CN107441094A - Medicine and its pharmaceutical applications of the nilotinib as treatment dengue virus infection - Google Patents
Medicine and its pharmaceutical applications of the nilotinib as treatment dengue virus infection Download PDFInfo
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- CN107441094A CN107441094A CN201710670369.7A CN201710670369A CN107441094A CN 107441094 A CN107441094 A CN 107441094A CN 201710670369 A CN201710670369 A CN 201710670369A CN 107441094 A CN107441094 A CN 107441094A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to medicine and its pharmaceutical applications of the nilotinib as treatment dengue virus infection, specifically discloses purposes of the AMN107 in the medicine for treating or preventing dengue virus infection is prepared.For the present invention by confirming that AMN107 has good inhibitory action to DENV2 to DENV Inhibition test, inherently demonstrate the medicine has a wide range of application prospect in treatment DENV2 infectious diseases.The invention can provide good drug candidate for clinical treatment disease as caused by DENV2, have very good application prospect.
Description
Technical field
The present invention relates to drug field, and in particular to purposes of the AMN107 in terms of anti-dengue virus.
Background technology
Dengue virus (dengue virus, DENV) belongs to flaviviridae, and Flavivirus (Flaviviridae), is to work as this life
A kind of most wide arboviruse is distributed in boundary, is mainly propagated by the Aedes aegypti and aedes albopictus that bite people and causes dengue fever, its
In to there are dengue hemorrhagic fever/dengue shock syndrome (dengue hemorrhagic fever/dengue shock
Syndrome, DHF/DSS) it is even more serious.The virus has four serotypes, and the type of serum 2 is popular diseased plant dengue fever (dengue
Fever it is) acute infectious disease through mosquito matchmaker propagation, it is mainly popular in tropical and subtropical region.Dengue was found first from 1779
Since heat, Epidemic Situation of Dengue Fever has been broken out successively all over the world.Estimate according to WHO, at present prestige of the population in the whole world about 2/5 by dengue fever
The side of body, the people for having hundred million meters every year infect the virus.In addition to there is prevalence in China except Taiwan, its epidemic situation is concentrated mainly on Guangdong, is in more
Outburst and the popular feature of Introduced cases, it is known that 4 kinds of serotype dengue virus be found in China, and increased in diffusion
Trend.At present, the mechanism of dengue virus infection is thrown away indefinite, due to lacking effective cross protection between each serotype, is deposited again
In humidification of antibody-dependant etc., still it can use so far without safely and effectively vaccine, clinically also without effective medicine.
Although being found that many bioactive molecules for being directed to dengue fever virus major protein, (such as toxic side effect is asked for various reasons
Topic), there is presently no the medicine for dengue fever virus, and therefore, the discovery for the antiviral activity molecule of dengue fever has
Important biological study meaning and practice significance, support is provided to develop the active drug of dengue fever virus.
The content of the invention
The purpose of the present invention is to be the provision of a kind of antineoplastic AMN107 listed to control as preparation
Treat or prevent the application in dengue virus infection medicine, AMN107 is under 10.0M concentration to the inhibiting rate of 2 type dengue fever virus
For 90%.And AMN107 is under the conditions of 10M, the survival rate to BHK21 cells is 95%.AMN107 can effectively suppress
The increment of dengue fever virus, it can be further developed as treating the medicine of dengue virus infection, have to cytotoxicity very little
It is widely applied prospect.
The AMN107 structure is as follows：
One aspect of the invention provides use of the AMN107 in the medicine for treating or preventing flavivirus virus infection
On the way.
Another aspect of the invention provides AMN107 in the medicine for treating or preventing dengue virus infection is prepared
Purposes.
In the inventive solutions, dengue virus is dengue virus 1-4 types.
In the inventive solutions, dengue virus is dengue type 2 virus.
Another aspect of the present invention provides the AMN107 NS1 and mRNA of E protein in suppression dengue virus is prepared
Purposes in medicine.
Another aspect of the present invention provides AMN107 NS1 and protein of E protein in suppression dengue virus is prepared
Purposes in the medicine of expression.
Another aspect of the present invention provides a kind of pharmaceutical composition for treating dengue virus infection, and it contains as activity
The AMN107 of material.
In the inventive solutions, described pharmaceutical composition is ejection preparation, oral formulations or external preparation.
In the inventive solutions, described pharmaceutical composition is tablet, capsule, powder, pill, granule, note
Penetrate agent or emulsion.
Medicine AMN107 of the present invention is improved by the molecular structure of Imatinib, and BCR-ABL is swashed
Enzymatic activity has stronger selectivity, strong compared with Imatinib to the inhibitory action of EGFR-TK 30 times, can suppress to Imatinib
The kinase activity of the BCR-ABL saltant types of resistance.KIT and PDGFR kinase activities can also be suppressed simultaneously, clinically it is strong
Accurately second generation tyrosine kinase inhibitor, effectively treatment produce chronic myelogenous leukemia that is resistance or not tolerating and suffered from effect
Person.Inventor is found that the antiviral effect of AMN107 by screening existing marketed drug, for Buddhist nun of the present invention
Purposes of the Lip river for Buddhist nun in 2 type dengue virus infection medicines for the treatment of or prevention are prepared belongs to first public, because it is listing
Medicine, Pharmacokinetic Characteristics are good, and it has good effect to 2 type dengue fever virus inhibitory activity, is not present
Because other compounds provide the possibility of any enlightenment, possess prominent substantive distinguishing features, while be used for dengue virus infection
Treatment and preventing and treating obviously have it is significant progressive, it is most likely that be developed to the medicine of new viral infection resisting.
Brief description of the drawings
Fig. 1 is the cytopathic effect figure of dengue virus induction；
Fig. 2 is protein immunoblot testing result figure；
Fig. 3 is plaque assays result figure.
Embodiment
Toxicity test of the AMN107 of embodiment 1 to BHK-21 cells
BHK-21 cells (newborn hamster kidney cell) are DENV2 permissive cells.BHK-21 cells in experiment are this section office
It is all；MTT is purchased from green skies biotechnology research institute；Hyclone is purchased from GIBICO companies of the U.S.；Tissue Culture Plate is purchased from U.S.
Corning Incorporated of state；The culture mediums of RPMI 1640 are purchased from GIBICO companies of the U.S..
Experimental procedure is as follows：
1) BHK-21 cells are inoculated with：Individual cells are made into the culture mediums of RPMI 1640 containing 10% (V/V) hyclone to hang
Liquid, 96 porocyte culture plates are inoculated into every 10000 cells in hole；
2) BHK-21 cells are cultivated：At 37 DEG C, 5% (V/V) CO2Cultivated 24 hours under condition of culture；
3) AMN107 is added：The culture medium abandoned in each hole is inhaled, 100 μ l are added with 10% (V/V) tire ox to each hole
The culture mediums of RPMI 1640 of serum are diluted to the AMN107 of respective concentration, and control wells add 10% (V/V) tire of not drug containing
The μ l of 1640 culture mediums of RPMI 100 of cow's serum；
4) colour generation：Culture 48 hours after, to ordinary optical microscope under observation find Formazan all dissolve；
5) measurement and calculating：The survival rate of cell under 570nm measure absorption values, AMN107 various concentrations is dense for this
Light absorption value of the lower cell absorbance than upper control wells is spent, multiplied by with 100%.
Toxicity test of the AMN107 of the various concentrations of table 1 to BHK-21 cells
Experimental result
BHK-21 is newborn hamster kidney cell (Baby Hamster Syrian Kidney), can be by 2 type dengue virus
(DENV2) infect, be that dengue virus research uses one of more cell.It is thin to BHK-21 that this experiment detects AMN107 first
The cytotoxicity of born of the same parents, BHK-21 cells are acted on the AMN107 of various concentrations, to understand in cell survival more than 90%
The maximum concentration of AMN107, reference data is provided for inhibitory action experiment of the follow-up AMN107 to DENV2.
The AMN107 of embodiment 2 infects DENV2 the Inhibition test of BHK-21 cells：
It is as follows as the cell for cultivating viral DENV2,10TCID50, experimental procedure using BHK-21：
1) BHK-21 is accessed in Tissue Culture Plate, cell length is to individual layer after 24 hours, and the area of cell covering bottom hole is about
For 80%~90%, culture medium is suctioned out, PBS is washed 1 time, and the μ l of access viral sample 200,37 DEG C adsorb 1 hour.After the completion of absorption,
Inhale the virus liquid abandoned in each hole, PBS 1 time.Add what the culture mediums of RPMI 1640 containing 10% (V/V) hyclone diluted
The AMN107 of prescribed concentration, in 37 DEG C of 5% (V/V) CO2Cultivated under condition of culture.After 96 hours, cell occurs obvious thin
After born of the same parents' lesion, micro- Microscopic observation cytopathic effect.See Fig. 1.
2) supernatant is collected, surveys lactic dehydrogenase (LDH) content that cell discharges in supernatant；Or cultivate to after 48 hours, receive
Collect cell conditioned medium, do virus plaque experiment；Or cultivate to after 48 hours, the total mRNA of total protein for collecting cell passes through albumen respectively
Western blot and the content of real-time fluorescence quantitative PCR detection intracelluar toxalbumin.
3) Dehydrogenase Content that cell discharges in supernatant is surveyed：The μ l of 96 orifice plate cell conditioned medium 120 are drawn, use lactic dehydrogenase
Enzyme citotoxicity detection kit (LDH Cytotoxicity Assay Ki, Beyotime) detection DENV institutes are cytotoxicity caused
When the activity of lactic dehydrogenase that discharges.
The LDH for the BHK-21 cells release that the AMN107 of the various concentrations of table 2 is infected DENV2 influence
Experimental result:
See Fig. 1, after (10 μM) processing of AMN107, significantly reduce the cytopathic effect of DENV2 inductions.And with difference
BHK-21 cell of (10, the 5,2.5 μM) effects of AMN107 of concentration with having infected DENV2, LDH emission levels are notable
Reduce, so as to obtain suppression efficiency of the AMN107 to virus.
Suppression experiment of the AMN107 of embodiment 3 to DENV2 key proteins NS3 and E protein
1) total protein of cell is collected：After BHK-21 cells medicine and dengue virus (DENV2) processing, 48h carries egg
In vain, it is collected in 1.5ml Eppendorf pipes.
2) sample protein concentration is detected：Protein standard substance is diluted to 0,0.0008,0.0016,0.0032 with distilled water,
0.004,0.006,0.008mg/ml gradient concentration；The protein concentration in sample is calculated according to standard curve.Make each sample
Product protein concentration is consistent.
3) differential expression of the dengue virus albumen after the processing of protein immunoblot detection gradient concentration AMN107：By suitable
Sequence adds various reagents, and electrophoresis starting carries out electrophoresis with 80V constant pressures, after dye front enters separation gel, then is changed to 120V, root
Electrophoresis time 75min is determined according to pre-dyed albumen Marker separation degree and the molecular weight of target protein.
4) transferring film：Gel, the pvdf membrane of shear gel size are taken out from glass plate, and soaks 1min in methyl alcohol, then
5min is soaked with transfering buffering liquid (1*tris/glycine buffer, Biorad).By gel, filter paper, pvdf membrane is all immersed in
Shift in liquid.Membrane-transferring device is placed in transferring film box, confirms that electrode is errorless, transferring film liquid is added to whole membrane-transferring device is covered, turns
Bellows and top are covered with ice cube, are switched on power, 100V constant pressure transferring film 70min, after terminating, take out pvdf membrane.
5) protein blocking：Pvdf membrane is placed in confining liquid, room temperature shaker immersion 1h, to close heterogenetic antigen.Envelope
After closing, TBS/TT room temperature shakers wash film 3 times, and each 5min is then incubated primary antibody.
6) primary antibody hybridizes：Pvdf membrane albumen is placed in etui upwardly, addition contains Dengue viral envelope albumen
(Dengue virus Envelope protein antibody, GeneTex) and non-structural protein 1 (Dengue virus
NS3glycoprotein antibody, abcam) primary antibody TBS/T configuration 5% (w/v) skim milk buffer solution, 4 DEG C are shaken
Bed is overnight.PBST room temperature shakers wash film six times, each 5min.
7) secondary antibody hybridizes：Pvdf membrane albumen is placed in etui upwardly, add containing secondary antibody (rabbit-anti or mouse resist,
Proteintech 5% (w/v) skim milk buffer solution of TBS/T configurations), room temperature shaker 1 hour.PBST room temperature shakers are washed
Film six times, each 5min.
8) chemiluminescence is developed：ECL developer solution A/B liquid (CST) is uniformly added into proportion, PVDF films is immersed in luminous
In liquid, 2min is reacted.Pvdf membrane is taken out, is placed in magazine, darkroom exposure, exograph is placed, exposure, takes out development, dry
Film, record, preserve.
Include structural proteins and non-structural protein in DENV2 viruses, and structural proteins E protein and NS3 gene egg
Played an important role in vain in the breeding amplification of DENV2 viruses, therefore detect the AMN107 of various concentrations to NS3 and E protein
MRNA suppression levels.
Experimental result:
Referring to Fig. 2, with the increase structure albumen E protein and NS3 gene albumen suppression level of nilotinib dosage
Also gradually enhancing, so as to further confirm that the HIV suppression effect of AMN107.
The AMN107 of embodiment 4 produces the plaque inhibition test of progeny virus to DENV2
1) C6/36 cells are accessed in 24 orifice plates, (area of cell covering bottom hole is about to individual layer for cell length after 24 hours
90%~100%) culture medium abandoned in each hole, is inhaled, PBS is washed 1 time, accesses the μ l of viral sample 200 with PBS dilutions, 37 DEG C of suctions
Attached 1 hour.
2) supernatant in each hole is inhaled after the completion of adsorbing and abandoned, PBS washes away unadsorbed virus.Add fine containing 1.2% methyl
The culture mediums of RPMI 1640 of plain 2% (V/V) hyclone of dimension, in 37 DEG C, 5% (V/V) CO2Incubator in cultivate 96~120
Hour.
3) inhaled after plaque test and abandon 4% paraformaldehyde (the doctor's moral biology) fixation of methylcellulose covering culture medium,
Again with 1% (w/v) violet staining, wash away crystal violet with flowing water after 2 hours, 24 orifice plates scanned after drying, according to plaque number and
Extension rate calculates titre (PFU/ml, the PFU of virus：Plaque formation unit plaque forming units).PFU=diseases
Malicious dilution factor × P/V, (P：Plaque number；V：Inoculum concentration).
Experimental result
Referring to Fig. 3, plaque inhibition test is to detect an important indicator of virus titer and infection ability, and virus infection is thin
After born of the same parents, due to the limitation of solid dielectric, the virus of release can only be from the cell that initially infects to circumferential expansion.By several propagation
In the cycle, a Focal lesion cellular regions are just formed, this is virus plaques.After dyeing and washing, virus plaques will not contaminate
Upper color, so as to be presented as blank, remainder cell is intact to be presented blueness.On the BHK-21 cells that AMN107 is treated
After clear liquid takes out, the virus plaque experiment of supernatant is carried out, after so further confirming AMN107 processing, in cell conditioned medium
Viral level, the level of titre and infection ability.The more accurate anti-DENV2 progeny virus effect for judging AMN107.It is logical
Cross experimental result and understand that the plaque for then increasing formation with AMN107 concentration gradually decreases.
Claims (9)
1. purposes of the AMN107 in the medicine for treating or preventing flavivirus virus infection.
2. purposes of the AMN107 in the medicine for treating or preventing dengue virus infection is prepared.
3. purposes according to claim 2, wherein, dengue virus is dengue virus 1-4 types.
4. purposes according to claim 2, wherein, dengue virus is dengue type 2 virus.
5. purposes of the AMN107 in NS1 and the mRNA of E protein medicine in preparing suppression dengue virus.
6. purposes of the AMN107 in the medicine of NS1 and the protein expression of E protein in preparing suppression dengue virus.
7. a kind of pharmaceutical composition for treating dengue virus infection, it contains the AMN107 as active material.
8. pharmaceutical composition according to claim 7, wherein, described pharmaceutical composition be ejection preparation, oral formulations or
External preparation.
9. pharmaceutical composition according to claim 7, described pharmaceutical composition be tablet, capsule, powder, pill,
Granula, injection or emulsion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710670369.7A CN107441094B (en) | 2017-08-08 | 2017-08-08 | Nilotinib as medicine for treating dengue virus infection and pharmaceutical application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710670369.7A CN107441094B (en) | 2017-08-08 | 2017-08-08 | Nilotinib as medicine for treating dengue virus infection and pharmaceutical application thereof |
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| Publication Number | Publication Date |
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| CN107441094A true CN107441094A (en) | 2017-12-08 |
| CN107441094B CN107441094B (en) | 2020-05-22 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201710670369.7A Expired - Fee Related CN107441094B (en) | 2017-08-08 | 2017-08-08 | Nilotinib as medicine for treating dengue virus infection and pharmaceutical application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111346079A (en) * | 2020-02-24 | 2020-06-30 | 南方医科大学 | Bacterial DNA gyrase inhibitor BRD7716 as medicine for treating and/or preventing dengue virus infection and pharmaceutical application thereof |
| WO2021097008A1 (en) * | 2019-11-12 | 2021-05-20 | Bp Asset V, Inc. | Use of pyridyloxypyridines for treating infectious diseases |
| WO2021097009A1 (en) * | 2019-11-12 | 2021-05-20 | Bp Asset V, Inc. | Small molecule furin inhibitors for treating infectious diseases |
| WO2021097002A1 (en) * | 2019-11-12 | 2021-05-20 | Bp Asset V, Inc. | Use of pyridyloxypyrimidines for treating infectious diseases |
| US11773078B2 (en) | 2018-05-11 | 2023-10-03 | Glaxosmithkline Intellectual Property Development Limited | Furin inhibitors |
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| CN104274837A (en) * | 2014-09-18 | 2015-01-14 | 福格森（武汉）生物科技股份有限公司 | Nilotinib oral preparation |
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| CN104306350A (en) * | 2006-09-27 | 2015-01-28 | 诺华股份有限公司 | Pharmaceutical compositions comprising nilotinib or its salt |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11773078B2 (en) | 2018-05-11 | 2023-10-03 | Glaxosmithkline Intellectual Property Development Limited | Furin inhibitors |
| WO2021097008A1 (en) * | 2019-11-12 | 2021-05-20 | Bp Asset V, Inc. | Use of pyridyloxypyridines for treating infectious diseases |
| WO2021097009A1 (en) * | 2019-11-12 | 2021-05-20 | Bp Asset V, Inc. | Small molecule furin inhibitors for treating infectious diseases |
| WO2021097002A1 (en) * | 2019-11-12 | 2021-05-20 | Bp Asset V, Inc. | Use of pyridyloxypyrimidines for treating infectious diseases |
| CN114929220A (en) * | 2019-11-12 | 2022-08-19 | Bp资产V股份有限公司 | Small molecule furin inhibitors for the treatment of infectious diseases |
| CN111346079A (en) * | 2020-02-24 | 2020-06-30 | 南方医科大学 | Bacterial DNA gyrase inhibitor BRD7716 as medicine for treating and/or preventing dengue virus infection and pharmaceutical application thereof |
| CN111346079B (en) * | 2020-02-24 | 2023-06-20 | 南方医科大学 | Bacterial DNA gyrase inhibitor BRD7716 as medicament for treating and/or preventing dengue virus infection and pharmaceutical application thereof |
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| CN107441094B (en) | 2020-05-22 |
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