CN110151767A - Application of the GNF-7 in the drug of preparation treatment influenza infection - Google Patents
Application of the GNF-7 in the drug of preparation treatment influenza infection Download PDFInfo
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- CN110151767A CN110151767A CN201910380033.6A CN201910380033A CN110151767A CN 110151767 A CN110151767 A CN 110151767A CN 201910380033 A CN201910380033 A CN 201910380033A CN 110151767 A CN110151767 A CN 110151767A
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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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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Abstract
The invention discloses application of the GNF-7 in preparation treatment influenza infection drug.Applicant has detected GNF-7 to the toxicity of cell on human monocyte cell line U937, determined in non-toxic or low toxicity concentration range again GNF-7 in U937 cell line to IL-8, the secretion inhibition of these three important inflammatory factors of IP-10 and MCP-1, this small molecule compound has significant anti-inflammatory activity as the result is shown, and is in dose-dependent effect.In lethal mouse influenza infection model, infecting mouse is treated using GNF-7, the inflammatory factor concentration in infecting mouse lung washing lotion can be effectively reduced, delay mouse weight decrease speed and improve mouse survival rate.Therefore, the GNF-7 of present disclosure is a kind of anti-inflammatory drug of novel pin to influenza, has the advantages that safety is good, selection index is high and animal model experiment is effective, can be used for developing the drug for the treatment of influenza infection, have broad application prospects.
Description
Technical field
The invention belongs to pharmaceutical technology fields, relate generally to GNF-7 in the drug of preparation treatment influenza infection
Using.
Background technique
Influenza virus belongs to orthomyxoviridae family (Orthomyxoviridae), Influenza Virus.According to virion daughter nucleus egg
The difference of the antigenic characteristic and genetic characteristics of white (NP) and stromatin (M), influenza virus are divided into tri- type of A, B, C, also referred to as first,
Second, the third three types.The sub-thread strand RNA that influenza A full-length genome is differed in size by 8 forms, respectively with segment 1 to segment
8 names.Full length viral genome about 13.6kb encodes 10 kinds of structural proteins (PB2, PB1, PA, HA, NP, NA, M1, M2, PB1-
F2 and NS2/NEP) and non-structural protein (NS1).According to virion surface glycoprotein hemagglutinin (HA) and neuraminidase
(NA) difference, influenza A can be further divided into 17 H (H1-H17) and 10 N (N1-N10) hypotypes.Human influenza virus
Mainly H1, H2 and H3 hypotype.And endangering serious highly pathogenic bird flu at present is mostly H5, H7 and H9 hypotype, wherein with
H5N1 hypotype lethality highest.Type B influenza virus often causes influenza localized epidemics, does not cause worldwide influenza great outburst, only exists
It is found in people and sea dog.C-type influenza virus exists mostly in the form of being dispersed in, and primary attack infant does not cause influenza pandemic generally,
The mankind and pig can be infected.
Influenza virus has caused to be very popular for five times in the world since early 20th century finds, can generate within 10 years or so
Outbreak of epidemic, causes huge loss in the world.Influenza pandemic can lead 250,000~500,000 death every year,
3000000~5,000,000 grave illness examples, the people that the whole world about shares 5~15% are infected.The drug for the treatment of influenza is mainly neural ammonia at present
Sour enzyme inhibitor, the representative of such medicine are oseltamivir and Zha La meter Wei.Such drug to all known human influenza virus and
Highly pathogenic avian influenza virus is effective.These medicine antiviral drugs (such as Oseltamivir) need symptom appearance after 48 hours with
It inside takes and just has good therapeutic effect.Beyond this time window, therapeutic effect has larger decline.The reason of causing this phenomenon
It is that can cause excessive inflammatory reaction in infection middle and later periods virus, inspires " inflammatory factor storm ", only suppresses virus and be not enough to
Control the progress of disease, it is therefore desirable to develop the drug that influenza inflammation can be effectively relieved.
[[- 2- oxopyrimidin is simultaneously for Isosorbide-5-Nitrae-dihydro -1- methyl -7- [(6- methyl -3- pyridyl group) amino] by 3- by GNF-7, i.e. N-
[4,5-D] pyrimidine -3 (2H)-yl] -4- aminomethyl phenyl] -3- (trifluoromethyl) benzamide, it is novel Bcr-Abl inhibitor,
It is applied to the preclinical study of anti-tumor aspect at present, does not find any relevant report about GNF-7 treatment-resistant influenza.
Summary of the invention
It is an object of the invention to make up the deficiencies in the prior art, provides a kind of small molecule compound GNF-7 and preparing
The application in influenza infection drug is treated, so that the treatment for clinically influenza provides a kind of safely and effectively small molecule
Close object.GNF-7 can effectively inhibit the inflammatory factor of influenza virus induction in non-toxic range, can be further developed as controlling
The drug that influenza infection causes inflammation is treated, is with a wide range of applications.GNF-7 has structure shown in structural formula I:
In order to achieve the above purpose, the technical solution adopted by the present invention is that:
Application of the GNF-7 in preparation treatment influenza infection drug:
1 evaluates the toxicity of GNF-7, anti-inflammatory activity in influenza infection cell model and calculates its and select index,
Steps are as follows:
(1) by monocytic series U937 with 105Every hole is spread into 96 orifice plates, to detect antiphlogistic effects, is then infected simultaneously
0.1MOI (infection multiplicity) influenza H1N1 virus.
(2) addition simultaneously is diluted to the GNF-7 of various concentration gradient with culture medium, cultivates 48h.
(3) cell viability of drug-treated group and untreated fish group is detected, to detect the cytotoxicity of GNF-7.
(4) detection drug-treated group and inflammatory factor concentration in untreated fish group supernatant, are drawn with assessing GNF-7 resisiting influenza virus
The activity of inflammation.
(5) selection index of the GNF-7 in two kinds of cell lines is calculated.
2 evaluate antiphlogistic effects of the GNF-7 in living animal in lethal animal influenza infection model, and its step are as follows
(1) lethal mouse influenza virus infected animal model is established.
(2) the third day after virus infection, i.e., when mouse weight is decreased obviously, the mode being administered orally is used
GNF-7 treatment infecting mouse, continuous four days, once a day.
(3) the 7th day after infecting, control group and drug-treated group mouse lung-douching fluid are taken, detects wherein inflammatory factor water
It is flat.
(4) mouse weight, the death rate are recorded daily, and draw changes of weight curve and mouse survival rate curve.
(5) GNF-7 effect is evaluated with mouse weight variation, survival rate after infection.
The influenza virus includes but is not limited to: Influenza virus H1N1 hypotype (A/PuertoRico/8/1934),
H3N2 hypotype (A/Human/Hubei/3/2005).
Compared with prior art, the present invention having the following advantages that and effect:
1.GNF-7 is small molecule compound, the CC in U937 cell50(half lethal concentration) is each about 10.0 μM.
GNF-7 to three kinds of inflammatory factors IL-8, IP-10 and MCP-1 can dose-dependent inhibition inflammatory factor secrete, in U937
To the EC of IL-8 in cell50(half-inhibitory concentration) is only 0.05 μM, to the EC of IP-1050It is 0.05 μM, to the EC of MCP-150
It is 0.01 μM.By calculating, the selection index (SI) of GNF-7 illustrates that it is comprehensive anti-to being all larger than 100 in three kinds of inflammatory factors
The activity for the inflammation that influenza virus causes.
2.GNF-7 is effective in mouse lethal influenza infection model, and mouse weight decline degree can be significantly reduced,
The inflammatory factor reduced in mouse lung washing lotion is horizontal, improve mouse time-to-live and final survival rate.The medicine can be simultaneously
Infection is administered after three days and plays a role, complementary with existing antiviral agent, this makes GNF-7 latent with very big clinical treatment
Power.
3.GNF-7 has been listed, and has a large amount of clinical laboratory data, if as treatment of influenza medication, it can be significant
Clinical testing times are reduced, great amount of cost is saved.
Detailed description of the invention
Fig. 1 is toxicity and antiphlogistic effects of the GNF-7 in U937；
A is U937 cell viability after various concentration GNF-7 processing in Fig. 1；
B is the inhibiting rate that various concentration GNF-7 induces on U937 H1N1 influenza IL-8 in Fig. 1；
C is the inhibiting rate that various concentration GNF-7 induces on U937 H1N1 influenza IP-10 in Fig. 1；
D is the inhibiting rate that various concentration GNF-7 induces on U937 H1N1 influenza MCP-1 in Fig. 1.
Fig. 2 is effect of the GNF-7 in mouse lethal influenza infection model；
A is mouse weight change curve in Fig. 2；
B is mouse survival rate curve in Fig. 2.
Specific embodiment
In order to better understand the content of the present invention, the content of present invention is made furtherly below with reference to specific implementation method
Bright but of the invention protection content is not limited to following embodiment.Technical solution of the present invention is if not otherwise specified
Routine techniques；Agents useful for same or material derive from commercial channel if not otherwise specified.
Currently, treatment flu pharmaceutical evaluation model is broadly divided into external model (in vitro model) and In vivo model
(in vivo model).External model mainly uses various influenza sensitive cell lines or influenza pathology relevant cell system to drug
It is evaluated, the advantage is that can provide the identical cell of a large amount of inhereditary features is research object, it is easy to operate, it can eliminate other
The influence of extraneous factor, and can detecte drug toxicity, effective concentration and selection indexes Index, it is provided more for later period mechanism study
It is mostly basic.In vivo model generally uses various model animal infection models, is weighed by the various phenotype indexs after drug-treated
Measure overall effect of the drug in living animal.Its advantage is that true, system can be carried out to the effect of drug candidate in vivo
Evaluation.The present invention imitates the extracorporeal anti-inflammatory of GNF-7 using the human monocyte cell line U937 that can generate three important proinflammatory factors
Fruit carries out quantitative analysis, and calculates it and select index.Then, using lethal mouse influenza infection model, to the internal of GNF-7
The evaluation of anti influenza effect progress real system.
Experimental material:
(1) cell line needed for testing, experimental animal and virus
U937 cell is purchased from American Type Culture Collecti (ATCC)；
6 to 8 week old Balb/c mouse of SPF grade is purchased from Beijing Vital River Experimental Animals Technology Co., Ltd..
Strain used: influenza A H1N1 hypotype (A/PuertoRico/8/1934) H3N2 hypotype (A/Human/
Hubei/3/2005)。
Drug needed for testing: GNF-7 is purchased from Med Chem Express company；When cell experiment, drug is dissolved with DMSO；
It is dissolved when zoopery using sterile citrate buffer solution.
(2) reagent needed for testing
RPMI-1640 culture medium, fetal calf serum (FBS) are purchased from GIBCO company；
MTS cell proliferation detecting kit is purchased from Promega company.
(3) instrument needed for testing
EnSpire multi-function microplate reader is purchased from PerkinElmer company；
CO2 cell incubator is purchased from Thermo company
The evaluation for the inflammatory activity that resisiting influenza virus of the embodiment 1:GNF-7 in U937 cell line causes
1 cell culture
Cell after taking cryopreservation resuscitation after 2 passages, with containing 10% fetal calf serum and it is dual anti-(penicillin 100U/ml,
100 μ g/ml of streptomysin) RPMI-1640 culture medium amplification cultivation, inoculum density be not less than 5x105Cell/ml passes on density
Not higher than 2x106cell/ml。
The cytotoxicity of 2GNF-7 detects
U937 cell presses 1.5 × 105Cells/well (100 μ L of volume) is inoculated in 96 porocyte culture plates；With every 100 μ of hole
L liquid medium (+10% serum of RPMI-1640 culture medium+dual anti-) compounding pharmaceutical, and be added in corresponding cell hole and mix.Drug
Set 9 concentration gradients, each gradient concentration sets 2 multiple holes, final concentration of 0.02 μM, 0.05 μM, 0.14 μM, 0.41 μM,
1.23 μM, 3.7 μM, 11.11 μM, 33.33 μM and 100 μM.After cultivating 48h, tissue culture plate is centrifuged with 1500rpm/min
3min abandons supernatant.It is added the serum-free RPMI-1640 culture medium 100 μ L containing 20%MTS reagent into remaining cell, 37 DEG C
1h is educated, 1500rpm/min is read after being centrifuged 3min with EnSpire microplate reader detection OD490, calculates cell survival rate.
Cell survival rate (%)=drug-treated group/untreated control group * 100%
As a result as shown in figure 1 shown in A, GNF-7 half toxic concentration CC50About 10 μM.
The anti-inflammatory activity of 3GNF-7 infected by influenza strain A/PuertoRico/8/34 (H1N1)
U937 cell is pressed 1.5 × 10 by 3.15Cells/well (100 μ L of volume) is inoculated in 96 porocyte culture plates, infection
The H1N1PR8 virus of 0.1MOI (infection multiplicity) is added in group, while the drug that each gradient concentration is added is (dense to originate with 100 μM
Degree, continuous 3 times of gradient dilutions, 9 gradients, two multiple holes of every gradient) to the culture solution that total volume is 200 μ L, (RPMI-1640 is trained
Feeding+10% serum of base+dual anti-), take each experimental port supernatant to carry out inflammatory factor level after 37 DEG C of culture 48h in cell incubator
Detection.
3.2 every holes are drawn 5 μ L cell conditioned mediums and are added in 384 hole detection plates (OptiPlates), and it is dilute that 20 μ L are added in every hole
The acceptor bead (acceptorbeads) released, then room temperature is protected from light incubation 1 hour, adds the donor bead that 25 μ L have diluted
(donorbeads), it then with room temperature is protected from light after being incubated for 0.5h, with the inspection of AlphaScreen mode on multifunctional enzyme mark detector
It surveys.
Inhibiting rate of the drug to inflammatory factor in 3.3 each detection holes of calculating
Inhibiting rate (%)=100- (drug-treated hole-blank control)/(virus control wells-blank control) * 100%
As a result as shown in figure 1 shown in B, C, D, GNF-7 obviously inhibits the secretion of IL-8, IP-10 and MCP-1, and is in agent
Measure dependence, medium effective concentration EC50Respectively 0.01 μM, 0.05 μM and 0.05 μM.
3.4 medicament selection indexes calculate
Medicament selection index (SI) is used to judge the safe range of effect of drugs, and selecting index to be greater than 1.00, the above are have
Effect, index is bigger, and safe range is bigger.Its calculation formula is: SI=CC50/EC50
In conjunction with above-mentioned data, GNF-7 is greater than 100 to the selection index of three inflammatory factors on U937, has very strong
The inflammatory effect that resisiting influenza virus causes.
The evaluation that resists other influenza viruses initiation inflammatory activity of the embodiment 2:GNF-7 in U937 cell line
The present embodiment infects U937 cell line with H3N2 hypotype (A/Human/Hubei/3/2005), and method is the same as embodiment 1.
As a result, it was confirmed that GNF-7 obviously inhibits these three inflammatory factors to secrete, and it is in dose-dependence, belongs to wide
The resisiting influenza virus of spectrum causes anti-inflammatory drugs.
The effect for the inflammation that resisiting influenza virus of the embodiment 3:GNF-7 in mouse lethal influenza infection model causes is commented
Valence
1 experiment flow:
1) 6-8 week old BALB/c mouse is randomly divided into drug evaluation group, negative control group (PBS), every group 8.Formally
Before experiment, mouse adapts to 2~3d of environment.
2) on the day of attacking poison, mouse is then used through 1% yellow Jackets light anesthesia (every gram of weight about 0.1ml arcotic)
Liquid-transfering gun infects the 20 μ L of H1N1 mouse lung adapted strain virus liquid of 2LD50 using collunarium mode.
3) start to be administered within the 3rd day after virus infection, be continued until after infection the 6th day, amount to administration 4 days.Using oral
Administration, once a day for 15mg/kg, interval is for 24 hours for dosage.Every group of the weight of animals is periodically weighed daily, observes mouse survival situation.
4) after the completion of being administered, continue the weight and symptom that observe and record mouse daily, timing is replaced and addition padding, drinking-water
And food, dead mouse is taken out in time, until experiment is completed.
5) according to statistical result, changes of weight curve and Survival curves are drawn out.
2 experimental results
Changes of weight result is as shown in A in Fig. 2, after mouse administration, compares virus control group, it is flat that GNF-7 group handles mouse
Equal weight loss trend slightly lowers.
Survival results are as shown in B in Fig. 2, virus control group the 20th day death rate 91.7% (11/ after mouse infection
12) the 20th day death rate 50% (6/12), and after GNF-7 processing group mouse infection.
The above results explanation, GNF-7 have apparent therapeutic effect for influenza infection in Mice Body.
To sum up result can be seen that GNF-7 cellular level and internal animal level all have good anti influenza in vitro
The effect for the inflammation that virus infection causes can be used for developing the drug for the treatment of influenza infection, before wide application
Scape.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example
Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not
It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be in office
It can be combined in any suitable manner in one or more embodiment or examples.In addition, without conflicting with each other, the skill of this field
Art personnel can tie the feature of different embodiments or examples described in this specification and different embodiments or examples
It closes and combines.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is not considered as limiting the invention.Those skilled in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, modifies, replacing or modification.
As it will be easily appreciated by one skilled in the art that the foregoing is merely illustrative of the preferred embodiments of the present invention, not to
The limitation present invention.Any modification, equivalent replacement or improvement done within the spirit and principles of the present invention etc. should all include
Within protection scope of the present invention.
Claims (6)
- Application of the 1.GNF-7 in the drug of preparation treatment influenza infection.
- 2. application as described in claim 1, it is characterised in that: the influenza virus is influenza A virus.
- 3. application as described in claim 1, it is characterised in that: any pharmacy is made as active pharmaceutical ingredient in GNF-7 Upper acceptable dosage form.
- 4. application according to claim 3, it is characterised in that: the dosage form be tablet, capsule, granule, oral solution, Injection.
- 5. application according to claim 2, the influenza virus is Influenza virus H1N1 hypotype (A/ PuertoRico/8/1934), H3N2 hypotype (A/Human/Hubei/3/2005).
- Application of the 6.GNF-7 in the anti-inflammatory drugs that preparation inhibits influenza virus to cause.
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Citations (3)
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| CN104736569A (en) * | 2012-01-12 | 2015-06-24 | 耶鲁大学 | Compounds & methods for the enhanced degradation of targeted proteins & other polypeptides by an e3 ubiquitin ligase |
| CN109081828A (en) * | 2017-06-14 | 2018-12-25 | 上海时莱生物技术有限公司 | Poly- (ADP- ribose) polymerase inhibitors, Preparation method and use |
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2019
- 2019-05-08 CN CN201910380033.6A patent/CN110151767B/en active Active
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| CN104736569A (en) * | 2012-01-12 | 2015-06-24 | 耶鲁大学 | Compounds & methods for the enhanced degradation of targeted proteins & other polypeptides by an e3 ubiquitin ligase |
| KR20130084083A (en) * | 2012-01-16 | 2013-07-24 | 한국과학기술원 | Indole derivatives, abl kinase inhibiting composition and pharmaceutical compositions for prevention and treatment of abnormal cell growth diseases comprising the same |
| CN109081828A (en) * | 2017-06-14 | 2018-12-25 | 上海时莱生物技术有限公司 | Poly- (ADP- ribose) polymerase inhibitors, Preparation method and use |
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