CN101843893B - Application of cyclosporin A in preparing anti-rotavirus medicaments - Google Patents
Application of cyclosporin A in preparing anti-rotavirus medicaments Download PDFInfo
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- CN101843893B CN101843893B CN2010101800129A CN201010180012A CN101843893B CN 101843893 B CN101843893 B CN 101843893B CN 2010101800129 A CN2010101800129 A CN 2010101800129A CN 201010180012 A CN201010180012 A CN 201010180012A CN 101843893 B CN101843893 B CN 101843893B
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Abstract
The invention discloses the application of cyclosporin A in preparing of anti-rotavirus medicaments. by combining with human cyclophilin A, the cyclosporin A can block interaction of rotavirus VP6 protein and the human cyclophilin A, thereby inhibiting the formation of rotavirus particles to achieve the effect of resisting rotavirus. Adopting the cyclosporin A as an active ingredient, it is helpful to develop specific anti-rotavirus medicaments with high efficiency and low toxin.
Description
Technical field
The present invention relates to novel application of compound, particularly the new purposes of ciclosporin A.
Background technology
Rotavirus (Rotavirus, RV) infect be the main diseases that causes infantile diarrhea because of, cause about 1.25 hundred million routine child's gastroenteritiss every year, cause 352,000-592,000 example child below 5 years old is dead because of rotavirus infection, mainly occurs in developing country.
Rotavirus belongs to arc reovirus virus section; Be no after birth double-stranded RNA (dsRNA) virus; Article 11, dsRNA respectively twines the guanyl of 1 RNA molecule dependenc RNA polymerase (VP1) and 1 molecule and the core that transmethylase (VP3) is positioned at virion; The 12 kinds of protein of encoding comprise 6 kinds of structural protein (VP1～4,6～7) and 6 kinds of non-structural proteins (NSP1～6).VP2 constitutes the internal layer capsid parcel viral genome of rotavirus; The middle level capsid that VP6 constitutes holds VP2 and forms rotavirus double capsid granule (DLP); The outer capsid that VP4 and VP7 constitute holds DLP again and forms three layers of capsid particles of complete rotavirus (TLP).Rotavirus passes cell membrane and gets into cell under the mediation of receptor; Take off outer capsid formation DLP and begin reproduction process, newly-generated viral dsRNA and albumen are assembled the formation virus particle in endochylema, and assembling generates DLP therein; DLP does not have infection ability; It gets into endoplasmic reticulum subsequently, is assembled into the TLP justacrine with infection ability with new synthetic VP4 and VP7 and goes out host cell, accomplishes the reproduction process of virus.
Up to now, people are also very insufficient to the rotavirus infection Mechanism Study, mainly are symptomatic treatment clinically, lack directly to viral safe and effective medicine.Traditional antiviral drugs IFN-and metabolism class antiviral drugs are used for anti-rotavirus and infect owing to reasons such as toxic and side effects or poor effect are less.Be to reduce infection rate and mortality rate, clinically specific medicament that can anti-rotavirus is had very urgent need.
Ciclosporin A (CsA) is known immunosuppressant; Be mainly used in the rejection that suppresses after organ and the tissue transplantation clinically; Also be used for the treatment of autoimmune disease in addition, as type i diabetes, psoriasis, rheumatoid arthritis, systemic lupus erythematosus (sle) etc. are all had sure curative effect.But up to now, do not see the relevant report of ciclosporin A aspect anti-rotavirus both at home and abroad as yet.
Summary of the invention
In view of this, the object of the present invention is to provide the new purposes of ciclosporin A, i.e. the application of ciclosporin A in the preparation anti-rotavirus medicaments.
The present invention uses the protein science method that the albumen of human body cell after by rotavirus infection is changed spectrum and analyzes, and (Cyclophilin A CypA) expresses and raises to find rotavirus infection can to induce people's cyclophilin A.The utilization bioinformatics method is analyzed the interaction of rotavirus vp 6 albumen and people's cyclophilin A, finds that rotavirus vp 6 albumen and people's cyclophilin A have interaction.Utilization homologous protein mould construction method has made up rotavirus vp 6 albumen and the interactional complex 3 d structure model of people's cyclophilin A, has confirmed the functional area and the avtive spot of these two protein-interactings.The immunofluorescence laser co-focusing shows rotavirus vp 6 albumen and cyclophilin A co in the rotavirus infection cell, has proved to exist really between rotavirus vp 6 albumen and the people's cyclophilin A to interact.This interaction is relevant with the rotavirus infection human body, can be used as the drug effect target, and screening or design can be blocked this interactional chemical compound, are expected to develop the specific anti rotavirus medicaments of high-efficiency low-toxicity.So; The present invention is directed to rotavirus vp 6 albumen and interactional functional area of people's cyclophilin A and avtive spot; The existing compound database of utilization computer virtual screening technique search finds that the above-mentioned functions zone of ciclosporin A and people's cyclophilin A and avtive spot have strong affinity.Then plasma surface laser resonant bio-sensing (SPR) shows that ciclosporin A can effectively suppress combining of rotavirus vp 6 albumen and people's cyclophilin A.The anti-rotavirus activity experiment of virus levels finds that ciclosporin A can significantly suppress the particulate generation of rotavirus, and the MA104 cell of rotavirus infection is had than the significant protection effect.Above-mentioned experimental result explanation, ciclosporin A can be blocked the interaction of rotavirus vp 6 albumen and people's cyclophilin A through combining with people's cyclophilin A, reaches the anti-rotavirus effect thereby suppress the particulate formation of rotavirus.With it is active component, is expected to develop the specific anti rotavirus medicaments of high-efficiency low-toxicity.
Thus, the invention provides the application of ciclosporin A in the preparation anti-rotavirus medicaments.
Beneficial effect of the present invention is: the invention provides the application of ciclosporin A in the preparation anti-rotavirus medicaments; Be expected to develop the specific anti rotavirus medicaments of high-efficiency low-toxicity; Solve existing antiviral drugs poor effect or the bigger problem of toxic and side effects when the treatment rotavirus infection; Satisfy the clinical treatment needs, ensure people's health.
Description of drawings
In order to make the object of the invention, technical scheme and advantage clearer, will combine accompanying drawing that the present invention is made further detailed description below, wherein:
Fig. 1 shows that rotavirus infection induces people's cyclophilin A express to raise, and wherein A is the protein of two dimensional electrophoresis screening rotavirus infection up-regulated expression after 12 hours, and the protein that obviously raises one is expressed by arrow indication place; B is the enlarged drawing at arrow indication place among the A; C is that mass spectrum binding data library searching identifies that this protein is cyclophilin A; D is that Western-blot confirms that this protein is cyclophilin A;
Fig. 2 shows that rotavirus vp 6 albumen contain the identification of people's cyclophilin A, combine and catalytic af-ag domain;
Fig. 3 shows the 3 d structure model of the complex of rotavirus vp 6 albumen and people's cyclophilin A, and wherein rotavirus vp 6 albumen show that by blue and green banded structure green portion is represented and the interactional functional area of people's cyclophilin A; Cyclophilin A shows that by orange and yellow banded structure yl moiety is represented the functional area with rotavirus vp 6 protein-interactings;
Fig. 4 shows the cell co of rotavirus vp 6 albumen and people's cyclophilin A, and wherein rotavirus vp 6 albumen are used the green fluorescence antibody labeling; People's cyclophilin A is used the red fluorescence antibody labeling; Figure B is the enlarged drawing at square frame place among the corresponding figures A;
Fig. 5 shows the protective effect of ciclosporin A to the MA104 cell of infection rotavirus, and wherein A is the influences (C-for do not add ciclosporin A, C+ for add ciclosporin A) of 2 μ M ciclosporin As (CsA) to rotavirus output in the course of infection; B is the influences (F-for do not add FK506, F+ for add FK506) of 2 μ M FK506 to rotavirus output in the course of infection.
The specific embodiment
Below will carry out detailed description to the preferred embodiments of the present invention with reference to accompanying drawing.The experimental technique of unreceipted actual conditions in the preferred embodiment, usually according to normal condition, the molecular cloning experiment guide (third edition for example; J. work such as Sa nurse Brooker, Huang Peitang etc. translate, Science Press; 2002) described in condition, or the condition of advising according to manufacturer.
1, the albumen of protein science methods analyst host cell after by rotavirus infection changes spectrum and does two-dimensional electrophoresis (IEF) with the prefabricated adhesive tape of the IPG of 13cm pH3-11NL; The MA104 cell protein stave that Wa strain rotavirus or SA11 strain and simulated infection (mock infected) have been infected in analysis reach situation (Figure 1A, B).With the simulated infection group is contrast, and Wa strain infected group can detect 772 and 798 protein sites respectively, and SA11 strain infected group can detect 1230 and 1312 protein sites respectively.Through the comparison of graphical analysis and glue and image, repeat 3 times, find that Wa strain infected group infected after 12 hours, 14 protein site up-regulateds are arranged more than 2 times, 37 protein site down-regulated expressions are more than 50%; SA11 strain infected group infected after 12 hours, 24 protein site up-regulateds was arranged more than 2 times, and 29 protein site down-regulated expressions are more than 50%.Seeing that can cause the generally decline of expression of cellular proteins after the rotavirus infection, it is more meaningful in rotavirus and host cell interaction that those infect the albumen of expressing rise on the contrary in the back, carries out Identification of Fusion Protein so be chosen in the protein site that infects the back up-regulated.
Adopt the MALDI-TOF-MS technology, and carry out database retrieval to identify the albumen of up-regulated after infection with the NCBInr data base through mascot.Mass spectrometry results shows; Expressing the albumen that raises comprises: rotavirus non-structural protein NSP3; Plectin 1isoform 6, cortactin-binding protein 2 and leucine-zipper-like transcription regulator, the complex of 1 isoform 1; The complex of KRT8 protein and reticulocalbin 1, cyclophilin A etc. (Fig. 1 C).These albumen maybe with suppress host protein expressions, intracellular signal transmission, born of the same parents' intracellular metabolite, virus replication and transportation and host cell and grow and break up relevantly, demonstrate after the rotavirus infection the transformation of host cell, make it to be suitable for oneself and in born of the same parents, survive.Further Western-blot result confirms up-regulated expression (Fig. 1 D) after rotavirus infection such as cyclophilin A.
2, the interaction of bioinformatic analysis rotavirus vp 6 albumen and people's cyclophilin A
Bioinformatic analysis rotavirus vp 6 proteic aminoacid primary structures and three-dimensional crystalline structure are found, contain the easiest identification of cyclophilin A in the VP6 PROTEIN C end sequence af-ag ring, combine the also X-GP-X sequence (Fig. 2) of catalysis proline conformational change wherein.Prompting rotavirus vp 6 albumen and people's cyclophilin A have interaction, infer that this effect plays an important role to the maturation of virus, viral formation of duplicating with reovirion.
3, homologous protein mould construction method makes up rotavirus vp 6 albumen and the interactional complex 3 d structure model of people's cyclophilin A
(accession number is P03530 according to Wa strain rotavirus VP6 albumen; Aminoacid sequence is shown in SEQ No.1) three-dimensional crystalline structure and people's cyclophilin A (aminoacid sequence is shown in SEQ No.2) three-dimensional crystalline structure (protein three-dimensional structure data base PDB is numbered 1AK4); Adopt the INSIGHTII work station; The loop district that rotavirus vp 6 albumen Leu 343 to Arg 392 are formed is docked in people's cyclophilin A binding pocket; Obtain the initiating structure of the complex of rotavirus vp 6 albumen and people's cyclophilin A, the reuse molecular mechanics is optimized, and the force field parameter of employing is the Amber field of force and Kollman-all-atom electric charge.The complex 3 d structure model of optimizing is as shown in Figure 3.Can be known by this complex 3 d structure model: rotavirus vp 6 albumen and the interactional functional area of people's cyclophilin A are the 52nd to the 100th and the 343rd to the 392nd amino acids; Wherein main avtive spot is Asn 53; Ala 348, and Val 349, Ile 355 and Pro 363; The functional area of people's cyclophilin A and rotavirus vp 6 protein-interactings is the 54th to the 150th amino acids, and wherein main avtive spot is Arg 55, and Gln 63, Lys 125 and Arg 148.
4, the interaction of immunofluorescence laser co-focusing checking rotavirus vp 6 albumen and people's cyclophilin A
On the basis of confirming rotavirus vp 6 albumen and interactional functional area of people's cyclophilin A and avtive spot; The present invention is with different colours fluorescent antibody difference labelling rotavirus vp 6 albumen and people's cyclophilin A; The immunofluorescence laser co-focusing shows VP6 albumen and cyclophilin A co (Fig. 4) in the rotavirus infection cell, proves to exist really between rotavirus vp 6 albumen and the people's cyclophilin A to interact.This interaction has coat protein mutual group such as the rotavirus vp of helping 6 proteic polies, DLP formation and later stage and VP4, VP7 and dresses up TLP, forms sophisticated rotavirus granule.
Can judge by The above results; Rotavirus vp 6 albumen are relevant with the rotavirus infection human body with the interaction of people's cyclophilin A; This interaction can be used as the drug effect target; Screening or design can be blocked this interactional chemical compound, are expected to develop the specific anti rotavirus medicaments of high-efficiency low-toxicity.
5, the computer virtual screening technique is to the interaction screening reactive compound of rotavirus vp 6 albumen and people's cyclophilin A and the anti-rotavirus active testing of gained chemical compound
At first; The present invention is directed to rotavirus vp 6 albumen and interactional functional area of people's cyclophilin A and avtive spot; Screened the compound sample storehouse of the drug data base CMC and the existing compound database ACD of MDL company with the computer virtual screening method; Obtain the chemical compound that a collection of and cyclophilin A have strong affinity, comprised known immune suppressive cyclosporin A.
Secondly; The present invention adopts plasma surface laser resonant bio-sensing (SPR) to study ciclosporin A inhibition rotavirus vp 6 albumen and the bonded ability of people's cyclophilin A: earlier with 100mM NHS/400mM EDC activated b IAcore sensing chip (Pharmacia LKB Biotechnology); Inject VP6 albumen through activatory surface; Unreacted active group is with 1M ethanolamine (pH 8.5) inactivation; Again the ciclosporin A of variable concentrations and cyclophilin A are injected flow cell with the flow velocity of 10ul/min; The resonance signal of continuous record gained (RU) with the binding curve of BIAevaluation 2.1 softwares (Pharmacia Biosenor) analysis gained, calculates the apparent dissociation constant of VP6 albumen and cyclophilin A.The result shows, the association rate constant ka=3.16x10 of VP6 albumen and cyclophilin A
3S, dissociation rate constant kd=2.56x10
-4s
-1, binding equilibrium constant K a=1.38x10
8M
-1, dissociation equilibrium constant K d=7.89x10
-9M; Ciclosporin A can suppress combining of rotavirus vp 6 albumen and people's cyclophilin A effectively, and along with the concentration of ciclosporin A increases, it suppresses VP6 albumen and the bonded intensity of cyclophilin A also increases, and demonstrates good dose-effect relationship.
Once more; The present invention has tested the protective effect of ciclosporin A to the rotavirus infection cell on virus levels: with the MA104 cell inoculation in 96 well culture plates; Be to cultivate under 5% the condition in 37 ℃ of temperature, carbon dioxide volume fraction; The ciclosporin A that adds rotavirus and different diluted concentrations; Establish viral blank, the contrast of 293FT cell and sample F K506 contrast simultaneously, observation of cell reaction of degeneration (CPE), and measure virus titer with rotavirus specificity fluorescent antibody staining and write down the FFU value.The result is as shown in Figure 5, and concentration is that the ciclosporin A of 1uM or 2uM all has than the significant protection effect rotavirus infection MA104 cell.
Can judge that by The above results ciclosporin A can be blocked the interaction of rotavirus vp 6 albumen and people's cyclophilin A through combining with people's cyclophilin A, reaches the anti-rotavirus effect thereby suppress the particulate formation of rotavirus.It can be used as active component; Use separately or form compound recipe with other active component; Adopt acceptable accessories and preparation conventional method, process the anti-rotavirus medicaments of various dosage forms such as tablet, capsule, granule, powder, oral liquid or injection, supply clinical use.
Explanation is at last; Above embodiment is only unrestricted in order to technical scheme of the present invention to be described; Although through invention has been described with reference to the preferred embodiments of the present invention; But those of ordinary skill in the art should be appreciated that and can make various changes to it in form with on the details, and the spirit and scope of the present invention that do not depart from appended claims and limited.
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Claims (1)
1. the application of ciclosporin A in the preparation anti-rotavirus medicaments.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1795000A (en) * | 2003-03-28 | 2006-06-28 | 布里斯托尔-迈尔斯斯奎布公司 | Compositions containing lactulose for treating potavirus infections |
| CN1964735A (en) * | 2004-04-08 | 2007-05-16 | 诺瓦提斯公司 | Use of cyclosporins for treatment of cerebral ischemia and brain and spinal cord injury |
| CN101557819A (en) * | 2006-10-12 | 2009-10-14 | 诺瓦提斯公司 | Use of modified cyclosporins |
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2010
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1795000A (en) * | 2003-03-28 | 2006-06-28 | 布里斯托尔-迈尔斯斯奎布公司 | Compositions containing lactulose for treating potavirus infections |
| CN1964735A (en) * | 2004-04-08 | 2007-05-16 | 诺瓦提斯公司 | Use of cyclosporins for treatment of cerebral ischemia and brain and spinal cord injury |
| CN101557819A (en) * | 2006-10-12 | 2009-10-14 | 诺瓦提斯公司 | Use of modified cyclosporins |
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| Title |
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| Satoshi Matsuda et al..Mechanisms of action of cyclosporine.《Immunopharmacology》.2000,第47卷(第2-3期),119-125. * |
| 何海洋等.轮状病毒不同毒株感染宿主细胞的感染效力研究.《免疫学杂志》.2007,第23卷(第3期),255-259. * |
| 魏静等.轮状病毒结构蛋白VP6 HLA-A*0201限制性CTL表位的初步鉴定.《第三军医大学学报》.2006,第28卷(第6期),499-502. * |
| 魏静等.轮状病毒结构蛋白VP7 HLA-A2.1限制性CTL表位的初步鉴定.《免疫学杂志》.2006,第22卷(第1期),5-8. * |
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