CN103690536A - Application of ciclopirox olamine in preparing medicine for treating or preventing influenza virus infection - Google Patents
Application of ciclopirox olamine in preparing medicine for treating or preventing influenza virus infection Download PDFInfo
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Abstract
The invention discloses application of ciclopirox olamine in preparing a medicine for preventing or treating influenza virus infection. According to the application, firstly, the toxicity of ciclopirox olamine to MDCK (madin-darby canine kidney) cells is detected, and results indicate that maximum non-cytotoxic concentration of the ciclopirox olamine is 50.0 mu M; secondly, the anti-virus activity of the ciclopirox olamine is detected in a complete non-cytotoxic concentration range, and results indicate that the small molecular compound has a remarkable anti-virus activity, and the anti-virus effect shows a dose dependent effect; finally, the anti-virus activity of the ciclopirox olamine to different types and sub-type influenza viruses is detected, and results indicate that ciclopirox olamine can be used for inhibiting replication of all detected influenza virus strains in a dose dependent manner, and the anti-influenza virus activity of the ciclopirox olamine has broad spectrum. Therefore, the ciclopirox olamine is a novel broad-spectrum anti-influenza virus medicine, and can be used for preparing the medicine for preventing or treating influenza virus infection.
Description
Technical field
The present invention relates to the application of ciclopirox olamine in the medicine of preparation treatment or flu-prevention viral infection, belong to medical technical field.
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-types, also claims first, second, the third three types.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.Viral genome total length approximately 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), A type influenza virus can be further divided into 17 H (H1-H17) and 10 N (N1-N10) hypotype.Human influenza virus is mainly H1, H2 and H3 hypotype.And endanger at present serious high pathogenic avian influenza, 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 in people and sea dog, finds.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.
The whole biocycle of influenza virus need to complete in Cytoplasm and nucleus.Infect initial be the furcella HA 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.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.VRNPs forwards to subsequently and in nucleus, carries out genomicly copying and transcribing, and while copying, first to take self RNA be template synthesize complementary rna (cRNA) to virus, then take cRNA as template resynthesis vRNA.Transcribe the mRNA of generation by transferring to endochylema in core, translate viral structural protein and non-structural protein.Part synthetic proteins is assembled into vRNP as NP need to transfer in core again with newly-generated vRNA, vRNP starts to be assembled into new virion with remaining virus protein after going out core, newly-generated progeny virus is by the glycoprotein of neuraminidase (NA) hydrolysis cell surface, discharge N-acetyl-neuraminate, impel 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 has been caused in the world and has been very popular for five times since 20 beginnings of the century were found, can produce a fulminant popular about 10 years, has caused in the world huge loss.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.Vaccination and use antiviral drugs are the important means of reply flu outbreak, yet because influenza antigen variation ability is strong, substantially can not large-scale production vaccine before being very popular.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 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 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.Therefore, research development of new anti-influenza virus medicament are significant.
Ciclopirox olamine, Chinese another name ciclopiroxolamin, Ciclopirox, English common name ciclopirox olamine, chemistry 6-cyclohexyl-1-hydroxy-4-methyl pyridine-2 (1H) by name-one 2-ethylaminoethanol, trade name Loprox, Penlac or Stieprox.Ciclopirox olamine has stronger antibacterial and bactericidal action to dermatophytosis, yeast, actinomycetes, mycete and other fungus, and various Gram-positives and gram negative bacteria and mycoplasma, chlamydia, trichomonacide etc. are also had to certain antagonism.Its antibacterial mechanisms thinks that it is as a metal ion species (Fe
3+and Al
3+) chelating agen, suppress to comprise many enzymatic activitys of cytochrome, thereby caused intracellular plastochondria electron transfer chain impaired.It also has anti-inflammatory activity, anti-inflammatory mechanisms main with its inhibition 5-lipoxygenase and cyclooxygenase activity.Recent research report shows that it can suppress HIV-I gene expression, but so far there are no to the report of ciclopirox olamine resisiting influenza virus.The structural formula of ciclopirox olamine is as follows:
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 ciclopirox olamine in preparation treatment or flu-prevention virus infective medicament, thereby provide a kind of micromolecular compound safely and effectively for the treatment of influenza clinically.Ciclopirox olamine can effectively suppress copying of influenza virus within the scope of avirulence, can further be developed as the medicine for the treatment of or flu-prevention virus infection, is 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 ciclopirox olamine in preparation treatment or flu-prevention virus (A type or B-mode) infection medicine, the steps include:
the toxicity test of ciclopirox olamine to 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, with the ciclopirox olamine of 1.6 μ M, 3.125 μ M, 6.25 μ M, 12.5 μ M, 25.0 μ M, 50.0 μ M, 100.0 μ M and 200.0 μ M, process respectively, every group is repeated two holes, is placed in 37 ℃, 5% CO
2in incubator, cultivate after 48 hours, Alamarblue detects the survival rate of cell.Result shows, the CC of ciclopirox olamine to MDCK
50(median lethal concentration) is 119.4 μ M.
the evaluation of ciclopirox olamine anti-influenza virus activity:by mdck cell according to 1.5 * 10
4cells/well is inoculated in 96 Tissue Culture Plates, 37 ℃, 5% CO
2in cell culture incubator, cultivate 18-24h after cell grows up to monolayer, use 100TCID
50the influenza virus liquid (A/PuertoRico/8/34(H1N1) in/hole) infection cell, the medicine that simultaneously adds each gradient concentration is to cumulative volume in the cell maintenance medium of totally 200 μ l (DMEM+0.3%BSA+2.5 μ g/L pancreatin), gets each experimental port supernatant after cultivating 48h carry out the detection of neuraminidase expression in cell culture incubator in 37 ℃.Result shows that ciclopirox olamine can rely on copying of ground inhibition influenza virus, its EC by dosage
50(medium effective concentration) is 3.0 μ M.
the broad spectrum activity analysis of ciclopirox olamine resisiting influenza virus effect:by mdck cell according to 1.5 * 10
4cells/well is inoculated in 96 Tissue Culture Plates, 37 ℃, 5% CO
2in cell culture incubator, cultivate 18-24h and grow up to after monolayer, using 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 that simultaneously adds each gradient concentration is to the cumulative volume cell maintenance medium of totally 200 μ l (DMEM+0.3%BSA+2.5 μ g/L pancreatin), in cell culture incubator, after 37 ℃ of cultivation 48h, get each experimental port supernatant and carry out the detection of neuraminidase expression.Result show ciclopirox olamine can dose-dependent inhibition influenza A hypotype H1N1 strain, the copying of 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.
The present invention compared with prior art, has the following advantages and effect:
1. ciclopirox olamine is micromolecular compound, its CC
50(median lethal concentration) is 119.4 μ M.Ciclopirox olamine can copy by dose-dependent inhibition influenza virus, its EC
50(medium effective concentration) is 3.0 μ M.Selection index (SI) is about 39.8.And ciclopirox olamine had the application of many decades clinically, safety is good.This explanation ciclopirox olamine is the medicine of resisiting influenza virus safely and effectively.
2. ciclopirox olamine can rely on copying of ground inhibition influenza A hypotype 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 by dosage, has the very anti-influenza virus activity of wide spectrum.
3. utilize modern common drug preparation means, can make using ciclopirox olamine as active component any pharmaceutically acceptable dosage forms such as tablet, capsule, granule, oral liquid, slow releasing preparation, controlled release preparation, nanometer formulation or injection.
Accompanying drawing explanation
Fig. 1 is ciclopirox olamine chemical structural formula.
Fig. 2 is that ciclopirox olamine cytotoxicity detects schematic diagram.
Fig. 3 is that ciclopirox olamine treatment dosage relies on the flat schematic diagram processed of inhibition influenza virus rehydration.
Fig. 4 is that ciclopirox olamine 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 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 mdck cell to cultivate screening method and detects the impact that ciclopirox olamine infected by influenza infects, based on to representing the detection of the neuraminidase expression of influenza virus levels of replication, the anti-influenza virus activity of quantitative analysis ciclopirox olamine in supernatant.
Embodiment 1: the evaluation of ciclopirox olamine anti-influenza virus activity
1. experiment material
1.1 cells, virus and medicine
Mdck cell is purchased from US mode DSMZ (ATCC); Strain: A/PuertoRico/8/34(H1N1); Medicine: ciclopirox olamine is purchased from Sigma company.
1.2 experimental apparatus
Multiple labeling microwell plate reads instrument (Perkin Elmer).
2. experimental technique and result
2.1 cell culture: 37 ℃, 5% CO
2in humidification incubator, cultivate.The DMEM culture medium of the penicillin that use contains 10%FBS, 100U/mL and 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, use Egg checker inspection before virus inoculation, and at the position mark away from embryo, inoculate 2-by 0.2ml/ piece after sterilizing and punching
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 4 ℃ of centrifugal 30min of 3000rpm detect hemagglutinative titer, and 200 μ l/ pipe subpackage juxtaposition-70 are ℃ frozen standby.
The cytotoxicity of 2.3 ciclopirox olamine detects: mdck cell is by 8 * 10
3cells/well (volume 100 μ l) is inoculated in 96 porocyte culture plates, standby after cell attachment; With cell maintenance medium (DMEM+2% serum) by medicine according to 1.6 μ M, 3.125 μ M, 6.25 μ M, 12.5 μ M, 25.0 μ M, 50.0 μ M, 100.0 μ M and 200.0 μ M totally 8 gradient concentrations preparation, each gradient concentration is established 2 multiple holes.After cultivating 48h, discard culture supernatant, the new DMEM culture medium that adds 100 μ l to contain 10% Alamarblue reagent in every hole, put in cell culture incubator and continue to cultivate 1h, after 1h, with microwell plate, read instrument and measure respectively fluorescence intensity and light absorption value, calculate cell survival rate.
Result (Fig. 2) shows in the concentration range of ciclopirox olamine below 50.0 μ M does not have cytotoxicity completely to mdck cell.In the present embodiment, the dosage scope of ciclopirox olamine cellular level antiviral experiment is 1.6～50.0 μ M, is in safety non-toxic concentration range completely.
The antiviral activity of 2.4 ciclopirox olamine infected by influenza strain 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 producing under neuraminidase effect is under 355nm excitation light irradiation, can produce 460nm fluorescence, the power of fluorescence intensity has represented the number of viral neuraminidase expression, has reflected the virus quantity in cultured cell supernatant.
2.4.2. mdck cell is pressed to 1.5 * 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, and PBS liquid washes twice, adds 100TCID
50/ hole (100 μ l) virus liquid infection cell, add the medicine of each gradient concentration (the 50.0 μ M of take are initial concentration simultaneously, 8 gradients of continuous 2 times of gradient dilutions, two multiple holes of every gradient) to cumulative volume, be in the cell maintenance culture solution (DMEM+0.3 %BSA+2.5ug/L pancreatin) of 200 μ l, in cell culture incubator, after 37 ℃ of cultivation 48h, get each experimental port supernatant and carry out the detection of neuraminidase expression.Experiment arranges blank group, positive controls (ribavirin), negative control group (after viral infection without drug treating) and Experimental agents group.
2.4.3. (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 60min, add reaction terminating liquid (0.014 μ M NaOH, 83% ethanol) 100 μ l/ holes, micropore reads to measure on plate instrument fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
2.4.4. calculate and respectively detect the suppression ratio that hole Chinese medicine infected by influenza copies
Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result shows: ciclopirox olamine has obviously suppressed influenza virus to be copied, and is dose-dependence (seeing Fig. 3).
Embodiment 2: the evaluation of ciclopirox olamine resisiting influenza virus effect broad spectrum activity
This experiment detects the antiviral activity of ciclopirox olamine to influenza A hypotype 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 is used 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 to 1.5 * 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, and PBS liquid washes twice, adds 100TCID
50/ hole (100 μ l) virus liquid infection cell, add the medicine of each gradient concentration (the 50.0 μ M of take are initial concentration simultaneously, 6 gradients of continuous 2 times of gradient dilutions, the multiple holes of two of every gradients) to cumulative volume be in 200 μ l maintain liquid (DMEM+0.3 %BSA+2.5ug/L pancreatin), in cell culture incubator, cultivate and get each experimental port supernatant after 48h and carry out the detection of neuraminidase expression for 37 ℃.
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 60min, 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 and respectively detect the suppression efficiency that hole Chinese medicine infected by influenza copies
Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result shows: ciclopirox olamine is dosage and relies on copy (the seeing Fig. 4) that has suppressed various influenza virus strains.
Claims (4)
1. the application of ciclopirox olamine in the medicine of preparation treatment or flu-prevention viral infection.
2. application as claimed in claim 1, is characterized in that: described influenza virus is influenza A virus or Influenza B virus.
3. application as claimed in claim 1, is characterized in that: described medicine be with ciclopirox olamine be 6-cyclohexyl-1-hydroxy-4-methyl pyridine-2 (1H)-one 2-ethylaminoethanol as active constituents of medicine, make any pharmaceutically acceptable dosage form.
4. application as claimed in claim 3, is characterized in that: described dosage form is tablet, capsule, granule, oral liquid, injection, slow releasing preparation, controlled release preparation or nanometer formulation etc.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114949219A (en) * | 2022-01-26 | 2022-08-30 | 中国中医科学院中药研究所 | microRNA-205-5 p: novel therapeutic targets against influenza a virus |
| WO2023230435A1 (en) * | 2022-05-23 | 2023-11-30 | Glaxo Wellcome Uk Limited | Inhibitor of deoxyhypusine hydroxylase for the treatment and prevention of respiratory virus infections |
| CN117625540B (en) * | 2024-01-25 | 2024-04-05 | 昆明医科大学 | Human leukemia ciclopirox olamine drug-resistant cell line and construction method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101877968A (en) * | 2007-11-30 | 2010-11-03 | 詹森药业有限公司 | Fungicidal azole compounds and pyrion combination of compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101877968A (en) * | 2007-11-30 | 2010-11-03 | 詹森药业有限公司 | Fungicidal azole compounds and pyrion combination of compounds |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114949219A (en) * | 2022-01-26 | 2022-08-30 | 中国中医科学院中药研究所 | microRNA-205-5 p: novel therapeutic targets against influenza a virus |
| CN114949219B (en) * | 2022-01-26 | 2024-04-19 | 中国中医科学院中药研究所 | MicroRNA-205-5p: novel therapeutic targets against influenza a virus |
| WO2023230435A1 (en) * | 2022-05-23 | 2023-11-30 | Glaxo Wellcome Uk Limited | Inhibitor of deoxyhypusine hydroxylase for the treatment and prevention of respiratory virus infections |
| CN117625540B (en) * | 2024-01-25 | 2024-04-05 | 昆明医科大学 | Human leukemia ciclopirox olamine drug-resistant cell line and construction method and application thereof |
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Application publication date: 20140402 |