CN107625761A - Applications of the A771726 in the medicine for preparing treatment influenza infection relevant disease - Google Patents
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Abstract
Applications of the A77 1726 in the medicine for preparing treatment influenza infection relevant disease, belongs to biomedicine field, and A77 1726 can be used as anti-influenza virus medicament to be used to treat or prevent influenza infection.The present invention passes through the infection experiment to the influenza virus of a variety of humans and animals such as including H5N1, H1N1 and H9N2, it was confirmed that the active metabolite A77 1726 of leflunomide can effectively suppress the influenza virus of a variety of hypotypes.And suppress the gene transcription test of influenza virus by A77 1726, it was confirmed that A77 1726 suppresses the albumen synthesis of three of the above virus.Find that A77 1726 also has an antiphlogistic effects by research, with anti-inflammatory double effectses, the effect of " killing two birds with one stone " will can be played with antiviral when A77 1726 treats influenza infection.
Description
Technical field
The invention belongs to biomedicine field, it is related to the active metabolite A77 1726 of leflunomide new application skill
Art, it is directed to the production technical field of resisiting influenza virus infection medicine.
Background technology
Influenza（Influenza）It is by influenza virus（Influenza Virus, IV）Caused acute respiratory disease,
Have the characteristics that highly infectious, propagation are fast, can cause humans and animals high incidence and the death rate, to animal doctor across kind of a propagation
Health and public health constitute serious threat.The mankind undergo four human influenzas and are very popular since 20th century：That is nineteen fifty-seven
H2N2, nineteen sixty-eight H3N2,1918 and H1N1 in 2009, wherein causing tens of millions of people dead.And ten since entrance 21 century
Yu Nian, the outburst of other new type influenzas are substantially accelerated, and harm is huge.As the end of the year 2003 came from the highly pathogenic H5N1 fowl in Southeast Asia
Influenza virus quickly spreads, and then across Europe, Asia and Africa, is popular in 60 several countries and continues to this day, make thousands of poultry
It is dead with wild fowl, and it is dead to cause nearly 800 people in the whole world to infect, case fatality rate is up to 60%.The H7N9 of global the first explosion in 2013 is sub-
Type avian influenza virus, successively already lead to 319 people and infect death.Except the Influenza epidemic situation of these new outbursts, the whole world is put down every year
There is the disease that 25~500,000 people die from seasonal influenza initiation.Influenza not only carrys out great prestige to the health care belt of human and animal
The side of body, while also bring huge economic loss and white elephant to society and country.
The major way for successfully managing influenza virus at present is biological agent and chemotherapy.Biological agent is mainly
Prevented and treated using vaccine, vaccine is one of effective means for suppressing influenza virus, but the validity of vaccine prevention is to establish
On the basis of the Strain of vaccine is similar to popular strains of influenza viruses, due to the antigenic variability of influenza virus,
So that the validity of vaccine significantly reduces to add needs the long period from vaccine injection to protection antibody is produced, it is now chemical
The effect for just serving key of drug therapy.For current research, chemotherapy influenza virus is concentrated mainly on
Neuraminidase inhibitor（Such as：The oral capsule Tamiflu of Roche companies production）, inhibitors of ion channels（Such as：M2 ions lead to
Road inhibitor）And RNA polymerase inhibitor.Neuraminidase inhibitor is the focus of current anti-influenza virus medicament research, but
It is that its R＆D process is filled with hardships, opportunities and challenges, it is necessary to put into substantial amounts of expense and time support.M2 ion channel eggs
White inhibitor is the influenza clinical treatment medicine listed earliest, but neurotoxicity be present, long-term use be also easy to produce resistance strain and
The defects of invalid to Type B influenza.But it is exactly to occur different degrees of influenza successively that this few class medicine, which faces a common problem,
Viral resistance.In addition, after many patients infect these new influenza viruses such as H5N1, H7N9, serious lung inflammation is died from
Reaction.Clinically there is an urgent need to a kind of efficient antiviral drugs preferably while having antiphlogistic effects.
Although existing vaccine to a certain extent can flu-prevention virus infection and morbidity, many problems be present, one
Be influenza virus antigenic variation it is fast, if the vaccine of annual prediction inoculation and the virus subtype of prevalence are not inconsistent, its immune effect
Suffer from very big influence；Second, the patient of some immunodeficiency types and old patient are caused due to immunologic hypofunction
The immune effect of vaccine is bad；Third, existing antiviral drugs is also easy to produce the resistance to the action of a drug；Fourth, these medicines are sent out in virus infection
Often effect is limited after being ill.
Screened using molecular genetics means and to existing small-molecule chemical storehouse, find some crucial cells
Interior composition participates in the duplication of virus.It is several more molecular targeted including propylhomoserin protein kinase then whey acidohydrogenase than more prominent
And PI-3 kinase signal pathway.Whey acidohydrogenase participates in the nucleotides synthesis of virus, and disease can be influenceed by suppressing the activity of the enzyme
The duplication of virus gene group.EGFR-TK plays an important role to the nuclear translocation of viral M1 albumen.
Leflunomide（Leflunomide）It is clinically a kind of anti-inflammatory finished medicines for treating rheumatic arthritis, it is secondary
Effect has been studied clear, is easy to prevention and control.But up to now, people do not have found that leflunomide also has other purposes also.But
Found in the early-stage Study of the present inventor, the active metabolite A77 1726 of leflunomide can suppress intracellular and participate in virus
The a variety of enzymes replicated, including LCK, S6K1 kinases and whey acidohydrogenase.
The content of the invention
The present invention seeks to a kind of new application for the active metabolite A77 1726 for proposing leflunomide.
The active metabolite A77 1726 of leflunomide can be used as anti-influenza virus medicament to be used to treat or prevent influenza
Virus infection.
The present invention passes through the infection experiment to the influenza virus of a variety of humans and animals such as including H5N1, H1N1 and H9N2, card
The active metabolite A77 1726 of real leflunomide can effectively suppress the influenza virus of a variety of hypotypes.And pass through A77
1726 suppress the gene transcription test of influenza virus, it was confirmed that A77 1726 suppresses the albumen synthesis of three of the above virus.Can
With the prevention and treatment for a variety of influenza infection humans and animals.Find that A77 1726 also has anti-inflammatory effect by research
Fruit, by with antiviral and anti-inflammatory double effectses when A77 1726 treats influenza infection, it can play " killing two birds with one stone "
Effect.
The present inventor also by study A77 1726 antiviral-mechanism find A77 1726 control virus replication ability and its
It is unrelated to suppress lactic acid dehydrogenase activity.The antiviral effect that uridine is played A77 1726 influences little.Uridine can be with carrying out fluorine
Meter Te is used in combination, for preventing leflunomide because suppressing side effect caused by the synthesis of pyrimidine mononucleotide.
The active metabolite A77 1726 of leflunomide is in the medicine of the treatment influenza infection relevant disease
Concentration >=50 μM.Taking leflunomide in patient body, the concentration of A77 1726 in blood plasma can be readily achieved 200 μM.
It is expected that the concentration of A77 1726 in blood plasma will reach the effect of suppressing virus replication.
Brief description of the drawings
Fig. 1 is the chemical structural formula of leflunomide.
Fig. 2 is the active metabolite A77 1726 of leflunomide chemical structural formula.
Fig. 3 is that A77 1726 reduces titre results of the H5N1 virus in CEF culture supernatants.
Fig. 4 is that A77 1726 still reduces H5N1 in chicken embryo fibroblasts culture in the culture medium of addition uridine
Titre results in clear.
Fig. 5 is that A77 1726 reduces titre results of the H5N1 virus in mdck cell culture supernatant.
Fig. 6 is that A77 1726 reduces titre results of the H5N1 virus in A549 cells and supernatants.
Fig. 7 is that A77 1726 reduces titre results of the H1N1 viruses in chicken embryo fibroblasts culture supernatant.
Fig. 8 is that A77 1726 reduces titre results of the H1N1 viruses in mdck cell culture supernatant.
Fig. 9 is that A77 1726 reduces titre results of the H1N1 viruses in A549 cells and supernatants.
Figure 10 is that A77 1726 reduces titre results of the H9N2 viruses in chicken embryo fibroblasts culture supernatant.
Figure 11 is that A77 1726 reduces titre results of the H9N2 viruses in mdck cell culture supernatant.
Figure 12 is that A77 1726 reduces titre results of the H9N2 viruses in A549 cells and supernatants.
Figure 13 is that immunoelectrophoresis Transfer Experiment shows that A77 1726 suppresses H5N1 virus virus in chicken embryo fibroblasts
The synthesis comparison diagram of albumen.
Figure 14 is that immunoelectrophoresis Transfer Experiment shows that A77 1726 suppresses conjunction of the H5N1 virus in mdck cell virus protein
In contrast with scheme.
Figure 15 is that immunoelectrophoresis Transfer Experiment shows that A77 1726 suppresses conjunction of the H5N1 virus in A549 cell virus albumen
In contrast with scheme.
Figure 16 is that immunoelectrophoresis Transfer Experiment shows that A77 1726 suppresses H1N1 viruses in chicken embryo fibroblasts virus egg
White synthesis comparison diagram.
Figure 17 is that immunoelectrophoresis Transfer Experiment shows that A77 1726 suppresses H1N1 viruses virus protein in mdck cell
Synthesize comparison diagram.
Figure 18 is that immunoelectrophoresis Transfer Experiment shows that A77 1726 suppresses H1N1 viruses virus protein in A549 cells
Synthesize comparison diagram.
Figure 19 is that immunoelectrophoresis Transfer Experiment shows that A77 1726 suppresses H9N2 viruses virus in chicken embryo fibroblasts
The synthesis comparison diagram of albumen.
Figure 20 is that immunoelectrophoresis Transfer Experiment shows that A77 1726 suppresses H9N2 viruses virus protein in mdck cell
Synthesize comparison diagram.
Figure 21 is that immunoelectrophoresis Transfer Experiment shows that A77 1726 suppresses H9N2 viruses virus protein in A549 cells
Synthesize comparison diagram.
Figure 22 is that real-time RT-PCR shows that A77 1726 suppresses the genome duplication comparing result of H5N1 virus.
Embodiment
Material used, reagent etc., unless otherwise specified, are commercially obtained in following embodiments.
First, the active metabolite A77 1726 of leflunomide reduces the H5N1 virus titre examination in cells and supernatant
Test：
1st, test material explanation：
Cell：A549 cells（Human lung cancer cell line）With MDCK cells（Martin's MDCK system）Purchase in US mode bacterial strain
Collection（ATCC）.CEF（Chicken fibroblasts）Prepare according to a conventional method.
H5N1 AIV A/mallard/Huadong/S/2005 (SY strains), by the Ministry of Agriculture of Yangzhou University livestock and poultry pestology
Emphasis open trial room preserves.DMEM culture mediums are produced by Gibco companies, article No. 1696189.Hyclone is by Gibco companies
Production, article No. 1652790.Leflunomide（Leflunomide）Active metabolite A771726（Hereinafter referred to as：A77
1726）There is provided by Cin Kate Corporation (Oak Park, IL).
2nd, test method：
Parallel test one：A549 cells will be taken（Human lung cancer cell line）, MDCK cells（Martin's MDCK system）And CEF（Chicken
Fibroblast）Each four parts, put into respectively in 12 test tubes, infect H5N1 virus respectively（Inoculum concentration is 0.1 MOI）Afterwards, then
The A77 1726 of four kinds of various concentrations is added respectively to the cell of each virus infection（0,50,100,200 μM）, different
Time collects culture supernatant, for using TCID50Method determines virus titer.
Parallel test two：A549 cells will be taken（Human lung cancer cell line）, MDCK cells（Martin's MDCK system）And CEF
（Chicken fibroblasts）Each four parts, put into respectively in 12 test tubes, infect H5N1 virus respectively（Inoculum concentration is 0.1 MOI）
Afterwards, then to the cell of each virus infection the A77 1726 of four kinds of various concentrations is added respectively（0,50,100,200 μM）And
200 μM of uridine, culture supernatant is collected in the different time, for using TCID50Method determines virus titer.
TCID50Method determines virus titer：By chicken embryo fibroblasts（CEF）It is inoculated into 96 porocyte culture plates, treats
After cell forms individual layer, remove culture supernatant and washed 2 times with PBS, obtain cell.Then above-mentioned two groups of parallel tests are collected
Each culture supernatant be seeded to cell surface respectively after 10 times of dilutions, then by metainfective cell in 37 DEG C, 5% CO2Condition
Under continue to cultivate.After 72h, added after each supernatant of culture is pressed into gradient doubling dilution to 96- holes V-type plate, add 1%
Chicken red blood cell, and result is observed after 15 min are acted under the conditions of being transferred to 37 DEG C, and HA-HI test is recorded, statistics infects positive hole
Number, tissue culture infective dose is calculated according to Reed-Muench methods（TCID50）.
3rd, result：
As Fig. 3 shows that A77 1726 reduces H5N1 virus in CEF in the culture medium for not adding uridine（Chicken fibroblasts）Training
Support the titre results in supernatant.
As Fig. 4 shows that A77 1726 still reduces H5N1 in CEF in the culture medium of addition uridine（Chicken is into fiber finer
Born of the same parents）Titre results in culture supernatant.
As Fig. 5 shows that A77 1726 reduces H5N1 virus in MDCK cells（Martin's MDCK system）In culture supernatant
Titre results.
As Fig. 6 shows that A77 1726 reduces H5N1 virus in A549 cells（Human lung cancer cell line）In culture supernatant
Titre results.
From Fig. 3~6：A77 1726 is reduced in CEF, MDCK and A549 cell culture in concentration gradient dependent form
The TCID of H5N1 virus in clear50Value.After adding uridine in cell culture, A77 1726 is still effectively reduced in culture supernatant
Virus titer ability（As shown in figures 4-6）.Meanwhile also show uridine to A77 1726 antiviral print effect very
It is limited.It is little that the antiviral effect that A77 1726 is played with it suppresses the activity relationship of whey acidohydrogenase.
2nd, A77 1726 reduces the H1N1 virus titers experiment in cells and supernatant：
1st, test material explanation：
H1N1 Influenza virus strains（A/California/ 04/09, CA/09, H1N1) China Agricultural University's offer.
2nd, test method：
Parallel test：A549 cells will be taken（Human lung cancer cell line）, MDCK cells（Martin's MDCK system）And CEF（Chicken embryo
Fibroblast）Each four parts, put into respectively in 12 test tubes, infect H1N1 viruses respectively（Inoculum concentration is 1 MOI）Afterwards, it is then right
The cell of each virus infection adds the A77 1726 of four kinds of various concentrations respectively（0,50,100,200 μM）, virus inoculation 24
Culture supernatant is collected respectively after hour, for using TCID50Method determines virus titer.
TCID50Method determines virus titer：Mdck cell is inoculated into 96 porocyte culture plates, treats that cell forms individual layer
Afterwards, remove culture supernatant and washed 2 times with PBS, obtain cell.Each culture supernatant that then above-mentioned parallel test is collected is through 10
Cell surface is seeded to respectively after diluting again, then by metainfective cell in 37 DEG C, 5% CO2Under the conditions of continue to cultivate.By
After 72h, added after each supernatant of culture is pressed into gradient doubling dilution to 96- holes V-type plate, add 1% chicken red blood cell, and shift
Result is observed after 15 min are acted under the conditions of to 37 DEG C, and records HA-HI test, statistics infects positive hole count, according to Reed-
Muench methods calculate tissue culture infective dose（TCID50）.
3rd, result：
From Fig. 7 to Fig. 9：Reduce CEF, MDCK and A549 cells and supernatant to the concentration gradient dependences of A77 1726
In H1N1 virus TCID50 values.A77 1726 suppresses medium effective concentration of the H1N1 viruses in A549 and mdck cell
（IC50Value）About 23~32 μM.
The active metabolite A77 1726 of leflunomide concentration in the medicine needed for the treatment influenza infection
Less than 50 μM.And it is higher than 200 μM receiving the drug concentration of the rheumatoid arthritis of leflunomide treatment in patient body, table
Concentration of the bright medicine in blood plasma is enough the effect for playing its effective antiviral duplication.
3rd, A77 1726 reduces the H9N2 virus titers experiment in cells and supernatant：
1st, test material explanation：
H9N2 Influenza virus strains are AIV Ck/SH/F/98.The strain is provided by Fan Liu Xiu laboratory of Yangzhou University.
2nd, test method：
Parallel test two：A549 cells will be taken（Human lung cancer cell line）, MDCK cells（Martin's MDCK system）And CEF（Chicken
Fibroblast）Each four parts, put into respectively in 12 test tubes, infect H9N2 Influenza virus strains respectively（Inoculum concentration is 1
MOI）Afterwards, then to the cell of each virus infection the A77 1726 of four kinds of various concentrations is added respectively（0,50,100,200 μ
M）, virus inoculation collects culture supernatant respectively after 24 hours, for using TCID50Method determines virus titer.
Parallel test two：A549 cells will be taken（Human lung cancer cell line）, MDCK cells（Martin's MDCK system）And CEF
（Chicken fibroblasts）Each four parts, put into respectively in 12 test tubes, infect H9N2 Influenza virus strains respectively（Inoculum concentration is 1
MOI）Afterwards, then to the cell of each virus infection the A77 1726 of four kinds of various concentrations is added respectively（0,50,100,200 μM）
And 200 μM of uridine, culture supernatant is collected in the different time, for using TCID50Method determines virus titer.
TCID50Method determines virus titer：By MDCK cells（Martin's MDCK system）It is inoculated into 96 porocyte culture plates
In, after cell forms individual layer, remove culture supernatant and washed 2 times with PBS, obtain cell.Then by above-mentioned two groups of parallel examinations
Check and accept each culture supernatant for taking and be seeded to cell surface respectively after 10 times of dilutions, then by metainfective cell 37 DEG C, 5%
CO2Under the conditions of continue to cultivate.After 72h, added after each supernatant of culture is pressed into gradient doubling dilution to 96- holes V-type plate, then
1% chicken red blood cell is added, and result is observed after 15 min are acted under the conditions of being transferred to 37 DEG C, and records HA-HI test, statistics infection sun
Property hole count, according to Reed-Muench methods calculate tissue culture infective dose（TCID50）.
3rd, result：
From Figure 10~12：Reduce to the concentration gradient dependences of A77 1726 TCID50 of the H9N2 viruses in culture supernatant
Value.
Experiment, which also demonstrates addition uridine in cell culture, can not significantly affect the suppression cytopathies of A77 1726 and culture
Virus titer in supernatant.
4th, Western blotting shows that A77 1726 suppresses influenza virus protein synthetic test：
1st, test material explanation：
The antibody of resisiting influenza virus HA, M1 and NP albumen is mouse source polyclonal antibody.Detect β-actin cell protein conducts
Internal reference, using β-actin mouse monoclonal antibodies (Santa Cruz companies, article No. H0515).Horseradish peroxidase-labeled
Sheep anti mouse secondary antibody (purchase company Cell Signaling companies, article No. 7076S).
2nd, test method：
Parallel test one：A549 cells will be taken（Human lung cancer cell line）, MDCK cells（Martin's MDCK system）And CEF（Chicken
Fibroblast）Each four parts, put into respectively in 12 test tubes, add the A77 1726 of four kinds of various concentrations respectively（0,50,
100,200 μM）, culture 20h cell sample is obtained respectively, and A77 is added for being detected by immunoelectrophoresis Transfer Experiment
After 1726 processing in each part cell sample influenza virus NP, M1 and HA albumen expression quantity.
Parallel test two：A549 cells will be taken（Human lung cancer cell line）, MDCK cells（Martin's MDCK system）And CEF
（Chicken fibroblasts）Each four parts, put into respectively in 12 test tubes, add the A77 1726 of four kinds of various concentrations respectively（0,
50,100,200 μM）And the cell sample of 200 μM of uridine, respectively acquirement culture 20h, for being shifted by immunoelectrophoresis
Testing inspection adds the expression quantity of influenza virus NP, M1 and HA albumen in each part cell sample after A77 1726 is handled.
Immunoelectrophoresis Transfer Experiment detection method：Each cell sample that two groups of parallel test cultures obtain by more than is first used
After PBS cleaning cells 1~2 time, add 1mL PBS and mother liquid concentration is that the μ L of 0.5M EDTA 10 treat that cell detachment gets off use
Collect, 5000rpm, 4 DEG C, centrifuge 5min, discard PBS supernatants, obtain cell.Respective volume is added according to the quantity of cell
Cell pyrolysis liquid（With preceding plus final concentration of 2mM Cocktail（Thermo companies sell, article No. QB214947））, whirlpool
It is placed in after rotation vibration and cracks 15min on ice.After cracking terminates, 15000rpm, 4 DEG C, centrifuge 10min, by supernatant move into it is new from
In heart pipe.Corresponding sample-loading buffer is added according to the supernatant amount of collection, after boiling 3min in 95 DEG C of metal baths, obtains sample mark
Remember.SDS-PAGE glue, transferring film, closing, incubation antibody, the expression of luminous detection NP, M1 and HA albumen of last applied chemistry
Amount.
3rd, result：
Figure 13,14,15 are respectively to whether there is A77 under the conditions of uridine in each cell sample that two groups of parallel test cultures obtain above
1726 significantly inhibit NP, M1 and HA viral protein expression of the H5N1 influenza viruses in CEF, MDCK and A549 cell.Figure 13,
14th, the symbolization "-" without uridine represents in 15, and the symbolization "+" for having uridine represents；Actin is Western blotting in each figure
The internal reference of sample in experiment, show that the total protein concentration in sample is relatively consistent.
From Figure 13,14,15：The ability that A77 1726 suppresses virus protein synthesis is in the relation of concentration dependent.Carefully
Uridine is added in born of the same parents' culture to have little to no effect the ability of the suppression virus protein synthesis of A77 1726.
Figure 16,17 and 18 do not add respectively A77 1726 under the conditions of uridine significantly inhibit H1N1 influenza viruses CEF,
NP and M1 viral protein expressions in MDCK and A549 cells.
Figure 19,20,21 do not add respectively A77 1726 under the conditions of uridine significantly inhibit H9N2 influenza viruses CEF,
NP and M1 viral protein expressions in MDCK and A549 cells.
Each figure explanation above：A77 1726 can efficiently suppress the synthesis of influenza virus NP, M1 and HA albumen, mechanism
It is：A77 1726 suppresses the duplication of influenza virus in the cell by suppressing the synthesis of virus protein.
5th, A77 1726 suppresses the genome duplication experiment of influenza virus：
1st, test method：
Parallel test：Take CEF（Chicken fibroblasts）Four parts, put into respectively in four test tubes, infect H5N1 virus respectively（Inoculation
Measure as 0.1 MOI）, first test tube is blank test（That is control group）, A77 1726 is added into second test tube（200μ
M）, uridine is added into the 3rd test tube（200μM）, A77 1726 is added into the 3rd test tube（200μM）And uridine（200
μM）.Cell was collected after 24 hours, RNA is extracted using Qiagen kits（Kit article No. 79656).Total serum IgE determines
Reverse transcription reagent box and real-time fluorescence quantitative PCR are applied after concentration, determines the copy number of viral M1 genes.Method therefor is according to text
Report is offered to carry out.
2nd, result：
As shown in figure 22：Addition A77 1726 cell in H5N1 influenza virus M1 genes copy number compared with control group,
Reduce 91%.Addition A77 1726 and uridine cell in H5N1 influenza virus M1 genes copy number compared with control group,
Reduce 67%.Therefore, the effect for suppressing viral RNA duplication that addition uridine mediates to A77 1726 is limited, and A77 1726
Significantly inhibit the RNA copy numbers of infection CEF cell H5N1 virus.
Claims (2)
1. the active metabolite A77 1726 of leflunomide is in the medicine for preparing treatment influenza infection relevant disease
Using.
2. apply according to claim 1, it is characterised in that the active metabolite A77 1726 of leflunomide controls described
Treat concentration >=50 μM in the medicine of influenza infection relevant disease.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108670965A (en) * | 2018-07-26 | 2018-10-19 | 中国人民解放军第二军医大学 | Application of the teriflunomide in preparing anti-west nile virus drug |
| WO2021164672A1 (en) * | 2020-02-18 | 2021-08-26 | 华东理工大学 | Anti-rna virus drug and application thereof |
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| WO2012012736A2 (en) * | 2010-07-23 | 2012-01-26 | The Ohio State University | Method of treating a viral infection dysfunction by disrupting an adenosine receptor pathway |
| CN108721281A (en) * | 2017-04-20 | 2018-11-02 | 华东理工大学 | New antiviral drugs and its application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012012736A2 (en) * | 2010-07-23 | 2012-01-26 | The Ohio State University | Method of treating a viral infection dysfunction by disrupting an adenosine receptor pathway |
| CN108721281A (en) * | 2017-04-20 | 2018-11-02 | 华东理工大学 | New antiviral drugs and its application |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108670965A (en) * | 2018-07-26 | 2018-10-19 | 中国人民解放军第二军医大学 | Application of the teriflunomide in preparing anti-west nile virus drug |
| WO2021164672A1 (en) * | 2020-02-18 | 2021-08-26 | 华东理工大学 | Anti-rna virus drug and application thereof |
| CN113456632A (en) * | 2020-02-18 | 2021-10-01 | 华东理工大学 | anti-RNA virus medicine and application thereof |
| CN113456632B (en) * | 2020-02-18 | 2023-09-26 | 华东理工大学 | anti-RNA virus medicine and its application |
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