CN108096562B - Application of 20S proteasome inhibitor in preparation of medicine for treating Japanese encephalitis virus infection - Google Patents
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Abstract
The invention discloses application of a 20S proteasome inhibitor in preparation of a medicine for treating Japanese encephalitis B virus infection, wherein the 20S proteasome inhibitor is a boric acid 20S proteasome inhibitor or an epoxy ketone 20S proteasome inhibitor. The boronic acid or epoxy ketone 20S proteasome inhibitor can effectively treat Japanese B encephalitis virus infection, and provides a new choice for clinical medication. The invention establishes a mouse animal model infected with Japanese encephalitis virus, analyzes the survival rate of a mouse treated by medication and pathological sections of brain tissues, takes a healthy mouse and a mouse not treated by administration after being infected with Japanese encephalitis virus as reference, and has certain treatment effect on the infection of the Japanese encephalitis virus by peptide 20S proteasome inhibitors such as bortezomib, Esazomib and carfilzomib in the aspects of survival rate, pathological changes of the brain tissues and the like through data statistical analysis.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of a 20S proteasome inhibitor in preparing a medicine for treating Japanese encephalitis virus infection.
Background
Japanese Encephalitis Virus (JEV) belongs to the genus Flaviviridae, and is a causative agent of infectious disease of the nervous system, Japanese encephalitis, and other members of the same genus include West Nile Virus (WNV), Yellow Fever Virus (YFV), Dengue virus (DENGue virus, DENV) types 1-4, Zika virus (ZIKV), and the like. The virus is mainly transmitted by the bite of mosquito carrying the virus, and the culex tritaeniorhynchus is the most main transmission medium of the virus, so the virus is obviously seasonal and is frequently transmitted in summer and autumn.
Japanese B encephalitis virus mainly infects animals such as pigs, horses, cattle and the like and humans. The pig is an intermediate host of Japanese encephalitis B virus, and the pregnant sow can have sudden abortion after being infected with the Japanese encephalitis B virus, and most of the aborted fetuses are dead fetuses or mummy fetuses; after the piglets are infected, the piglets are in the shapes of heat, depression, lethargy and anorexia, and are respectively shown as obvious neurological symptoms; after the boar is infected, the boar also shows orchitis symptoms besides the symptoms, and serious boars may lose mating ability. The people are generally susceptible to Japanese B encephalitis virus, acute encephalitis symptoms can appear after Japanese B encephalitis virus infection, mainly manifested as persistent high fever, disturbance of consciousness and dyskinesia, serious patients can also have symptoms such as epilepsy and respiratory failure, and even can cause death of patients.
Japanese B encephalitis virus epidemic areas are wide, and the epidemic areas are mainly distributed in Asia and the Western Pacific region, thereby seriously harming human health. Statistically, about 5 million people are infected with the disease every year worldwide, about 1.5 million people die of the disease, and about one half of the survivors suffer serious sequelae due to the disease. At present, no medicine can effectively treat Japanese encephalitis virus infection, but more researches on 'new application of old medicines' such as anti-inflammatory drugs, antibiotics and the like are focused on treating the disease.
Bortezomib (Bortezomib) has CA accession No. 179324-69-7, its chemical name is N- (2-pyrazinecarbonyl) -L-phenylalanine-L-leucine boronic acid, a boronic acid dipeptide, which is a highly selective reversible inhibitor of the 20S proteasome, acting on the degradation of misfolded proteins; eszolomide, having CA accession number 1072833-77-2, is chemically named B- [ (1R) -1- [ [2- [ (2, 5-dichlorobenzoyl) amino ] acetyl ] amino ] -3-methylbutyl ] boronic acid, is a nitrogen-end capped dipeptide leucine boronic acid, inhibits the chymotrypsin (beta 5) hydrolysis site of the 20S proteasome; carfilzomib has CA accession number 868540-17-4, its chemical name (S) -2- ((S) -2- (2- (2H-1, 4-oxazin-4 (3H) -yl) acetamido) -4-phenylbutanamide) -4-methyl-N- ((S) -1- ((S) -4-methyl-1- ((R) -2-methyloxiran-2-yl) -1-oxopentan-2-ylamino) -1-oxo-3-phenylpropan-2-yl) pentanamide, is a tetrapeptide based deoxidized backbone proteasome inhibitor that inhibits mainly the chymotrypsin of the 20S proteasome, the medicines are mainly used for treating multiple myeloma clinically. At present, bortezomib, carfilzomib and elsinozoli have no precedent for treating Japanese B encephalitis virus infection.
Disclosure of Invention
Aiming at the current clinical requirements on Japanese B encephalitis virus infection treatment drugs, the invention provides the application of the 20S proteasome inhibitor in the preparation of drugs for treating Japanese B encephalitis virus infection, and provides a new choice for clinical drugs for treating Japanese B encephalitis virus infection.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides application of a 20S proteasome inhibitor in preparing a medicament for treating Japanese encephalitis B virus infection, wherein the 20S proteasome inhibitor is a boronic acid 20S proteasome inhibitor or an epoxy ketone 20S proteasome inhibitor.
The inventor researches and discovers that the boronic acid or epoxy ketone 20S proteasome inhibitor can effectively treat Japanese B encephalitis virus infection, can be used for preparing a medicament for treating the Japanese B encephalitis virus infection, and provides a new choice for clinical medication.
As a preferred embodiment of the use according to the present invention, the boronic acid-type 20S proteasome inhibitor comprises the following (a) or (b):
(a) bortezomib or a pharmaceutically acceptable salt thereof;
(b) eszolomide or a pharmaceutically acceptable salt thereof.
As a preferred embodiment of the use according to the present invention, the epoxyketone 20S proteasome inhibitor comprises carfilzomib or a pharmaceutically acceptable salt thereof.
As a preferred embodiment of the use according to the invention, the boronic acid-type 20S proteasome inhibitor is bortezomib or elsazoib; the epoxy ketone 20S proteasome inhibitor is carfilzomib.
In a preferred embodiment of the use of the present invention, the dosage of the 20S proteasome inhibitor for adults is in a range of 0.5-2 mg/kg.
As a preferred embodiment of the use according to the invention, the medicament further comprises a pharmaceutically acceptable carrier or diluent.
As a preferred embodiment of the use according to the present invention, the carrier is at least one of glucose, maltodextrin, glycerol, mannitol, sorbitol, dextrin, lactose, gelatin, calcium sulfate, sodium stearate, tween, agar, calcium carbonate, starches and derivatives thereof, cellulose and derivatives thereof.
As a preferred embodiment of the use according to the invention, the diluent is water, ringer's solution or buffered saline.
As a preferable embodiment of the application of the invention, the dosage form of the medicament is injection, oral liquid or capsule.
Compared with the scheme in the prior art, the invention has the advantages that:
the invention analyzes the survival rate, clinical symptoms and brain tissue pathological sections of mice after drug treatment by establishing a mouse animal model infected with the Japanese B encephalitis virus, and simultaneously takes healthy mice and mice which are not treated after being infected with the Japanese B encephalitis virus as references, and has certain treatment effect on the infection of the Japanese B encephalitis virus by boric acid or epoxy ketone 20S proteasome inhibitors in the aspects of survival rate and brain tissue pathological changes through data statistical analysis. The boronic acid or epoxy ketone 20S proteasome inhibitor can effectively treat Japanese B encephalitis virus infection, and provides a new choice for clinical medication.
Drawings
Figure 1 is the effect of bortezomib on survival of JEV infected mice.
FIG. 2 is the effect of bortezomib on brain histopathological symptoms in JEV infected mice.
Figure 3 is the effect of carfilzomib on survival of JEV infected mice.
FIG. 4 is the effect of carfilzomib on brain histopathological symptoms in JEV infected mice.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments. It will be understood by those skilled in the art that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
For a better understanding of the invention, the following explanations and illustrations are provided:
JEV: japanese b encephalitis virus;
bortezomib;
carfilzomib.
In the examples, the experimental methods used were all conventional methods unless otherwise specified, and the materials, reagents and the like used were commercially available without otherwise specified.
Based on the new drug discovery technology of the laboratory, the pathogenic gene score obtained by PheWAS is used as the initial heat, and a pathogenic gene interaction network is constructed based on the HotNet2 algorithm in combination with the PPI network. Starting from the constructed pathogenic gene interaction network, multi-target drugs targeting the same sub-network and drugs targeting 20S proteasomes are found by querying a drug-target database, and drugs with potential therapeutic activity on Japanese B encephalitis virus, namely bortezomib, Esazomib and carfilzomib, are preliminarily obtained, wherein the effective drug dosage is determined according to the severity of the disease course, the drug administration way and other related factors.
The chemical name of bortezomib is N- (2-pyrazinecarbonyl) -L-phenylalanine-L-leucine boric acid, and the chemical structural formula of the bortezomib is shown as a formula I; the chemical name of the Esazomib is B- [ (1R) -1- [ [2- [ (2, 5-dichlorobenzoyl) amino ] acetyl ] amino ] -3-methylbutyl ] boric acid, and the chemical structural formula is shown as II; carfilzomib is chemically (S) -2- ((S) -2- (2- (2H-1, 4-oxazin-4 (3H) -yl) acetamido) -4-phenylbutanamide) -4-methyl-N- ((S) -1- ((S) -4-methyl-1- ((R) -2-methyloxiran-2-yl) -1-oxopentan-2-ylamino) -1-oxo-3-phenylpropan-2-yl) pentanamide, and its chemical structure is shown in iii.
Example 1 use of bortezomib for the treatment of Japanese encephalitis virus infected mice
Establishing a Japanese B encephalitis virus infected mouse model
1. Experimental Material
(1) Experimental animals: four-week-old Balb/c female mice.
(2) Strain: JEV P3 strain
(3) Other reagents:
1)0.01M PBS buffer: weighing NaH2PO4 0.593g，Na2HPO45.802g, NaCl 17.0g, deionized water (ddH)2O) constant volume to 2L, and storing at room temperature for later use.
2) DMEM basal medium: DMEM powder in one bottle, weighing NaHCO33.7g, HEPES 5.95g, 800mL ddH was added2And O, fully stirring and dissolving, diluting to 1000mL, filtering and sterilizing by a 0.22-micron filter, and storing at 4 ℃ for later use.
2. Experimental procedure
Intraperitoneal injection of mice 106PFU encephalitis B virus, control mice intraperitoneal injection of DMEM medium with the same dose. At a later time, the number of deaths of the mice was observed and recorded.
3. Results of the experiment
In 5-14 days after challenge, some mice infected with Japanese encephalitis virus die and show clinical symptoms such as paralysis, stroke, and trembling. Symptoms were most severe on day 6 post-infection, and were substantially recovered 23 days post-infection.
Evaluation of therapeutic Effect of Bortezomib on mice infected with Japanese encephalitis Virus
1. Experimental medicine
Bortezomib, properties: white powder, method of use: using 2% DMSO + 30% PEG 300+ ddH2Dissolving O, and performing intravenous injection.
2. Specific experimental procedures
(1) Grouping and collecting samples of animal experiments
Four-week-old Balb/c female mice were divided into four groups: PBS group (blank control group, 15), bortezomib group (drug reference group, 15), JEV group (P3 strain infection group, 15), JEV + bortezomib group (P3 strain infection treatment group, 15).
Intraperitoneal injection of mice 106PFU encephalitis B virus was administered by tail vein injection of 1mg/kg bortezomib on days 1, 2, 4, 6, 8, 10, and 12 of the inoculation. The number of deaths of the mice was observed and recorded.
Samples were collected at day 6 and day 23 post viral infection. In each group, 3 brain tissues were homogenized, another 2 were paraffin-embedded, and the remaining 10 were used for mortality statistics.
(2) Brain tissue fixing and embedding, HE staining for detecting pathological symptoms of mouse brain tissue
Killing mice by cervical dislocation method, soaking in 70% ethanol for 3-5min, taking out, sterilizing skin at neck and back, aseptically taking out brain tissue, cleaning in DMEM (basal DMEM), vertically transecting along sagittal plane, and fixing in 4% paraformaldehyde for 48 h. Washing with flowing water for 24h, trimming, dehydrating with gradient alcohol, treating with methyl salicylate for permeabilization for 2h, and embedding in wax. Paraffin sections (4 μm) were made and HE stained. Dewaxing and hematoxylin staining are sequentially carried out on successfully prepared rat brain slices, then eosin staining is carried out on the rat brain slices after 50%, 75% and 80% of alcohol is used for dehydration, then the rat brain slices are rinsed by 95% and 100% of alcohol respectively, finally xylene is used for slice transparency treatment, and neutral gum is used for sealing and storing.
3. Results of the experiment
(1) Effect of bortezomib on survival of JEV infected mice.
The challenge experiment continued until 23 days post-infection, and the surviving mice had essentially no apparent neurological symptoms. As can be seen from FIG. 1, the number of deaths in the JEV group sharply increased 5 to 10 days after infection, and no dead mice appeared until day 14, with a final mortality of 90%. The death number of mice in the JEV + bortezomib group is obviously less than that of mice in the JEV group, and the final death rate is 60%, which shows that the bortezomib can effectively reduce the death of the mice caused by JEV infection. No death was seen in the PBS group and the bortezomib group, indicating that bortezomib had no effect on the health of the mice.
(2) Effect of bortezomib on brain lesions in JEV-infected mice.
Through comparison and analysis of mouse brain tissue sections, the results are shown in fig. 2, on the 6 th day after virus infection, a large amount of inflammatory cells are obviously gathered in the JEV group meninges, the cortical cell layer is disordered, and in addition, a large amount of phenomena such as blood vessel oversleeves, glial cell nodules, neuron vacuole-like necrosis and the like can be observed in the cerebral cortex. The pathological changes of the JEV + bortezomib group were mild at the same time point, while no obvious lesions were observed in both the PBS group and the bortezomib group.
Therefore, the boric acid 20S proteasome inhibitor bortezomib related to the patent has certain treatment effect on Japanese B encephalitis virus infection.
The bortezomib in the embodiment can be replaced by other borate 20S proteasome inhibitors with similar effects, such as bortezomib pharmaceutically acceptable salts, elsamizomib or pharmaceutically acceptable salts thereof.
Example 2 use of carfilzomib for the treatment of Japanese encephalitis virus infected mice
Establishing a Japanese B encephalitis virus infected mouse model
The procedure for establishing a mouse model infected with Japanese B encephalitis virus was the same as in example 1, and the therapeutic effect of carfilzomib on mice infected with Japanese B encephalitis virus was as follows:
evaluation of therapeutic Effect of Carfilzomib on Japanese encephalitis Virus-infected mice
1. Experimental Material
(1) Medicine preparation: carfilzomib, character: white powder, method of use: using 2% DMSO + 30% PEG 300+ 2% Tween 80+ ddH2Dissolving O, and performing intravenous injection.
(2) Other reagents: 4% paraformaldehyde.
2. Specific experimental procedures
(1) Grouping and collecting animal experiments:
four-week-old Balb/c female mice were divided into four groups: PBS group (blank control group, 15), carfilzomib group (drug reference group, 15), JEV group (P3 strain infection group, 15), JEV + carfilzomib group (P3 strain infection treatment group, 15).
Intraperitoneal injection of mice 106PFU encephalitis B virus, control mice intraperitoneal injection of DMEM medium with the same volume. On days 1, 2, 4, 6, 8, 10 and 12 of the inoculation, 2mg/kg of carfilzomib was injected into the tail vein respectively. The number of deaths of the mice was observed and recorded.
Samples were collected at day 6 and day 23 post viral infection. In each group, 3 brain tissues were homogenized, another 2 were paraffin-embedded, and the remaining 10 were used for mortality statistics.
(2) Brain tissue fixing and embedding, HE staining for detecting pathological symptoms of mouse brain tissue
Killing mice by cervical dislocation method, soaking in 70% ethanol for 3-5min, taking out, sterilizing skin at neck and back, aseptically taking out brain tissue, cleaning in DMEM (basal DMEM), vertically transecting along sagittal plane, and fixing in 4% paraformaldehyde for 48 h. Washing with flowing water for 24h, trimming, dehydrating with gradient alcohol, treating with methyl salicylate for permeabilization for 2h, and embedding in wax. Paraffin sections (4 μm) were made and HE stained. Dewaxing and hematoxylin staining are sequentially carried out on successfully prepared rat brain slices, then eosin staining is carried out on the rat brain slices after 50%, 75% and 80% of alcohol is used for dehydration, then the rat brain slices are rinsed by 95% and 100% of alcohol respectively, finally xylene is used for slice transparency treatment, and neutral gum is used for sealing and storing.
3. Results of the experiment
(1) Effect of carfilzomib on survival of JEV infected mice.
The challenge experiment continued until 23 days post-infection, and the surviving mice had essentially no apparent neurological symptoms. As can be seen from FIG. 3, the number of deaths in the JEV group sharply increased 5 to 10 days after infection, and no dead mice appeared until day 14, with a final mortality of 80%. The death number of mice in the JEV + carfilzomib group is obviously less than that of mice in the JEV group, the final death rate is 60%, and the carfilzomib can effectively reduce the death of the mice caused by JEV infection. The PBS group and carfilzomib group did not see any death, indicating that carfilzomib had no effect on the health of the mice.
(2) Effect of carfilzomib on brain tissue pathology in JEV infected mice.
The results of the comparative analysis of mouse brain tissue sections are shown in FIG. 4. On day 6 after viral infection, the JEV meninges were significantly associated with a large accumulation of inflammatory cells and a disorder of the cortical cell layer, and in addition, a large number of vascular cuffs, glial nodules, neuronal vacuolar necrosis, etc. were observed in the cerebral cortex. Pathological changes of the JEV + Carfilzomib group at the same time point are mild, while no obvious lesion exists in the PBS group and the Carfilzomib group.
Therefore, the 20S proteasome inhibitor carfilzomib has certain treatment effect on Japanese B encephalitis virus infection.
Carfilzomib in this example can be replaced with other epoxy ketone 20S proteasome inhibitors, such as a pharmaceutically acceptable salt of carfilzomib.
The medicament related to the present invention may be prepared in any form, such as granules, powders, tablets, capsules, injections or oral liquids.
The medicament of the invention may further comprise one or more pharmaceutically acceptable carriers or diluents, which are suitably formulated for administration, and which may be water, ringer's solution, buffered saline; the pharmaceutically acceptable carrier is at least one of glucose, maltodextrin, glycerol, mannitol, sorbitol, dextrin, lactose, gelatin, calcium sulfate, sodium stearate, tween, agar, calcium carbonate, starch and its derivatives, and cellulose and its derivatives.
In conclusion, the invention establishes a mouse animal model infected with the Japanese B encephalitis virus, analyzes the survival rate, clinical symptoms and pathological sections of brain tissues of a mouse after being treated by a medicament, and simultaneously takes a healthy mouse and a mouse which is not treated by the medicament after being infected with the Japanese B encephalitis virus as reference, and has certain treatment effect on the infection of the Japanese B encephalitis virus by the boronic acid or epoxy ketone 20S proteasome inhibitor in the aspects of survival rate and brain tissue pathological changes through data statistical analysis. The boronic acid or epoxy ketone 20S proteasome inhibitor can effectively treat Japanese B encephalitis virus infection, and provides a new choice for clinical medication.
The above is only a preferred embodiment of the present invention, and it should be noted that the above preferred embodiment should not be considered as limiting the present invention, and the protection scope of the present invention should be subject to the scope defined by the claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and these modifications and adaptations should be considered within the scope of the invention.
Claims (6)
- Use of a 20S proteasome inhibitor for the manufacture of a medicament for the treatment of japanese b encephalitis virus infection, wherein the 20S proteasome inhibitor is a boronic acid 20S proteasome inhibitor or an epoxy ketone 20S proteasome inhibitor, and the boronic acid 20S proteasome inhibitor is bortezomib; the epoxy ketone 20S proteasome inhibitor is carfilzomib.
- 2. The use according to claim 1, wherein the 20S proteasome inhibitor is used in a dosage range of 0.5 to 2mg/kg for an adult.
- 3. Use according to claim 1 or 2, wherein the medicament further comprises a pharmaceutically acceptable carrier or diluent.
- 4. Use according to claim 3, wherein the carrier is at least one of glucose, glycerol, mannitol, sorbitol, dextrin, lactose, gelatin, calcium sulfate, sodium stearate, tween, agar-agar, calcium carbonate.
- 5. Use according to claim 3, wherein the diluent is water, ringer's solution or buffered saline.
- 6. The use according to claim 3, wherein the medicament is in the form of injection, oral liquid or capsule.
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