium in orifice plate is discarded, PBS liquid is washed twice, add 100TCID50/ hole virus liquid infection cell, add each Concentraton gradient medicine (the 200 μ M of take are initial concentration simultaneously, 6 gradients of continuous 2 times of gradient dilutions, multiple holes of 2 of every gradients) after totally 200 μ l maintain liquid (DMEM+0.3%BSA+2.5ug/L pancreatin) are cultivated 48h in 37 ℃ of cell culture incubators, get each experimental port supernatant and carry out the detection of neuraminic acid enzymatic activity.
3. in black 96 hole micro plates, add 40 μ l buffer (32.5mmol/L MES, pH6.5,4mmol/L CaCl
2) preparation substrate 20umol/L MUNANA, add again each experimental port culture supernatant 20 μ l, 37 ℃ of lucifuges are hatched 30min, add reaction terminating liquid (0.014 μ M NaOH, 83% ethanol) 100 μ l/ holes, on multi-tester, measure fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
4. calculate the suppressed rate of NA in hole that respectively detects.Suppression ratio (%)=100-(sample well-blank/(enzyme contrast-blank alive) * 100%
Result shows: diphhydramine hydrochloride has obviously suppressed other strains of influenza viruses to be copied, and is dose-dependence (see figure 5).
Other susceptible strain inhibition of DNA replication rate of variable concentrations diphhydramine hydrochloride convection current is as follows:
Claims (1)
1. the application in the medicine that diphhydramine hydrochloride copies preparation inhibition influenza virus as unique effective ingredient; Described influenza virus is influenza A virus or Influenza B virus.
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