CN108096562A - Purposes of the 20S proteasome inhibitors in the drug for preparing treatment Japanese B encephalitis virus infection - Google Patents
Purposes of the 20S proteasome inhibitors in the drug for preparing treatment Japanese B encephalitis virus infection Download PDFInfo
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- CN108096562A CN108096562A CN201711439804.1A CN201711439804A CN108096562A CN 108096562 A CN108096562 A CN 108096562A CN 201711439804 A CN201711439804 A CN 201711439804A CN 108096562 A CN108096562 A CN 108096562A
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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Abstract
The invention discloses purposes of the 20S proteasome inhibitors in the drug for preparing treatment Japanese B encephalitis virus infection, the 20S proteasome inhibitors are boric acid class 20S proteasome inhibitors or epoxy ketone 20S proteasome inhibitors.Boric acid class or epoxy ketone 20S proteasome inhibitors can effectively treat Japanese B encephalitis virus infection, and new selection is provided for clinical application.The present invention infects the mouse model of Japanese B encephalitis virus by establishing, the survival rate of mouse and histopathology section are analyzed after being treated to medication, simultaneously using the mouse of non-administration treatment after healthy mice, infection Japanese B encephalitis virus as reference, pass through data statistic analysis, in survival rate and cerebral tissue change etc., the peptides 20S proteasome inhibitors such as bortezomib, Ai Shazuo meter and Carfilzomib are to Japanese B encephalitis virus infected with certain therapeutic effect.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to 20S proteasome inhibitors are preparing treatment Japanese B brain
Purposes in the drug of scorching virus infection.
Background technology
Japanese B encephalitis virus (Japanese encephalitis virus, JEV) belongs to flaviviridae Flavivirus,
It is to cause nervous system infectious disease --- the pathogen of Japanese B encephalitis, other members belonged to together also have west nile virus
(West Nile virus, WNV), yellow fever virus (Yellowfever virus, YFV), dengue virus (Dengue virus,
DENV) 1-4 types, zika virus (Zika virus, ZIKV) etc..The virus is mainly passed by taking viruliferous bite by mosquitos
It broadcasts, and Culex tritaeniorhynchus is the most important communication media of the virus, therefore, apparent seasonal, the summer is presented in the popular of the virus
Autumn seasonal prevalence.
Animals and the mankind such as Japanese B encephalitis virus main infection pig, horse, ox.Pig is Japanese B encephalitis virus
Intermediate host is present with paroxysmal miscarriage after pregnant sow infection Japanese B encephalitis virus, aborted fetus be mostly stillborn foetus or
The mummification of fetus；In continued fever, spiritual depressed, drowsiness, anorexia after Infection in Piglets, apparent nervous symptoms are shown as individually；
After boar infection in addition to more than symptom, orchitis symptom is also shown, severe patient may lose breeding capacity.Crowd is to second
Encephalovirus is generally susceptible, is present with acute encephalitis symptom after Japanese B encephalitis virus is infected, is mainly shown as continuation
High fever, the disturbance of consciousness, ataxia, severe patient there is also the symptoms such as epilepsy, respiratory failure, in some instances it may even be possible to cause patient dead
It dies.
Japanese B encephalitis virus epidemic regions are extensive, and Endemic Area is distributed mainly on Asia and West Pacific region, sternly
Human health is endangered again.According to statistics, there are about 50,000 people every year in the whole world to infect this disease, and about 1.5 ten thousand people are diseased dead, about half
Survivor therefore disease and by serious sequelae.At present, still no drug can effectively treat Japanese B encephalitis disease
Poison infection, but have the more research on anti-inflammatory agent, antibiotic etc. " old medicine is newly used " and focus on the sick treatment.
The CA registration numbers of bortezomib (Bortezomib) are 179324-69-7, chemical entitled N- (2- pyrazinecarbonyls)-
L-phenylalanine-L-Leu boric acid is a kind of boric acid dipeptides, is the highly selective reversible inhibitor of 20S proteasomes, is made
For the degradation of misfolded protein；The CA registration numbers of Ai Shazuo meter are 1072833-77-2, entitled B- [(the 1R) -1- of chemistry
[[2- [(2,5- dichloro-benzoyl base) amino] acetyl group] amino] -3- methyl butyls] boric acid is the bright ammonia of the capped dipeptides of nitrogen end
Sour boric acid inhibits chymotrypsin (β 5) hydrolytic sites of 20S proteasomes；The CA registration numbers of Carfilzomib are 868540-17-
4, entitled (the S) -2- of chemistry ((S) -2- (2- (2H-1,4- oxazines -4 (3H)-yl) acetylamino) -4- phenylbutanamides) -4-
Methyl-N- ((S) -1- ((S) -4- methyl-1s-((R) -2- methyl oxirane -2- bases) -1- oxo-pentane -2- bases amino) -1-
Oxo -3- phenyl propyl- 2- yls) pentanamide, it is a kind of four peptidyls also oxygen skelemin enzyme body inhibitor, it is main to inhibit 20S albumen
These types of drug is clinically mostly used to treat Huppert's disease by the chymotrypsin of enzyme body.At present, there is no by bortezomib,
Carfilzomib, Ai Shazuo meter are used to treat the precedent of Japanese B encephalitis virus infection.
The content of the invention
For clinically to the demand of Japanese B encephalitis virus treatment of infection drug, the present invention provides 20S eggs at present
Purposes of the white enzyme body inhibitor in the drug for preparing treatment Japanese B encephalitis virus infection, is Japanese B encephalitis virus sense
The clinical application of dye treatment provides new selection.
To achieve the above object, the technical solution adopted in the present invention is：
The present invention provides 20S proteasome inhibitors in the drug for preparing treatment Japanese B encephalitis virus infection
Purposes, the 20S proteasome inhibitors inhibit for boric acid class 20S proteasome inhibitors or epoxy ketone 20S proteasomes
Agent.
Inventor is the study found that boric acid class or epoxy ketone 20S proteasome inhibitors can effectively treat Japanese B
Available for the drug for preparing treatment Japanese B encephalitis virus infection, new choosing is provided for clinical application for encephalitis virus infection
It selects.
As the preferred embodiment of purposes of the present invention, the boric acid class 20S proteasome inhibitors are included such as
Under (a) or (b):
(a) bortezomib or its pharmaceutically acceptable salt；
(b) Ai Shazuo meter or its pharmaceutically acceptable salt.
As the preferred embodiment of purposes of the present invention, epoxy ketone 20S proteasome inhibitors include blocking non-
Help rice or its pharmaceutically acceptable salt.
As the preferred embodiment of purposes of the present invention, the boric acid class 20S proteasome inhibitors replace for boron
Help rice or Ai Shazuo meter；The epoxy ketone 20S proteasome inhibitors are Carfilzomib.
As the preferred embodiment of purposes of the present invention, the adult of the 20S proteasome inhibitors uses agent
Amount scope is 0.5~2mg/kg.
As the preferred embodiment of purposes of the present invention, the drug further include pharmaceutically acceptable carrier or
Diluent.
As the preferred embodiment of purposes of the present invention, the carrier for glucose, maltodextrin, glycerine,
Mannitol, sorbierite, dextrin, lactose, gelatin, calcium sulfate, odium stearate, tween, agar, calcium carbonate, starch and its derivative
At least one of object, cellulose and its derivates.
As the preferred embodiment of purposes of the present invention, the diluent is water, ringer's solution or buffered saline.
As the preferred embodiment of purposes of the present invention, the dosage form of the drug is parenteral solution, oral liquid or glue
Wafer.
Scheme in compared with prior art, the advantage of the invention is that：
The present invention infects the mouse model of Japanese B encephalitis virus by establishing, and mouse is deposited after being treated to medication
Motility rate, clinical symptoms and histopathology section analyzed, while with healthy mice, infection Japanese B encephalitis virus after not
The mouse of drug treatment passes through data statistic analysis, in terms of survival rate, cerebral tissue change, boric acid class or epoxy as reference
Ketone 20S proteasome inhibitors are to Japanese B encephalitis virus infected with certain therapeutic effect.The present invention boric acid class or
Epoxy ketone 20S proteasome inhibitors can effectively treat Japanese B encephalitis virus infection, be provided newly for clinical application
Selection.
Description of the drawings
Fig. 1 is influence of the bortezomib to JEV infection mouse survival rate.
Fig. 2 is influence of the bortezomib to JEV infection Mice brain tissues pathological symptom.
Fig. 3 is influence of the Carfilzomib to JEV infection mouse survival rate.
Fig. 4 is influence of the Carfilzomib to JEV infection Mice brain tissues pathological symptom.
Specific embodiment
For the object, technical solutions and advantages of the present invention are better described, below in conjunction with the drawings and specific embodiments pair
The present invention further illustrates.It will be appreciated by those skilled in the art that specific embodiment described herein is only explaining this hair
It is bright, it is not intended to limit the present invention.
For a better understanding of the present invention, relevant explanation and illustration is provided below：
JEV：Japanese B encephalitis virus；
Bortezomib:Bortezomib；
Carfilzomib:Carfilzomib.
In embodiment, used experimental method is conventional method unless otherwise specified, material used, reagent etc.,
It is commercially available unless otherwise specified.
Drug discovery new technology based on this laboratory, using Disease-causing gene marking obtained by PheWAS as initial temperature, knot
PPI networks are closed, Disease-causing gene interaction network is built based on HotNet2 algorithms.From the Disease-causing gene interaction network of structure, lead to
More target agents that inquiry drug-target database finds targeting same subnet network are crossed, target the drug of 20S proteasomes, just
Step obtains drug --- bortezomib, Ai Shazuo meter and the Carfilzomib for having potential treatment activity to Japanese B encephalitis virus,
Its active drug dosage should be determined according to the severity of the course of disease, drug delivery route and other correlative factors.
Entitled N- (the 2- pyrazinecarbonyls)-L-phenylalanine-L-Leu boric acid of chemistry of bortezomib, chemical structural formula
As shown in formula I；Entitled B- [(1R) -1- [[2- [(2,5- dichloro-benzoyls base) amino] acetyl group] ammonia of chemistry of Ai Shazuo meter
Base] -3- methyl butyls] boric acid, chemical structural formula is as shown in II；Entitled (S) -2- ((S) -2- (2- of chemistry of Carfilzomib
(2H-1,4- oxazines -4 (3H)-yl) acetylamino) -4- phenylbutanamides) -4- methyl-N- ((S) -1- ((S) -4- methyl-1s -
((R) -2- methyl oxirane -2- bases) -1- oxo-pentane -2- bases amino) -1- oxo -3- phenyl propyl- 2- yls) pentanamide,
Chemical structural formula is as shown in III.
Application of 1 bortezomib of embodiment in the mouse for the treatment of infection Japanese B encephalitis virus
First, the mouse model of infection Japanese B encephalitis virus is established
1st, experiment material
(1) experimental animal：Four week old Balb/c female mices.
(2) strain：P3 plants of JEV
(3) other reagents：
1) 0.01M PBS buffer solution：Weigh NaH2PO40.593g, Na2HPO45.802g, NaCl 17.0g, deionization
Water (ddH2O 2L) is settled to, room temperature preservation is spare.
2) DMEM basal mediums：One bottle of DMEM powder, weighs NaHCO33.7g, HEPES 5.95g add in 800mL
ddH2O is sufficiently stirred dissolving, is settled to 1000mL, 0.22 μm of filter filtration sterilization, 4 DEG C save backup.
2nd, experimental procedure
Mouse peritoneal injection 106The same dose of DMEM culture mediums are injected intraperitoneally in PFU encephalitis B virus, control group mice.
In the subsequent time, the The dead quantity of mouse is observed and recorded.
3rd, experimental result
In 5-14 days after attacking poison, the dead mouse of Japanese B encephalitis virus is infected in part, and shows to paralyse, draw
Water, the clinical symptoms such as be all of a tremble.The 6th day symptom is the most serious after infection, and recovers substantially after infecting 23 days.
2nd, bortezomib is to the treatment effectiveness evaluation of the mouse of infection Japanese B encephalitis virus
1st, experimental drug
Bortezomib, character：White powder, application method：Use 2%DMSO+30%PEG 300+ddH2O dissolves, quiet
Arteries and veins is injected.
2nd, specific experiment step
(1) zoopery grouping is with receiving sample
Four week old Balb/c female mices are divided into four groups：PBS groups (blank control group, 15), (the drug reference of bortezomib group
Group, 15), JEV groups (P3 plants of infected groups, 15), JEV+ bortezomibs group (P3 plants for the treatment of of infection groups, 15).
Mouse peritoneal injection 106PFU encephalitis B virus is connecing malicious 1st, 2,4,6,8,10,12 day difference tail vein injection
The bortezomib of 1mg/kg.Observe and record the The dead quantity of mouse.
Sample was received with the 23rd day within the 6th day after virus infects.Every group of 3 Zhi Qu brain tissue homogenates separately take 2 progress paraffin bags
It buries, residue 10 is served only for the statistics death rate.
(2) brain tissue is fixed and embedding, HE dyeing detect the pathological symptom of Mice brain tissues
Mouse is put to death with dislocation of cervical vertebra method, puts and 3-5min is impregnated in 70% ethyl alcohol, skin at nape is sterilized after taking-up, it is sterile
Brain tissue is taken out, is cleaned in basic DMEM once, along median sagittal plane vertical cross, is put into 4% paraformaldehyde fixed
48h.Flowing water rinses for 24 hours, repaiies block and with gradient alcohol dehydration, and gaultherolin processing permeabilization 2h enters wax and embeds.Paraffin is made to cut
Piece (4 μm), and carry out HE dyeing.The mouse brain section being successfully prepared is dewaxed successively, hematoxylin dyeing, with 50%, 75%,
Eosin stains are used after 80% dehydration of alcohol, then section is rinsed with 95%, 100% alcohol respectively, finally use diformazan
Benzene does section transparent processing, is sealed up for safekeeping with neutral gum.
3rd, experimental result
(1) influence of the bortezomib to JEV infection mouse survival rate.
Challenge viral dosage continue to infection after 23 days, survival mice is substantially without apparent nervous symptoms.As shown in Figure 1, feeling
Dye 5-10 days, JEV group The dead quantities steeply rise, and until the 14th talent does not occur dead mouse, the final death rate reaches 90%.
And JEV+ bortezomib group dead mouse quantity is considerably less than JEV groups, the final death rate is 60%, illustrates that bortezomib can be effective
Dead mouse caused by reducing JEV infection.PBS groups have no any death with bortezomib group, illustrate bortezomib to mouse
Health is without influence.
(2) influence of the bortezomib to JEV infection Mice brain tissues lesion.
By the way that Mice brain tissues section is compared, the results are shown in Figure 2, the 6th day after virus infects, JEV
Group meninx substantially has a large amount of inflammatory cells to assemble, and cortex cell layer is disorderly, in addition, a large amount of blood also can be observed in its Cerebral cortex
Phenomena such as pipe oversleeve, spongiocyte tubercle, downright bad neuron vacuole sample.The pathological change of same time point JEV+ bortezomib groups
It is light and slow, and PBS groups and bortezomib group are all without apparent lesion.
It can be seen that the boric acid class 20S proteasome inhibitor bortezomibs that this patent is related to are for Japanese B encephalitis
Virus infection has certain therapeutic effect really.
Bortezomib in the present embodiment can be replaced other boric acid class 20S proteasome inhibitors with similar effect
Fruit, such as bortezomib pharmaceutically acceptable salt, Ai Shazuo meter or its pharmaceutically acceptable salt.
Application of 2 Carfilzomib of embodiment in the mouse for the treatment of infection Japanese B encephalitis virus
First, the mouse model of infection Japanese B encephalitis virus is established
The step of establishing the mouse model of infection Japanese B encephalitis virus is with embodiment 1, and Carfilzomib is to infection Japan
The mouse therapeutic effect of japanese encephalitis virus is as follows：
2nd, Carfilzomib is to the treatment effectiveness evaluation of the mouse of infection Japanese B encephalitis virus
1st, experiment material
(1) drug：Carfilzomib, character：White powder, application method：Use 2%DMSO+30%PEG 300+2%
Tween 80+ddH2O dissolves, intravenous injection.
(2) other reagents：4% paraformaldehyde.
2nd, specific experiment step
(1) zoopery grouping is with receiving sample：
Four week old Balb/c female mices are divided into four groups：PBS groups (blank control group, 15), (the drug reference of Carfilzomib group
Group, 15), JEV groups (P3 plants of infected groups, 15), JEV+ Carfilzomibs group (P3 plants for the treatment of of infection groups, 15).
Mouse peritoneal injection 106The DMEM culture mediums of same volume are injected intraperitoneally in PFU encephalitis B virus, control group mice.It is connecing
The Carfilzomib of the 1st, 2,4,6,8,10,12 day difference tail vein injection 2mg/kg of poison.Observe and record the The dead quantity of mouse.
Sample was received with the 23rd day within the 6th day after virus infects.Every group of 3 Zhi Qu brain tissue homogenates separately take 2 progress paraffin bags
It buries, residue 10 is served only for the statistics death rate.
(2) brain tissue is fixed and embedding, HE dyeing detect the pathological symptom of Mice brain tissues
Mouse is put to death with dislocation of cervical vertebra method, puts and 3-5min is impregnated in 70% ethyl alcohol, skin at nape is sterilized after taking-up, it is sterile
Brain tissue is taken out, is cleaned in basic DMEM once, along median sagittal plane vertical cross, is put into 4% paraformaldehyde fixed
48h.Flowing water rinses for 24 hours, repaiies block and with gradient alcohol dehydration, and gaultherolin processing permeabilization 2h enters wax and embeds.Paraffin is made to cut
Piece (4 μm), and carry out HE dyeing.The mouse brain section being successfully prepared is dewaxed successively, hematoxylin dyeing, with 50%, 75%,
Eosin stains are used after 80% dehydration of alcohol, then section is rinsed with 95%, 100% alcohol respectively, finally use diformazan
Benzene does section transparent processing, is sealed up for safekeeping with neutral gum.
3rd, experimental result
(1) influence of the Carfilzomib to JEV infection mouse survival rate.
Challenge viral dosage continue to infection after 23 days, survival mice is substantially without apparent nervous symptoms.From the figure 3, it may be seen that feeling
Dye 5-10 days, JEV group The dead quantities steeply rise, and until the 14th talent does not occur dead mouse, the final death rate reaches 80%.
And JEV+ Carfilzomib group dead mouse quantity is considerably less than JEV groups, the final death rate is 60%, illustrates that Carfilzomib can be effective
Dead mouse caused by reducing JEV infection.PBS groups have no any death with Carfilzomib group, illustrate Carfilzomib to mouse
Health is without influence.
(2) influence of the Carfilzomib to JEV infection Mice brain tissues lesion.
By the way that Mice brain tissues section is compared, as a result as indicated at 4.The 6th day after virus infects, JEV groups
Meninx substantially has a large amount of inflammatory cells to assemble, and cortex cell layer is disorderly, in addition, a large amount of blood vessels also can be observed in its Cerebral cortex
Phenomena such as oversleeve, spongiocyte tubercle, downright bad neuron vacuole sample.The pathological change of same time point JEV+ Carfilzomib groups has
Institute is light and slow, and PBS groups and Carfilzomib group are all without apparent lesion.
It can be seen that the 20S proteasome inhibitors Carfilzomib that this patent is related to is for Japanese B encephalitis virus sense
Dye has certain therapeutic effect really.
Carfilzomib in the present embodiment can be replaced other epoxy ketone 20S proteasome inhibitors, such as Ka Feizuo
Rice pharmaceutically acceptable salt.
Drug of the present invention can be prepared as any form, such as particle, powder, tablet, capsule, parenteral solution or mouth
Take liquid.
The drug of the present invention can further comprise one or more pharmaceutically acceptable carriers or diluent, these carriers
It will suitably prepare in order to be administered, pharmaceutically acceptable diluent can be water, ringer's solution, buffered saline；Pharmaceutically may be used
The carrier of receiving is glucose, maltodextrin, glycerine, mannitol, sorbierite, dextrin, lactose, gelatin, calcium sulfate, stearic acid
At least one of sodium, tween, agar, calcium carbonate, starch and its derivative, cellulose and its derivates.
To sum up, the present invention infects the mouse model of Japanese B encephalitis virus by establishing, small after being treated to medication
Survival rate, clinical symptoms and the histopathology section of mouse are analyzed, while with healthy mice, infection Japanese B encephalitis disease
The mouse that non-administration is treated after poison passes through data statistic analysis, in terms of survival rate, cerebral tissue change, boric acid class as reference
Or epoxy ketone 20S proteasome inhibitors to Japanese B encephalitis virus infected with certain therapeutic effect.The boron of the present invention
Acids or epoxy ketone 20S proteasome inhibitors can effectively treat Japanese B encephalitis virus infection, be carried for clinical application
New selection is supplied.
It the above is only the preferred embodiment of the present invention, it is noted that above-mentioned preferred embodiment is not construed as pair
The limitation of the present invention, protection scope of the present invention should be subject to claim limited range.For the art
For those of ordinary skill, without departing from the spirit and scope of the present invention, several improvements and modifications can also be made, these change
Protection scope of the present invention is also should be regarded as into retouching.
Claims (9)
- Purposes of the 1.20S proteasome inhibitors in the drug for preparing treatment Japanese B encephalitis virus infection, feature exist In the 20S proteasome inhibitors are boric acid class 20S proteasome inhibitors or epoxy ketone 20S proteasome inhibitors.
- 2. purposes according to claim 1, which is characterized in that the boric acid class 20S proteasome inhibitors include as follows (a) or (b):(a) bortezomib or its pharmaceutically acceptable salt；(b) Ai Shazuo meter or its pharmaceutically acceptable salt.
- 3. purposes according to claim 1, which is characterized in that the epoxy ketone 20S proteasome inhibitors include card Fei Zuo meter or its pharmaceutically acceptable salt.
- 4. purposes according to claim 1, which is characterized in that the boric acid class 20S proteasome inhibitors are boron for assistant Rice or Ai Shazuo meter；The epoxy ketone 20S proteasome inhibitors are Carfilzomib.
- 5. purposes according to claim 1, which is characterized in that adult's dosage of the 20S proteasome inhibitors Scope is 0.5~2mg/kg.
- 6. according to Claims 1 to 5 any one of them purposes, which is characterized in that the drug further includes pharmaceutically acceptable Carrier or diluent.
- 7. purposes according to claim 6, which is characterized in that the carrier is glucose, maltodextrin, glycerine, sweet Dew alcohol, sorbierite, dextrin, lactose, gelatin, calcium sulfate, odium stearate, tween, agar, calcium carbonate, starch and its derivative, At least one of cellulose and its derivates.
- 8. purposes according to claim 6, which is characterized in that the diluent is water, ringer's solution or buffered saline.
- 9. purposes according to claim 6, which is characterized in that the dosage form of the drug is parenteral solution, oral liquid or capsule Agent.
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| CN112841137A (en) * | 2021-02-04 | 2021-05-28 | 四川农业大学 | Method for establishing model of mouse reproductive system infected by encephalitis B virus and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112841137A (en) * | 2021-02-04 | 2021-05-28 | 四川农业大学 | Method for establishing model of mouse reproductive system infected by encephalitis B virus and application |
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