CN102772789A - Pharmaceutical application of PEG-modified recombinant humanized catalase - Google Patents
Pharmaceutical application of PEG-modified recombinant humanized catalase Download PDFInfo
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- CN102772789A CN102772789A CN2011101198834A CN201110119883A CN102772789A CN 102772789 A CN102772789 A CN 102772789A CN 2011101198834 A CN2011101198834 A CN 2011101198834A CN 201110119883 A CN201110119883 A CN 201110119883A CN 102772789 A CN102772789 A CN 102772789A
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Abstract
The invention relates to the field of biotechnology, and relates to a pharmaceutical application of PEG-modified recombinant humanized catalase. In the invention, the PEG-modified recombinant humanized catalase is a product obtained from PEG modification, expression of humanized catalase cDNA in pichia pastoris via DNA sequence and purification. The PEG-modified recombinant humanized catalase can effectively antagonize acute pneumonia caused by influenza viruses of H1N1 and FM1, decreases pulmonary virus titers, enhances antioxidant ability and animal immune protection, slows down the pathological process of the acute pneumonia, reduces a mortality rate, and prolongs survival time. The PEG-modified recombinant humanized catalase can be made into a nasal inhalant, an intraperitoneal injection preparation or an external preparation, and can be used for treating the acute pneumonia and burn infections caused by infections of viruses, bacteria, ambustions, etc.
Description
Technical field
The invention belongs to biological technical field; The medicinal usage that relates to the recombination human source catalase of PEG modification; Be specifically related to prepare the purposes in treatment virus, the bacterial infection medicine, relate in particular to acute pneumonia that recombination human source catalase that PEG modifies causes in infection such as preparation treatment virus, antibacterial and burns and the purposes in the burn infection medicine.
Background technology
Catalase extensively is present in various aerobies and some Anaerobes, is one of the composition and the most significant enzyme of body endoperoxidase body, accounts for about 40% of peroxisome enzyme amount.Discover that catalase differential high efficient ground is with hydrogen peroxide decomposes Cheng Shui and oxygen.In normal physiological activity, the O that the cell aerobic respiration is consumed
2About 10% is reduced into H
2O
2, and then produce a series of reactive oxygen free radical, and catalatic normal physiological function is exactly to remove the hydrogen peroxide that generates in the body, and suppress hydrogen peroxide to other reactive oxygen free radical conversions.
Under the normal condition, activity in vivo oxygen generates and removing is in an equilibrated state, and under pathological state; The balance of Redox State of Human Body is broken; Antioxidant system is suppressed, and causes reactive oxygen free radical excessive in the body to exist, and then causes the oxidative damage of body.Have research to confirm, under some pathological states, biological intravital catalase content all descends to some extent, significantly is lower than the normal person like the intravital catalase content of diabetes patient, and the activity of catalase in the Alzheimer patient brain also is suppressed.Also have research to be illustrated in the external tumor model, weakening of activity of catalase is important factors in the tumor development process.
At present, the existing many reports of the research of relevant above-mentioned aspect, as: adopt transgene method to make mice mitochondrion catalase high expressed can prolong mice life, delay heart disease and cataractous generation and development, alleviate oxidative damage.There is research to think that the expression of inductor hydrogen peroxide enzyme can be used as a new approach in the antioxidation treatment.Have a lot of reports to point out, exogenous catalase is to disease, and especially the process of oxidisability disease has certain mitigation.Result of study confirms; The outer source catalase of mouse mainline has greatly reduced the lipid peroxidation of hydrogen peroxide-induced; Keep sanguimotor catalase activity and can suppress the lung tumors transfer, the high expressed catalase can make the antioxidation toleration of lens epithelial cells strengthen; Described catalase has suppressed the inductive human artery's smooth muscle cell proliferation of oxidisability low density lipoprotein, LDL (oxLDL).Above-mentioned report has shown that all the research of catalase aspect oxidative damage is in the ascendant.
Summary of the invention
The purpose of this invention is to provide the new medicinal usage of recombination human source catalase that PEG modifies, relate to recombination human source catalase that PEG the modifies purposes in the medicine of acute pneumonia that infection such as preparation treatment virus, antibacterial and burn cause and burn infection.
Particularly, the medicinal usage of the recombination human source catalase that PEG of the present invention modifies after it is characterized in that the human source catalase of gene engineering expression modified with PEG, is used for the oxidative damage property disease that treatment is caused by oxygen-derived free radicals (ROS); Said oxidative damage property disease specifically comprises acute pneumonia and the burn infection that infection such as virus, antibacterial and burn cause.
The present invention is through zoopery; The result shows; The recombination human source catalase that described PEG modifies comprises influenza virus, SARS virus, respiratory syncytial virus, coronavirus to virus, antibacterial: comprise that staphylococcus aureus, streptococcus pneumoniae, the rich Salmonella of kerekou pneumonia have the obvious suppression effect.
Among the present invention, the recombination human source catalase that described PEG modifies, for modify through PEG, DNA sequence is that human source catalase cDNA expresses also purified product in Pichia sp.;
Described recombination human source catalase has the sequence of sequence 1.
The recombination human source catalase that PEG of the present invention modifies prepares through following method:
Human source catalase and activatory PEG 5000 are put into borate buffer with certain molar ratio, stirring reaction 12h behind 4 ℃ of mix homogeneously, every 2h sampling once detects the activity of catalase in the mixture; Reaction is accomplished the back through Sephacryl S-300 resin column, and with the PBS eluting of the pH 7.0 of 20mmol/L, collection modification and unmodified get component respectively, carry out the SDS-PAGE electrophoretic analysis; The ampere bottle of sterilization is gone in the human source catalase dialysis back packing that said PEG modifies, and lyophilization is with the PBS buffer dissolving of 0.05M, 0.22um membrane filtration.
The recombination human source catalase that PEG of the present invention modifies has carried out the antioxidation zoopery:
Adopt ICR mice (providing) by Shanghai Electrolux laboratory animal company limited; Influenza infection causes a series of oxidative damages of body; Give the recombination human source catalase of modifying with PEG through nasal cavity, carry out the antioxidation test, detect body weight change, dead protection, local pathological section; And carry out the oxidation resistance evaluation, data all adopt SPSS15.0 software to carry out statistical analysis.
Experimental result confirms; The recombination human source catalase that described PEG modifies; The acute pneumonia that can effectively cause resisiting influenza virus H1N1, FM1 makes pulmonary's virus titer minimizing, oxidation resistance and animal immune protection strengthen, slow down the pathology process of acute pneumonia, thereby the lung tissue damage is alleviated and the mice weight loss; The final mortality of mice that reduces prolongs the time-to-live.
The recombination human source catalase that PEG of the present invention modifies can with pharmacy acceptable carrier still; Process pharmaceutical preparation; Nasal cavity inhalant, lumbar injection agent and external preparation are processed in described pharmaceutical preparation; Through administering modes such as nasal cavity inhalation, intraperitoneal administration or medicine for external use, be used for treatment by the oxidative damage property disease that oxygen-derived free radicals (ROS) causes, be specifically related to treat acute pneumonia and the burn infection that infection such as virus, antibacterial and burn cause.
For the ease of understanding, below will describe in detail through the medicinal usage of concrete embodiment to the recombination human source catalase of PEG modification of the present invention.What need particularly point out is that these descriptions only are exemplary descriptions, do not constitute limitation of the scope of the invention.According to the argumentation of this description, many variations of the present invention, change all are conspicuous concerning one of ordinary skill in the art.
Description of drawings
Fig. 1 has shown the human source catalase separation and purification situation of Pichia anomala expression; Wherein, A is SDS-PAGE evaluation figure; 1 is fermented liquid supernatant ammonium sulfate concentrated solution, 2 for fermentation liquid through ammonium sulfate concentrate the back, after the drainage column desalination, upper prop has reached in Q-S post, purity 80%, 3 is with Q-S post separatory, reach 95% through hydroxyapatite, purity again; B is westen-blot evaluation figure, and 1 is the fermented liquid supernatant concentrated solution, and 2 is the human source catalase behind the Q-S ion exchange column purification, and 3 are the human source catalase behind the hydroxyapatite column branch.
Fig. 2 has shown the separation and purification situation of the PEG modified outcome of human source catalase, and wherein, 1 is the human source catalase of unmodified; 2 for modifying the back mixture; 3 is last all article, and 4 is isolated without the human source catalase of modifying, 5 human source catalases for the PEG modification; 6 is the molecular weight of albumen standard, is followed successively by 94kD, 66kD, 43kD from top to bottom.
Fig. 3 has shown the influence of infective virus concentration to mortality rate.
Fig. 4 is a body weight change curve chart after the infection postoperative infection virus.
Fig. 5 has shown lung tissue pathological analysis (* 100), and wherein, A is the lung tissue section of N group, can be observed complete normal lung tissue structure; B is the lung tissue section of V group, and the severe interstitial pneumonia can be observed serious tissue blood vessel edema, the inflammatory cell infiltration and the pulmonary collapse; C is the lung tissue section of R group, the no pulmonary collapse, but inflammatory cell infiltration is arranged around the blood vessel; D is the lung tissue section of C group, and the slight pulmonary collapse has inflammatory cell infiltration around the blood vessel; E is the lung tissue section of H group, and the pulmonary collapse makes moderate progress, and organizational structure is complete substantially; F is the lung tissue section of M group, and the pulmonary collapse makes moderate progress, but around the blood vessel serious inflammation is arranged; G is the lung tissue section of L group, and serious cellular infiltration and pulmonary collapse pneumonopathy become does not have improvement basically.
Fig. 6 is viral hemoagglutination titer determination figure, wherein, compares * with the V group: p 0.05, * *: p < 0.01.
Fig. 7 has shown oxidation resistance, and wherein, A is each group lung tissue activity of catalase, and compare * with the V group: p < 0.05; B removes superoxide anion and superoxide radical ability for each group, compares * with the V group: p 0.05, * *: p < 0.01; C is each group MDA content, compares * with the V group: p 0.05, * *: p < 0.01.
Fig. 8 is the reticuloendothelial system phagocytic activity comparison diagram, compares * with the V group: p 0.05, * *: p < 0.01.
Fig. 9 has shown that to immune protection wherein, A is each group lung index comparison, compares * with the V group: p 0.05, * *: p < 0.01; B compares for each group thymus index, compares * with the V group: p 0.05, * *: p < 0.01.
The specific embodiment
The recombination human source catalase that embodiment 1 PEG modifies is to the effect of acute pneumonia due to the influenza virus
1, the preparation of the recombination human source catalase of PEG modification
Adopt the human source catalase of Pichia anomala expression, 4 ℃ of fermentation liquids is centrifugal, collect supernatant; Use the ammonium sulfate precipitation crude enzyme liquid; Go up benzyl cellulose drainage column, Q-Sepharose FF and hydroxyapatite then successively, obtain the destination protein of 95% purity, the human source catalase of purification and activatory PEG 5000 are put into borate buffer with certain molar ratio; Stirring reaction 2h behind 4 ℃ of mix homogeneously; The modification reaction mixture is got suitable protein content be splined on pre-packed Sephacryl S-300 resin, with the PBS eluting of the pH 7.0 of 20mmol/L, flow velocity 1ml/min; The nucleic acid-protein detector is monitoring eluent protein content in the 280nm place, and collects each flow point with automatic collection instrument, carries out the SDS-PAGE electrophoretic analysis; The ampere bottle of sterilization is gone in the human source catalase dialysis back packing that the PEG that collects modifies, lyophilization, and-20 ℃ of preservations are subsequent use.
2, the preparation of the recombination human source catalase nasal cavity drop of PEG modification
The recombination human source catalase that cryodesiccated PEG is modified dissolves with the PBS buffer of 0.05M, and the 0.22um membrane filtration is subsequent use.
3, zoopery
Laboratory animal adopts ICR mice, body weight 16-18g; Strain adopts influenza virus A 1 (H1N1) Mus lung adapted strain FM1.Influenza infection mice:, establish three groups of the human source catalases high, normal, basic (H, M, L) that normal control group (N group), virus control group (V group), unmodified human source catalase group (C group), ribavirin group (R group), PEG modify with each random packet of mice male and female.Virus group and administration group mice infect 8TCID with the etherization posterula
50Virus; Infect back 2h and begin administration for the first time, one day administered twice, administration is 4 days altogether; Cutd open extremely in the 5th day, and took a blood sample and get lung.
4, detect index virus TCID
50Body weight change, mortality rate, pulmonary's pathology, and carry out the oxidation resistance evaluation.
(1) respectively organizes mice body weight and mortality rate variation after infection and the administration
As shown in Figure 4, after infection and the administration, the body weight of mice in each group of weighing every day, the result shows that the prolongation in time of normal mouse body weight is day by day risen, the infection group and viral infection group body weight obviously descends;
The result shows that the human source catalase that PEG modifies has dose-effect relationship to the effect that suppresses weight loss and mortality rate.
(2) lung exponential sum pneumonopathy variability
The result is as shown in table 1, and the normal group mouse lung does not have pathological changes, and the lung index is less; Respectively organize the lung index behind the viral infection and all significantly rise, average lung heavily increases to 3 times of normal level.Pulmonary's histological scores, behind the viral infection the 5th day, the average congestion area of pulmonary surpassed 75% of total surface area.
The result shows that the human source catalase that said PEG modifies can significantly be alleviated pathological changes such as pulmonary's congestion edema, and the lesion region area is reduced to below 50%, has demonstrated dose dependent.
Table 1
| Group | Number | Pneumonopathy becomes scoring | The lung index |
| The N group | 12 | 0±0** | 0.0064±0.0008** |
| The R group | 12 | 1.82±0.09** | 0.0139±0.0018* |
| The C group | 12 | 2.59±0.32* | 0.0137±0.0012* |
| The H group | 12 | 1.56±0.41** | 0.01379±0.0014** |
| The M group | 12 | 2.37±0.38** | 0.0144±0.0027* |
| The L group | 12 | 2.82±0.19* | 0.0153±0.0041 |
| The V group | 12 | 3.43±0.57 | 0.0185±0.0034 |
(3) lung tissue's pathological analysis
As shown in Figure 5, the result shows, behind the influenza infection, occurs serious interstitial pneumonia in the lung tissue, and serious hyperemia and various inflammatory cell infiltration are arranged, and with the serious pulmonary collapse; The positive drug ribavirin can make pulmonary collapse situation improve; The human source catalase that high dose PEG modifies has not only improved the pulmonary collapse situation of tissue, and the inflammatory cell infiltration phenomenon of blood vessel is eased.
(4) pulmonary's virus titer determination data
As shown in Figure 6, experimental result shows that in normal control group and blank, any concentration of test specification is not all seen the blood clotting phenomenon; Infection group and viral infection group forms tangible blood coagulation phenomenon; Each dosage human source catalase after PEG modifies all can make the viral hemoagglutination titre in the LH obviously descend.
5, oxidation resistance evaluation
Viral infection has produced negative effect to pulmonary's antioxidant status, and the antioxidant system ability is suppressed, and causes reactive oxygen free radical content to raise, and causes apoptosis and causes weakening and tissue injury of lung tissue basic function.Give with exogenous catalatic experimental result to show, significantly improved activity of catalase, the anti-superoxide anion ability of mouse lung tissue and the content of lipid peroxidation product MDA is descended.
As shown in Figure 7, the result shows, reactive oxygen free radical: the human source catalase that PEG modifies, directly act on pulmonary through the nasal cavity suction, and effectively improve the activity of catalase in the lung tissue, thereby increase removing hydrogen peroxide.
6, reticuloendothelial system phagocytic activity
Reticuloendothelial system is the important congenital nonspecific immunity barrier of body, in infection immunity, plays a part very importantly, and it can engulf, digest, eliminate pathogenic microorganisms such as virus, the incidence and development that blocking-up is infected or make it to be confined to some specific region.As shown in Figure 8, the result shows that ribavirin and human source catalase have all improved the endothelial system phagocytic function that receives the virus inhibition extremely significantly.
7, to the mouse immune systematic influence
As shown in Figure 9, the result shows that viral infection causes mouse spleen and atrophy of thymus gland, thereby immune system is produced inhibition; The human source catalase that PEG modifies can reduce this depression effect significantly, and the ratio of IFN-γ/IL-4 is descended.
In sum; Human source catalase than unmodified; The acute pneumonia that the human source catalase that PEG modifies can effectively cause resisiting influenza virus H1N1, FM1 makes pulmonary's virus titer minimizing, oxidation resistance and animal immune protection strengthen, slow down the pathology process of acute pneumonia, thereby the lung tissue damage is alleviated and the mice weight loss; The final mortality of mice that reduces prolongs the time-to-live.
SEQUENCE?LISTING
< 110>Fudan University
< 120>medicinal usage of the recombination human source catalase of PEG modification
<130>
<160> 1
<170> PatentIn?version?3.3
<210> 1
<211> 1584
<212> DNA
<213> Artificial
<400> 1
atggctgaca?gccgggatcc?cgccagcgac?cagatgcagc?actggaagga?gcagcgggcc 60
gcgcagaaag?ctgatgtcct?gaccactgga?gctggtaacc?cagtaggaga?caaacttaat 120
gttattacag?tagggccccg?tgggcccctt?cttgttcagg?atgtggtttt?cactgatgaa 180
atggctcatt?ttgaccgaga?gagaattcct?gagagagttg?tgcatgctaa?aggagcaggg 240
gcctttggct?actttgaggt?cacacatgac?attaccaaat?actccaaggc?aaaggtattt 300
gagcatattg?gaaagaagac?tcccatcgca?gttcggttct?ccactgttgc?tggagaatcg 360
ggttcagctg?acacagttcg?ggaccctcgt?gggtttgcag?tgaaatttta?cacagaagat 420
ggtaactggg?atctcgttgg?aaataacacc?cccattttct?tcatcaggga?tcccatattg 480
tttccatctt?ttatccacag?ccaaaagaga?aatcctcaga?cacatctgaa?ggatccggac 540
atggtctggg?acttctggag?cctacgtcct?gagtctctgc?atcaggtttc?tttcttgttc 600
agtgatcggg?ggattccaga?tggacatcgc?cacatgaatg?gatatggatc?acatactttc 660
aagctggtta?atgcaaatgg?ggaggcagtt?tattgcaaat?tccattataa?gactgaccag 720
ggcatcaaaa?acctttctgt?tgaagatgcg?gcgagacttt?cccaggaaga?tcctgactat 780
ggcatccggg?atctttttaa?cgccattgcc?acaggaaagt?acccctcctg?gactttttac 840
atccaggtca?tgacatttaa?tcaggcagaa?acttttccat?ttaatccatt?cgatctcacc 900
aaggtttggc?ctcacaagga?ctaccctctc?atcccagttg?gtaaactggt?cttaaaccgg 960
aatccagtta?attactttgc?tgaggttgaa?cagatagcct?tcgacccaag?caacatgcca 1020
cctggcattg?aggccagtcc?tgacaaaatg?cttcagggcc?gcctttttgc?ctatcctgac 1080
actcaccgcc?atcgcctggg?acccaattat?cttcatatac?ctgtgaactg?tccctaccgt 1140
gctcgagtgg?ccaactacca?gcgtgacggc?ccgatgtgca?tgcaggacaa?tcagggtggt 1200
gctccaaatt?actaccccaa?cagctttggt?gctccggaac?aacagccttc?tgccctggag 1260
cacagcatcc?aatattctgg?agaagtgcgg?agattcaaca?ctgccaatga?tgataacgtt 1320
actcaggtgc?gggcattcta?tgtgaacgtg?ctgaatgagg?aacagaggaa?acgtctgtgt 1380
gagaacattg?ccggccacct?gaaggatgca?caaattttca?tccagaagaa?agcggtcaag 1440
aacttcactg?aggtccaccc?tgactacggg?agccacatcc?aggctcttct?ggacaagtac 1500
aatgctgaga?agcctaagaa?tgcgattcac?acctttgtgc?agtccggatc?tcacttggcg 1560
gcaagggaga?aggcaaatct?gtga 1584
Claims (7)
1.PEG the purposes of the recombination human source catalase of modifying in preparation treatment virus, bacterial infection medicine, described recombination human source catalase has the sequence of sequence 1.
2. by the described purposes of claim 1, it is characterized in that described infection is acute pneumonia and the burn infection that virus, antibacterial and burn infection cause.
3. by the described purposes of claim 1, it is characterized in that described virus is selected from influenza virus, SARS virus, respiratory syncytial virus or coronavirus.
4. by the described purposes of claim 1, it is characterized in that described antibacterial is selected from the rich Salmonella of staphylococcus aureus, streptococcus pneumoniae or kerekou pneumonia.
5. by the described purposes of claim 1, it is characterized in that, the recombination human source catalase that described PEG modifies, for modify through PEG, DNA sequence is that human source catalase cDNA expresses also purified product in Pichia sp..
6. by the described purposes of claim 1, it is characterized in that described medicine is processed nasal cavity inhalant, lumbar injection preparation or external preparation.
7. by the described purposes of claim 1, it is characterized in that the recombination human source catalase that described PEG modifies prepares through following method:
Adopt the human source catalase of Pichia anomala expression, 4 ℃ of fermentation liquids is centrifugal, collect supernatant; Behind the ammonium sulfate precipitation crude enzyme liquid; Go up benzyl cellulose drainage column, Q-Sepharose FF and hydroxyapatite successively, obtain the destination protein of 95% purity, the human source catalase of purification and activatory PEG 5000 are put into borate buffer with certain molar ratio; Stirring reaction 2h behind 4 ℃ of mix homogeneously; The modification reaction mixture is got suitable protein content be splined on pre-packed Sephacryl S-300 resin, with the PBS eluting of the pH 7.0 of 20mmol/L, flow velocity 1ml/min; The nucleic acid-protein detector is monitoring eluent protein content in the 280nm place, and collects each flow point with automatic collection instrument, carries out the SDS-PAGE electrophoretic analysis; The ampere bottle of sterilization is gone in the human source catalase dialysis back packing that the PEG that collects modifies, lyophilization, and-20 ℃ of preservations are subsequent use.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103060344A (en) * | 2013-01-29 | 2013-04-24 | 福州大学 | Sika deer hydrogen peroxidase and preparation method thereof |
| WO2020155688A1 (en) * | 2019-01-29 | 2020-08-06 | 苏州杰纳生物科技有限公司 | Natural polymer-protein complex and preparation method therefor and application thereof |
| WO2021173922A1 (en) * | 2020-02-27 | 2021-09-02 | Vivibaba, Inc. | Catalase nanocapsules and methods for use |
| CN114652847A (en) * | 2021-10-28 | 2022-06-24 | 严然 | Nano composite, preparation method and application thereof |
| CN114767839A (en) * | 2021-10-28 | 2022-07-22 | 严然 | Nano composite and application |
-
2011
- 2011-05-10 CN CN2011101198834A patent/CN102772789A/en active Pending
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| Title |
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| GUEY,L.T.ET AL.: "Homo sapiens catalase (CAT), mRNA", 《NCBI GENBANK》 * |
| 史训龙: "重组表达过氧化氢酶及抗氧化损伤生物活性的研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103060344A (en) * | 2013-01-29 | 2013-04-24 | 福州大学 | Sika deer hydrogen peroxidase and preparation method thereof |
| WO2020155688A1 (en) * | 2019-01-29 | 2020-08-06 | 苏州杰纳生物科技有限公司 | Natural polymer-protein complex and preparation method therefor and application thereof |
| WO2021173922A1 (en) * | 2020-02-27 | 2021-09-02 | Vivibaba, Inc. | Catalase nanocapsules and methods for use |
| CN114652847A (en) * | 2021-10-28 | 2022-06-24 | 严然 | Nano composite, preparation method and application thereof |
| CN114767839A (en) * | 2021-10-28 | 2022-07-22 | 严然 | Nano composite and application |
| CN114652847B (en) * | 2021-10-28 | 2024-02-06 | 上海巴久巴生物技术有限公司 | Nanocomposite, preparation method and application thereof |
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Application publication date: 20121114 |