CN101912602A - Application of ricinus agglutinin 120 to the resistance against influenza A virus - Google Patents
Application of ricinus agglutinin 120 to the resistance against influenza A virus Download PDFInfo
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- CN101912602A CN101912602A CN 201010271650 CN201010271650A CN101912602A CN 101912602 A CN101912602 A CN 101912602A CN 201010271650 CN201010271650 CN 201010271650 CN 201010271650 A CN201010271650 A CN 201010271650A CN 101912602 A CN101912602 A CN 101912602A
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Abstract
The invention relates to application of ricinus agglutinin 120 (RCA120) to the resistance against influenza A virus. Ricinus agglutinin 120 can be combined with sugar chain structures on HA (Hemagglutinin) and NA (Neuraminidase) on the surface of the influenza A virus, and can act on the influenza virus HA to take effect in the early stage of the infection of host cells by the virus. The virus cannot be absorbed on the surface of the host cells through influencing the combination of HA and sialoglycopeptide chain receptors on the cell membrane of the host cells, and therefore, the virus cannot infect the host cells. The ricinus agglutinin 120 can act on the influenza virus NA to inhibit the activity of neuraminidase, prevent the mature progeny viruses from going away from the host cells, and prevent the release and the diffusion of the mature progeny viruses.
Description
Technical field
The present invention relates to ricinus agglutinin in the application that suppresses aspect viral, be specifically related to ricinus agglutinin 120 in the application that suppresses aspect influenza A virus breeding and the diffusion.
Background technology
One, influenza A virus brief introduction
Influenza (Influenza) is called for short influenza, it is a kind of acute respiratory infectious disease that causes by influenza virus, clinical manifestation be onset urgency, hyperpyrexia, myalgia, headache with serious discomfort, dry cough, throat pain or rhinitis, most of patients can recovery in one to two week.But influenza also is different from general flu, and the fearful part of influenza virus is to infect fast, disseminates the zone and leads to complications extensively and to the weakling and can cause death.Influenza incubation period is short, through the respiratory tract droplet transmission, propagate rapidly, antigen easily makes a variation, the crowd is to the general susceptible of variant, the control difficulty is big.Influenza pandemic is certain seasonality, can occur in any season but be very popular, and can rapid spread to the whole world.The southern and northern epidemic season difference of China's influenza, northern area is generally popular in winter-spring season, and the south four seasons all have case to take place, and onset peak is in summer and winter.Influenza virus can be divided into first (A), second (B), third (C), three types, and first type and influenza B threaten bigger to the mankind, and wherein the influenza A antigenic variation is frequent, can cause worldwide being very popular, and the mankind are threatened maximum.Influenza is listed in China's Class C Notifiable disease.
Influenza A virus belongs to orthomyxovirus section, genome is made up of 8 minus strand single-stranded RNAs, encode the respectively many aggregation enzymes of viral RNA (PB1, PA and PB2), nucleocapsid protein (NP), neuraminidase (NA), hemagglutinin (HA), stromatin (M1 and M2), non-structural protein (NS1 and NS2) and mitochondrion associated protein (PB1-F2).Wherein HA and NA are glycosylated proteins, and all the other all are non-glycoproteins.HA and NA also are the major antigens of virus surface, different according to HA and NA, and influenza A virus can be divided into 16 HA hypotypes (H1-H16) and 10 NA hypotypes (N1-N10).HA exists with trimerical form at virus surface, can be divided into ball head and stem; Different with strain according to hypotype, each subunit contains 3-12 N-glycosylation site; HA is playing a role at the virus infection host cell in early days mainly, HA assists peplos and host cell membrane to merge mutually when host born of the same parents' endocytosis by combining with sialic acid sugar chain receptor (sialic acid oligosaccharide) on the host cell membrane and virus being adsorbed in host cell surface.NA exists with the form of homotetramer, has hydrolase of proteolysis, can the hydrolysis sialic acid, and promote the release of the ripe virus of filial generation, and can assist the absorption of HA host cell.Virus protein is synthetic by the RNA polymerase of virus itself, and this kind of enzyme lacks calibration function, and segmented influenza A virus genome makes virus have very high gene recombination fraction again, and two kinds of factors have caused the high mutability of influenza A virus jointly.In addition, often utilize the intravital post translational modification system of host to carry out the glycosylation modified of oneself protein after virus protein is synthetic, be used for the glycosyl transferase of protein glycosylation and the composition of glycosidase among the different hosts, ratios etc. are all inequality, thereby cause the different of HA and NA degree of glycosylation and sugar chain structure.Therefore, virus genomic high mutability and the dependent virus protein glycosylation of host mechanism have caused the multiformity of influenza virus jointly.
Two, ricinus agglutinin brief introduction
As one of phytohemagglutinin of finding the earliest, ricinus agglutinin is subjected to common people always and shows great attention to.At present, ricinus agglutinin (RCA) cytokine ELISA test kit is sold on the market as the biochemical reagents product.Ricinus agglutinin has a stronger narrow spectrum bioactive substance as a kind of, has good application prospects in the diagnosis of tumor and cancer.Yet, research through recent two decades, ricinus agglutinin still fails to be effectively applied to clinical disease diagnosis and treatment, conclude the actual application value of having got up following some cause influence is arranged ricinus agglutinin: (1) is although ricinus agglutinin has good specificity to the RCA receptor, but the RCA receptor exist scope and kind excessive, make RCA relatively low, be not easy to identify the cell of particular type by it and combining of receptor to the specificity of specific cells; (2) the toxicity in vivo Control Study of ricinus agglutinin is still waiting deeply, though RCA by coupling holder or medicine, can be in vivo exactly with the RCA receptors bind, RCA itself has very strong physiology toxicity, might bring potential hazard to human body.RCA is different from virus and monoclonal antibody, and mechanism of action, degradation pathway and self toxicity control method are also still indeterminate in its body.
Three, traditional treatment medicine brief introduction
At present, the treatment of influenza drug main of Gong Rening will have two kinds in the world: the one, and the oseltamivir phosphate capsule (trade name: " oseltamivir phosphate capsule ") of Roche Holding Ag's research and development.Oseltamivir phosphate capsule is a kind of very effective treatment of influenza medication, and can significantly reduce the generation and the antibiotic use of complication (mainly being trachea and bronchitis, pneumonia, pharyngitis etc.), thereby be one of the most frequently used medicine for the treatment of at present influenza, also be the anti-avian influenza of generally acknowledging, influenza A H1N1 one of the most effective medicine.Nearest popular H1N1 influenza A infects early stage effective with oseltamivir phosphate capsule (Oseltamivir).Another is the Zha Namiwei suction powder spray (trade name: " musicality is clear " or " Relenza ") of GlaxoSmithKline PLC company research and development.This product passes through to suppress the neuraminidase of influenza virus, thereby has changed gathering and the release of influenza virus in infection cell.Find during in vitro tests, when drug level constantly increases, still have influenza virus that the sensitivity of zanamivir is descended.By analysis, this causes that with virus mutation the aminoacid of neuraminidase and hemagglutinin the two or one changes relevant.
For the influenza patient, can use medicines such as interferon, diamantane (obsolete) amine, oseltamivir phosphate capsule or Relenza to treat at present.Interferon (Interferon) is a kind of cytokine that can suppress virus replication; Amantadine (Amantadine) then can act on the influenza m 2 memebrane protein with rimantadine (Rimantadine), stop hydrion to pass through, disturb the shelling process, to suppress the release of viral genetic, this class medicine only can be treated the A type influenza with M2 memebrane protein virus usually.Wherein early stage these two kinds of diamantane (obsolete) amine medicines that use, the Drug resistance of initiation virus, and the patient who takes easily can produce the uncomfortable side effect of certain degree, makes this type of medicine obviously be limited at the effectiveness of treatment influenza.Oseltamivir phosphate capsule or Relenza all are to belong to neural amino acid enzyme inhibitor, mainly are to suppress the nerve amines phytase activity, stop sophisticated progeny virus to leave host cell, carry out the diffusion of virus.It also is the influenza medicine of at present tool curative effect.Wherein oseltamivir phosphate capsule belongs to forerunner's medicine, is used as medicine with the capsule oral form, in gastrointestinal absorption enters body, is converted into tool by the ester hydrolase in the liver and suppresses active carboxylic acid molecules.According to clinical research, in influenza virus infection initial stage (about two days), the therapeutic effect of taking oseltamivir phosphate capsule is best." Relenza " is then because bioavailability of medicament is not good, thereby be used as medicine and then be sprayed on patient oral cavity or mucosa position in suction-type spray mode, absorb to enter by mucosa and suppress virus infraction in the body, but because application method is comparatively complicated loaded down with trivial details, and be not suitable for using for some lung functions obstacle persons, so the medicine popularity rate just is not so good as the oseltamivir phosphate capsule of oral form.
Summary of the invention
The present invention proposes the application of ricinus agglutinin 120 (RCA120) aspect anti-influenza A virus, about treating except that medicines such as interferon, diamantane (obsolete) amine, oseltamivir phosphate capsule or Relenza, looking for another way of influenza A, also therefore overcome the technology prejudice of relevant ricinus agglutinin application, application process.
The present invention finds by lot of experiments: all exist α, β-D-galactose or end to be Gal β 1-4GlcNAc sugar chain sequence material on the major antigen HA on the various hypotypes of influenza A virus surface and the NA.Because ricinus agglutinin can combine with α, β-D-galactose generation specificity, can be that Gal β 1-4GlcNAc sugar chain sequence material carries out specificity and combines also simultaneously with end; It can be discerned has the N-glucosides type glycoprotein (in fact also can discern the O-glycosides type glycoprotein with this sugar chain) that this specific sugar chain is expressed.
The present invention further draws through experiment, ricinus agglutinin 120 (Ricinus Communis Agglutinin120, RCA120) can be in conjunction with the major antigen HA on above-mentioned influenza A virus surface and the sugar chain structure on the NA, its sugar chain structure is specially α, β-D-galactose or end is Gal β 1-4GlcNAc sugar chain sequence material; Empirical tests, ricinus agglutinin 120 can stop virus breeding and diffusion, plays the effect of influenza.
Therefore, technical scheme of the present invention has illustrated:
Ricinus agglutinin 120 possesses the application aspect anti-influenza A virus.
Mainly be to be embodied in ricinus agglutinin 120 to infect host cell, stop the application of influenza A virus breeding and diffusion aspect at the inhibition influenza A virus.
Obviously, ricinus agglutinin 120 also will can be used in the medicine of preparation anti-influenza A.
The invention has the advantages that:
Ricinus agglutinin 120 can be in conjunction with the HA on influenza A virus surface and the sugar chain structure on the NA, acting on influenza virus HA can playing a role at the virus infection host cell in early days, by influencing sialic acid sugar chain receptors bind on HA and the host cell membrane, make virus can not be adsorbed in host cell surface, thereby make virus can not infect host cell; Act on influenza virus NA and can suppress the nerve amines phytase activity, stop sophisticated progeny virus to leave host cell, stop the release and the diffusion of the ripe virus of filial generation.
The specific embodiment
The investigative technique of glycoprotein mainly contains: glycoprotein technology and biological mass spectrometry technology etc. in agglutinin chip technology, the gel.The agglutinin chip is that the agglutinin with various separate sources is fixed on aldehyde radicalization, epoxidation or the glass chip after alternate manner is modified, again with labelling after the reaction of detected samples such as glycoprotein, thalline, cell, after subsequent treatment, to detect the sugared structure of detected sample.Easy, quick, the high-throughout check and analysis of agglutinin chip energy are proteinic glycosylation modified, provide the sugared structure finger printing of detected sample at short notice.
(Ricinus Communis Agglutinin RCA) is a kind of in numerous phytohemagglutinin to ricinus agglutinin, is the macromolecule protein of a kind of biologically active of separating from the Semen Ricini seed.Preparation method is after castor bean is shelled, and extracts with the phosphoric acid saline solution, utilizes the chromatographic analysis of Sepharose-4B affinity cylinder, and the castor-oil plants agglutinin that goes out with 0.2mol/L galactose (Gal) eluant solution is called for short RCA.Separate obtaining two kinds of albumen again through Sephadex G-100, be designated as RCA120 or RCA-I and RCA60 or RCA-II respectively.Natural RCA120 molecular weight is 120KD, has hypotoxicity; And the RCA60 molecular weight is 60KD, has strong toxicity.
The experimental technique scheme that the present invention realizes comprises the steps:
One, the agglutinin chip is to the screening of sugar chain in the influenza A virus
1) preparation agglutinin chip
1.1) to get epoxidation sheet base standby;
1.2) agglutinin is mixed with the sampling liquid that concentration is 1mg/ml;
1.3) sampling liquid of preparation is added in 384 orifice plates; The brilliant core 48 point sample systems of reuse point sample on epoxidation sheet base;
1.4) chip that point is made hatched 2.5-3.5 hour in humidity is the environment of 55%-65%;
1.5) to the chip of hatching evacuation 3 hours in 37 ℃ environment, make the chip drying, and agglutinin is fixed on the chip;
1.6) the agglutinin chip that fixes is placed in the exsiccator with standby.
2) preparation biological specimen
2.1) prepare required sample;
2.2) use the organic reagent ether to the sample virolysis;
2.3) virus after the cracking is concentrated, form and concentrate sample;
2.4) carry out labelling with fluorometric reagent to concentrating sample, remove unnecessary fluorescence with the G-25 post;
2.5) sample packing that labelling is good is frozen in the environment below-20 ℃.
3) biological specimen is loaded on the agglutinin chip to obtain the result of subtypes of influenza A virus and virulence thereof
3.1) the 1-2% bovine serum albumin is dissolved into is mixed with confining liquid in phosphate buffer-polysorbas20,
The agglutinin chip for preparing was placed confining liquid 1 hour;
3.2) agglutinin chip after will sealing cleans each respectively 2 times with phosphate buffer-polysorbas20 and phosphate buffer, and is each 3 minutes, standby after drying again;
3.3) the agglutinin chip after drying is added good sample of 3-5 μ g labelling and the incubation buffer of 750-800 μ L, and incubated at room 3 hours;
3.4) agglutinin chip after will hatching cleans each respectively 2 times with phosphate buffer-polysorbas20 and phosphate buffer, each 3 minutes, dry again;
3.5) to the agglutinin chip after drying with the scanning of GenePix4000B chip scanner, obtain the bonded fluoroscopic image of glycoprotein hemagglutinin behind agglutinin and the labelling;
3.6) by GenePix3.0 software fluoroscopic image is carried out the intermediate value analysis, after being crosschecked, the pairing sugar chain structure of the agglutinin in the image draws subtypes of influenza A virus and virulence result thereof.
Above-mentioned sample is highly pathogenic sample or low pathogenicity sample.
Wherein, highly pathogenic sample comprises H5N1 (DK/GD/17/08), H5N1 (CK/GX/4/09), H5N2 (Mallard/JX/16/05), H7N1 (KP);
The low pathogenicity sample comprises H5N2 (Ostrich/Denmark/96-72420/96), N7N2 (HB7), H9N2 (CK/FJ/S-1-521/08), H9N2 (DK/GD/S-7-134/04).
The above-mentioned chip that point is made is hatched 3 hours for best in humidity is 60% environment.
Above-mentioned agglutinin chip after drying is added good sample of 4 μ g labellings and the incubation buffer of 780 μ L, and 3 hours be the best in incubated at room.
Two, ricinus agglutinin 120 (RCA120) suppresses the influenza A virus experiment
(1) medicine: ricinus agglutinin 120 (RCA120)
(2) influenza A virus strain: H1N1, H5N1, H7N2 and H9N2
(3) influenza virus is cultivated and titer determination: respectively the influenza virus strain is inoculated in 9～11 age in days chick embryo allantoic cavities, hatch 48～72h for 35 ℃, then Embryo Gallus domesticus is put 4 ℃ of refrigerator overnight, gather in the crops allantoic fluid next day, the centrifugal 10min of 3000rpm discards precipitation, gets supernatant and carries out the blood clotting experiment, determine that its titre is greater than gathering in the crops supernatant ,-80 ℃ of preservations at 1: 64.
(4) dog kidney (MDCK) cell culture: DMEM culture fluid 190mL adds hyclone 20mL, the two anti-2mL of blue or green chain, 7.5%NaHCO
3Regulating pH is 7.4, and above-mentioned each component mixing is the MDCK complete culture solution, gets Pn+15 for the cell bottle, it is an amount of to add Digestive system, is advisable with the lucky cell that covered, and puts down about 10min in 37 ℃ of incubators gently, treat that the cell circle contracts, when not linking mutually each other, inhale gently and abandon Digestive system, add culture fluid, light repeatedly the suction blown and beaten, take off wall to cell, become even, counting cells 1.0 * 10
6/ mL is inoculated in the new 25mL culture bottle, puts 37 ℃, 5%CO
2Environment leaves standstill cultivation.
HEKC (AD293) is cultivated: DMEM culture fluid 190mL adds hyclone 20mL, the two anti-2mL of blue or green chain, 7.5%NaHCO
3Regulating pH is 7.2, and above-mentioned each component mixing is the AD293 complete culture solution, gets Pn+15 for the cell bottle, it is an amount of to add Digestive system, is advisable with the lucky cell that covered, and puts down about 10min in 37 ℃ of incubators gently, treat that cell is flat irregular polygon, in circular kernel is arranged, when closely being connected to monofilm, inhale gently and abandon Digestive system, add culture fluid, gently repeatedly inhale piping and druming, take off wall to cell, become even, counting cells 1.0 * 10
6/ mL is inoculated in the new 25mL culture bottle, puts 37 ℃, 5%CO
2Environment leaves standstill cultivation.
Human embryonic lung cell (WI-38) cultivates: DMEM culture fluid 190mL adds hyclone 20mL, the two anti-2mL of blue or green chain, 7.5%NaHCO
3Regulating pH is 7.2, and above-mentioned each component mixing is the WI-38 complete culture solution, gets Pn+15 for the cell bottle, it is an amount of to add Digestive system, is advisable with the lucky cell that covered, and puts down about 10min in 37 ℃ of incubators gently, treat that cell is irregular fusiformis, there is oval nuclear in central authorities, are radial during growth or during the swirl shape traveling, inhale gently and abandon Digestive system, add culture fluid, gently repeatedly inhale piping and druming, take off wall to cell, become even, counting cells 1.0 * 10
6/ mL is inoculated in the new 25mL culture bottle, puts 37 ℃, 5%CO
2Environment leaves standstill cultivation.
(5) to the extracorporeal antivirus effect effect of pathological changes caused by virus: this experiment is carried out on 96 hole micro plates, and every hole adds cell 0.1mL, and cell number is 5 * 10
5Individual, grow up to monolayer after, the minimum dilution factor that pathological changes do not occur with cell is the nontoxic boundary of this medicinal liquid pair cell.Observe the influence of each concentration cell growth by toxicity test, measure each strain of influenza A virus simultaneously and make MDCK, AD293 and WI-38 cell 50% that the minimum of death or pathological changes take place.Establish virus control, cell contrast, drug toxicity contrast during experiment, put 37 ℃ of CO
2In the incubator, under inverted microscope, observe pathological changes and record every day, when (D) pathological changes appears in virus control, continue to observe stopping in 4 days.The degree that pathological changes appears in cell is by following 6 grade standard records: (-) is the cell growth, no pathological changes appearance; (±): cytopathy is less than 10% of whole cell monolayer; (+) accounts for 25% of whole cell monolayer for cytopathy; (H) account for 50% of whole cell monolayer for cytopathy; (D) account for 75% of whole cell monolayer for cytopathy; (E) account for more than 75% of whole cell monolayer for cytopathy.
(6) the extracorporeal antivirus effect exercising result to pathological changes caused by virus infects MDCK, AD293 and WI-38 cell and certain density ricinus agglutinin 120 (RCA120) respectively 37 ℃ of cultivations with influenza A virus, detect the inhibition of RCA120 pair cell pathological changes (CPE), display density is that the RCA120 of 1～40 μ g/mL all can obviously kill influenza virus as a result.
Claims (3)
1. ricinus agglutinin 120, the application aspect anti-influenza A virus.
2. ricinus agglutinin 120 according to claim 1, the application aspect breeding of inhibition influenza A virus and diffusion.
3. ricinus agglutinin 120, in the application of the medicine for preparing anti-influenza A.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20150233922A1 (en) * | 2012-10-05 | 2015-08-20 | Denka Seiken Co., Ltd. | Method for measuring hemagglutinin from influenza virus |
| CN112262153A (en) * | 2018-06-06 | 2021-01-22 | 国立研究开发法人产业技术综合研究所 | Method for inducing antibody against hepatitis virus with high efficiency, antibody and detection system |
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| CN101308141A (en) * | 2007-05-16 | 2008-11-19 | 陕西北美基因股份有限公司 | Method for analyzing glucoprotein |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101308141A (en) * | 2007-05-16 | 2008-11-19 | 陕西北美基因股份有限公司 | Method for analyzing glucoprotein |
Non-Patent Citations (2)
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| 《Journal of Medicinal Chemistry》 20090626 Teruhiko Matsubara等 Inhibiton of Influenza Virus Infections by Siaylgalactose-Binding Peptides Selected from a Phage Library 第4247-4256页 1-3 第52卷, 第14期 2 * |
| 《上海中医药大学学报》 20010930 胡兴昌等 板蓝根凝集素效价与抑制感冒病毒作用关系的实验研究 第56-57页 1-3 第15卷, 第3期 2 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150233922A1 (en) * | 2012-10-05 | 2015-08-20 | Denka Seiken Co., Ltd. | Method for measuring hemagglutinin from influenza virus |
| US10365277B2 (en) * | 2012-10-05 | 2019-07-30 | Denka Seiken Co., Ltd. | Method for measuring hemagglutinin from influenza virus |
| CN112262153A (en) * | 2018-06-06 | 2021-01-22 | 国立研究开发法人产业技术综合研究所 | Method for inducing antibody against hepatitis virus with high efficiency, antibody and detection system |
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Application publication date: 20101215 |