CN103705497B - Application of liothyronine in preparation of medicine for treatment or prevention of influenza virus infection - Google Patents
Application of liothyronine in preparation of medicine for treatment or prevention of influenza virus infection Download PDFInfo
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- CN103705497B CN103705497B CN201310668460.7A CN201310668460A CN103705497B CN 103705497 B CN103705497 B CN 103705497B CN 201310668460 A CN201310668460 A CN 201310668460A CN 103705497 B CN103705497 B CN 103705497B
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Abstract
The invention discloses an application of liothyronine in preparation of a medicine for prevention or treatment of influenza virus infection. Reports related to liothyronine resistant to influenza viruses are unavailable so far. Liothyronine with completely non-toxic concentration is selected for an antiviral experiment, and a result shows that the small molecular compound has significant antiviral activity and is in dose-dependent association. Then, the antiviral activity of liothyronine to different types and subtypes of influenza viruses is detected, and a result shows that liothyronine can inhibit replication of all detected viral strains and has a dose dependent effect, thereby representing that the anti-influenza virus activity of liothyronine has a certain broad spectrum. Therefore, liothyronine can be used as a novel anti-influenza virus medicine for development, and provides a novel way and means for treating influenza.
Description
Technical field
The present invention relates to the application of liothyronine in the medicine preparing treatment or flu-prevention viral infection, belong to medical art.
Background technology
Influenza virus belongs to orthomyxoviridae family (Orthomyxoviridae), Influenza Virus.According to virion nucleoprotein (NP) and the antigenic characteristic of stromatin (M) and the difference of genetic characteristics, influenza virus is divided into A, B, C tri-type, also claims first, second, the third three types.Influenza A full-length genome is made up of the sub-thread strand RNA that 8 differ in size, and names respectively with sections 1 to sections 8.Full length viral genome about 13.6 kb, encode 10 kinds of structural protein (PB2, PB1, PA, HA, NP, NA, M1, M2, PB1-F2 and NS2/NEP) and non-structural protein (NS1).According to the difference of virion surface glycoprotein hemagglutinin (HA) and neuraminidase (NA), influenza A can be further divided into 17 H (H1-H17) and 10 N (N1-N10) hypotypes.Human influenza virus is H1, H2 and H3 hypotype mainly.And endanger serious high pathogenic avian influenza at present and mostly be H5, H7 and H9 hypotype, wherein the highest with the fatality rate of H5N1 hypotype.Type B influenza virus often causes influenza localized epidemics, does not cause worldwide influenza great outburst, only finds in people and sea dog.C type influenza virus exists mainly with being dispersed in form, and primary attack infant, does not generally cause influenza pandemic, can infect the mankind and pig.
The whole biocycle of influenza virus needs to complete in Cytoplasm and nucleus.Infect initial be the furcella HA of surfaces of viral particles identify and in conjunction with host cell surface containing sialic receptor.The connecting key of sialic acid and time terminal galactose, determine the host specificity of virus, this connecting key is α (2-3) in birds, is α (2-6) in the mankind.After virus absorption onto cell, cell takes in virus by the receptor-mediated pinocytosis of clathrin.In cell, clathrin molecular dissociation, virus and endosome merge and form phagosome, make the pH value around virion drop to about 5.0.Under this pH condition, the conformation of viral HA protein changes, and the fusogenic peptide being positioned at light chain (HA2) N end is exposed, thus causes virus envelope and cell membrane fusion.Low pH environment also causes a large amount of H
+enter virion inside via M2 ion channel, cause dissociating of M1 albumen and vRNPs.Both common results cause the vRNPs of virion to be discharged into the endochylema of infected cell.VRNPs forwards to subsequently in nucleus and carries out genomicly copying and transcribing, when copying virus first with self RNA for templated synthesis complementary RNA (cRNA), be then template resynthesis vRNA with cRNA.The mRNA transcribing generation transfers to endochylema by core, translates structural protein and the non-structural protein of virus.Part synthetic proteins is assembled into vRNP as NP needs again to transfer to vRNA in core with newly-generated, start to be assembled into new virion with remaining virus protein after vRNP goes out core, newly-generated progeny virus is by the glycoprotein on neuraminidase (NA) hydrolyzed cellular surface, release N-acetyl-neuraminate, impels virion to discharge from site of sprouting.The final step of virus maturation is that HA is cracked into HA1 and HA2 polypeptide under the effect of host protein enzyme, and such virion just has infectivity, thus starts copying of new round virus.
Influenza virus has been caused in the world and is very popular for five times since 20 beginnings of the century found, within about 10 years, can produce an outbreak of epidemic, cause huge loss in the world.Influenza pandemic can cause 250,000 ~ 500,000 examples dead every year, 3,000,000 ~ 5,000,000 severe disease examples, the whole world about have 5 ~ 15% people infected.Vaccination and use antiviral drugs to be the important means of reply flu outbreak, however due to influenza antigen variation ability strong, substantially can not large-scale production vaccine before being very popular.At present, the anti-influenza virus medicament ratifying official listing through food and drug administration (FDA) has two classes: the M2 ion channel blocking agent that (1) is representative with amantadine and rimantadine.This type of medicine only has preventive and therapeutic action to influenza A virus, and research shows that this type of medicine has the toxic and side effects such as neurotoxicity, and due to the ubiquity of persister, so CDC advises that this type of medicine is not used further to flu-prevention viral infection.(2) neuraminidase inhibitor, the representative of this type of medicine is oseltamivir and Zha La meter Wei.This type of medicine to all known human influenza viruses and high pathogenic avian influenza virus all effective.But but constantly there is report about oseltamivir persister in recent years.Therefore, also development of new anti-influenza virus medicament is significant in research.
Liothyronine, English Liothyronine by name.Medicinal structure is Cyronine clinically, and molecular weight is 690.7, is the sodium triiodothyronine of synthetic, acts on similar to thyroxine, for thyroid function decline patient.In vivo, it can strengthen basal metabolic rate, affects protein synthesis and strengthens human body to the sensitivity of catecholamines, play an important role to the growth and differ entiation of human body.At present, liothyronine causes disease report at resisiting influenza virus and treatment influenza infection is not seen.The structural formula of Cyronine is as follows:
Summary of the invention
The object of the invention is to make up the deficiencies in the prior art, be there are provided the application in preparation treatment or flu-prevention virus infective medicament of a kind of micromolecular compound liothyronine or its pharmaceutical salts, thus provide one micromolecular compound safely and effectively for the treatment of influenza clinically.Liothyronine can effectively suppress copying of influenza virus within the scope of avirulence, can be developed as the medicine for the treatment of or flu-prevention virus infection further, be with a wide range of applications.
In order to realize above-mentioned object, the technical solution used in the present invention is:
The application of liothyronine in the medicine that preparation is treated or flu-prevention virus (A type or B-mode) infects, the steps include:
liothyronine is to the toxicity test of mdck cell:madin-Darby canine kidney(cell line) (MDCK) is by 8 × 10
3individual cells/well is inoculated in 96 porocyte culture plates, after cell attachment, process with the liothyronine of 1.6 μMs, 3.125 μMs, 6.25 μMs, 12.5 μMs, 25.0 μMs, 50.0 μMs, 100.0 μMs and 200.0 μMs respectively, often organize repetition two holes, be placed in 37 DEG C, 5% CO
2cultivate in incubator after 48 hours, Alamarblue detects the survival rate of cell.Result shows, and liothyronine is to the CC of MDCK
50(median lethal concentration) is greater than 200.0 μMs.
the evaluation of liothyronine anti-influenza virus activity:by mdck cell according to 1.5 × 10
4cells/well is inoculated in 96 Tissue Culture Plates, 37 DEG C, 5% CO
2cultivating 18-24h in cell culture incubator grows up to after monolayer until cell, uses 100TCID
50the influenza virus liquid (A/PuertoRico/8/34(H1N1) in/hole) infection cell, the medicine simultaneously adding each gradient concentration, in the cell maintenance medium (DMEM+0.3%BSA+2.5 μ g/L pancreatin) of cumulative volume totally 200 μ l, gets detection that each experimental port supernatant carry out neuraminidase expression after cultivating 48h in cell culture incubator in 37 DEG C.Result display liothyronine can suppress copying of influenza virus, its EC in dose-dependant ground
50(medium effective concentration) is 15.4 μMs.
the broad spectrum activity analysis of liothyronine resisiting influenza virus effect:by mdck cell according to 1.5 × 10
4cells/well is inoculated in 96 Tissue Culture Plates, 37 DEG C, 5% CO
2cultivate 18-24h in cell culture incubator and after growing up to monolayer, use 100TCID
50the influenza virus liquid in/hole (is respectively A/Human/Hubei/1/2009 (H1N1), A/human/Hubei/3/2005 (H3N2), A/human/WSN/33/ (H1N1, S31N) and B/human/Hubei/1/2007) infection cell, the medicine simultaneously adding each gradient concentration, in the cell maintenance medium (DMEM+0.3%BSA+2.5 μ g/L pancreatin) of cumulative volume totally 200 μ l, gets detection that each experimental port supernatant carry out neuraminidase expression after cultivating 48h in cell culture incubator in 37 DEG C.Result display liothyronine can dose-dependent suppression influenza A subtype H1N1 strain, subtypes of influenza A virus H3N2 strain, the copying of subtypes of influenza A virus H1N1 amantadine persister and Influenza B virus.
The present invention compared with prior art, has the following advantages and effect:
1. liothyronine is micromolecular compound, its CC
50(median lethal concentration) is greater than 200.0 μMs.Liothyronine can copy by dose-dependent suppression influenza virus, its EC
50(medium effective concentration) is 15.4 μMs.Selection index (SI) is greater than 13.0.And liothyronine has had the application of many decades clinically, safety is good.This illustrates that liothyronine is anti-influenza virus medicament safely and effectively.
2. liothyronine can suppress influenza A subtype H1N1 strain, subtypes of influenza A virus H3N2 strain, the copying of subtypes of influenza A virus H1N1 amantadine persister and Influenza B virus in dose-dependant ground, has the anti-influenza virus activity of very wide spectrum.
3. utilize modern common drug preparation means, liothyronine 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 Cyronine chemical structural formula.
Fig. 2 is that liothyronine cytotoxicity detects schematic diagram.
Fig. 3 is that liothyronine dose-dependant suppresses influenza virus levels of replication schematic diagram.
Fig. 4 is that liothyronine 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 Influenza B virus (B/human/Hubei/1/2007).
Specific embodiments
In order to understand content of the present invention better, below in conjunction with specific implementation method, content of the present invention is described further, but protection content of the present invention is not limited to following examples.
At present, anti-influenza virus medicament in-vitro screening model is divided into the cell free system screening model of cell culture model and viral enzyme.Enzyme reaction screening model has high-throughout feature, but the compound of screening still needs to carry out more cytology, histology and toxicity in vivo, effect experiment etc. to determine its effect.Cell culture model is the most frequently used screening model, its advantage is: the cell that a large amount of hereditary character can be provided identical is object of study, easy to operate, can eliminate the impact of other extraneous factor, and can the valid density of detection of drugs and therapeutic index, for later stage study mechanism provides more how basis.The present invention adopts mdck cell to cultivate screening method and detects the impact that liothyronine 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 liothyronine.
Embodiment 1: the evaluation of liothyronine 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: liothyronine is purchased from Sigma company.
1.2 experimental apparatus
Multiple labeling microtiter plate reader (Perkin Elmer).
2. experimental technique and result
2.1 cell culture: 37 DEG C, 5% CO
2cultivate in humidified incubator.Use containing the penicillin of 10%FBS, 100U/mL and the DMEM culture medium of streptomycin.Go down to posterity after cell to 90% degree of converging, the ratio that goes down to posterity 1/3 – 1/4.
2.2 Virus culture: get 9 ~ 11 age in days SPF Embryo Gallus domesticus, use Egg checker inspection before virus inoculation, and at the position mark away from embryo, sterilize and punch rear by 0.2ml/ piece of inoculation 2-
4the virus liquid of hemagglutinative titer, with nial polish sealing, puts 37 DEG C of calorstats and hatches 48h(and inoculate Embryo Gallus domesticus dead after 24h to be generally misoperation lethal, abandon it).Take out Embryo Gallus domesticus and put 4 DEG C of cold embryo 12h.75% alcohol disinfecting chick embryo air sac, sterile working cuts off air chamber shell, and capillary pipette draws chick embryo allantoic liquid and amniotic fluid, 3000rpm 4 DEG C of centrifugal 30min, and detect hemagglutinative titer, 200 μ l/ pipe subpackage juxtapositions-70 DEG C are frozen for subsequent use.
The cytotoxicity of 2.3 liothyronines detects: mdck cell is by 8 × 10
3cells/well (volume 100 μ l) is inoculated in 96 porocyte culture plates, for subsequent use after cell attachment; With cell maintenance medium (DMEM+2% serum) by medicine according to 1.6 μMs, 3.125 μMs, 6.25 μMs, 12.5 μMs, 25.0 μMs, 50.0 μMs, 100.0 μMs and 200.0 μMs totally 8 gradient concentrations preparations, each gradient concentration establishes 2 multiple holes.Culture supernatant is discarded after cultivating 48h, the new DMEM culture medium that 100 μ l contain 10% Alamarblue reagent is added in every hole, put in cell culture incubator after continuing to cultivate 1h, 1h and measure fluorescence intensity and light absorption value respectively with microtiter plate reader, calculate cell survival rate.
Result (Fig. 2) shows in the concentration range of liothyronine below 200.0 μMs does not have cytotoxicity completely to mdck cell.In the present embodiment, liothyronine is 3.125 ~ 100.0 μMs in the dosage scope of cellular level Antiviral breeding, is in safety non-toxic concentration range completely.
The antiviral activity evaluation of 2.4 liothyronine infected by influenza strains A/PuertoRico/8/34 (H1N1)
2.4.1. experimental principle: MUNANA(4-methylumbelliferyl-α-N-acetyl-neuraminate) be the specific substrate of influenza neuraminidase, the catalysate produced under neuraminidase effect is under 355nm excitation light irradiation, 460nm fluorescence can be produced, the power of fluorescence intensity represents the number of neuraminidase expression, reflects the virus quantity in cultured cell supernatant.
2.4.2. mdck cell is pressed 1.5 × 10
4cells/well is inoculated in 96 porocyte culture plates, after cultivating 14 ~ 18h, grows up to after monolayer for subsequent use until cell in 37 DEG C of cell culture incubators.Culture medium in orifice plate discarded, PBS liquid washes twice, adds 100TCID
50/ hole (100 μ l) virus liquid infection cell, add the medicine of each gradient concentration (with 100.0 μMs for initial concentration simultaneously, continuous 2 times of gradient dilutions 6 gradients, every gradient two is hole again) be in the cell maintenance culture solution (DMEM+0.3 %BSA+2.5ug/L pancreatin) of 200 μ l to cumulative volume, in cell culture incubator, get the detection that each experimental port supernatant carries out neuraminidase expression after 37 DEG C of cultivation 48h.Setup Experiments blank group, positive controls (ribavirin), negative control group (without drug treating after viral infection) and Experimental agents group.
2.4.3. 40 μ l buffer (32.5mmol/L MES, pH 6.5,4mmol/L CaCl is added in the micro plate of black 96 hole
2) the substrate 20umol/L MUNANA for preparing, add each experimental port culture supernatant 20 μ l again, 37 DEG C of lucifuges hatch 60min, add reaction terminating liquid (0.014 μM of NaOH, 83% ethanol) 100 μ l/ holes, micropore is read plate instrument to measure fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
2.4.4. the suppression ratio that each detect aperture Chinese medicine infected by influenza copies is calculated
Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result shows: liothyronine obviously inhibits copying of influenza virus, and in dose-dependence (see Fig. 3).
Embodiment 2: the evaluation of liothyronine resisiting influenza virus effect broad spectrum activity
This experiment detects the antiviral activity of liothyronine to influenza A subtype H1N1 strain, subtypes of influenza A virus H3N2 strain, subtypes of influenza A virus H1N1 amantadine persister and Influenza B virus.
1. the Strain that experiment uses comprises: A/Human/Hubei/1/2009 (H1N1), A/human/Hubei/3/2005 (H3N2), A/human/WSN/33/ (H1N1, S31N), B/human/Hubei/1/2007.
2. mdck cell is pressed 1.5 × 10
4cells/well is inoculated in 96 porocyte culture plates, after cultivating 14 ~ 18h, grows up to after monolayer for subsequent use until cell in 37 DEG C of cell culture incubators.Culture medium in orifice plate discarded, PBS liquid washes twice, adds 100TCID
50/ hole (100 μ l) virus liquid infection cell, add the medicine of each gradient concentration (with 100.0 μMs for initial concentration simultaneously, continuous 2 times of gradient dilutions 6 gradients, the multiple hole of every gradient two) to cumulative volume be in 200 μ l maintain liquid (DMEM+0.3 %BSA+2.5ug/L pancreatin), in cell culture incubator 37 DEG C cultivate 48h after get the detection that each experimental port supernatant carries out neuraminidase expression.
3. in the micro plate of black 96 hole, add 40 μ l buffer (32.5mmol/L MES, pH 6.5,4mmol/L CaCl
2) the substrate 20umol/L MUNANA for preparing, add each experimental port culture supernatant 20 μ l again, 37 DEG C of lucifuges hatch 60min, add reaction terminating liquid (0.014 μM of NaOH, 83% ethanol) 100 μ l/ holes, multi-tester measures fluorescent value (excitation wavelength 355nm, wavelength of transmitted light 465nm).
4. calculate the suppression efficiency that each detect aperture Chinese medicine infected by influenza copies
Suppression ratio (%)=100-(sample well-blank)/(enzyme contrast-blank alive) * 100%
Result show: liothyronine be dose-dependant inhibit copying (see Fig. 4) of various Influenza virus strain.
Claims (4)
1. the application of liothyronine in preparation treatment or flu-prevention virus infective medicament; Described influenza virus is influenza A virus or Influenza B virus.
2. apply as claimed in claim 1, it is characterized in that: described liothyronine is liothyronine or its pharmaceutical salts.
3. apply as claimed in claim 1, it is characterized in that: described medicine is using liothyronine as active constituents of medicine, make the pharmaceutically acceptable dosage form of any one.
4. apply as claimed in claim 3, it is characterized in that: described dosage form is tablet, capsule, granule, oral liquid or injection.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101342165A (en) * | 2007-07-13 | 2009-01-14 | 肖正连 | Instant gel rubber of thyroxine liothyronine for eyes |
| CN102639009A (en) * | 2009-07-10 | 2012-08-15 | 林齐·O·斯科特三世 | Methods and compositions for treating thyroid-related medical conditions with reduced folates |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101342165A (en) * | 2007-07-13 | 2009-01-14 | 肖正连 | Instant gel rubber of thyroxine liothyronine for eyes |
| CN102639009A (en) * | 2009-07-10 | 2012-08-15 | 林齐·O·斯科特三世 | Methods and compositions for treating thyroid-related medical conditions with reduced folates |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022221480A1 (en) * | 2021-04-15 | 2022-10-20 | Vertice Pharma Llc | Stable liquid oral dosage forms of liothyronine |
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