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WO2020259109A1 - Protéine de fusion de la transferrine et de l'epo produite par des plantes et application de celle-ci - Google Patents

Protéine de fusion de la transferrine et de l'epo produite par des plantes et application de celle-ci Download PDF

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Publication number
WO2020259109A1
WO2020259109A1 PCT/CN2020/089980 CN2020089980W WO2020259109A1 WO 2020259109 A1 WO2020259109 A1 WO 2020259109A1 CN 2020089980 W CN2020089980 W CN 2020089980W WO 2020259109 A1 WO2020259109 A1 WO 2020259109A1
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Prior art keywords
plant
fusion protein
nucleotide sequence
epo
transferrin
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PCT/CN2020/089980
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Chinese (zh)
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王跃驹
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/505—Erythropoietin [EPO]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/79—Transferrins, e.g. lactoferrins, ovotransferrins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
    • C12N15/8241—Phenotypically and genetically modified plants via recombinant DNA technology
    • C12N15/8242—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits
    • C12N15/8257—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits for the production of primary gene products, e.g. pharmaceutical products, interferon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the present invention relates to the field of biotechnology, in particular to the application of plants to produce oral EPO and transferrin fusion protein capsules.
  • Erythropoietin also known as red blood cell stimulating factor, is a glycoprotein with a molecular weight between 25,000 and 45,000. It is an important factor in stimulating red blood cell production. Under the stimulation of animal hypoxia, the erythrogenin produced by the kidney acts on the pro-erythropoietin produced by the liver in the plasma to convert it into erythropoietin.
  • Erythropoietin acts on the primordial blood cells in the bone marrow to transform them into Proerythroblasts; promotes the mitosis of nucleated red blood cells and the synthesis of hemoglobin; promotes the release of reticulocytes and mature red blood cells in the bone marrow.
  • a large number of mature red blood cells carry more oxygen to the tissues.
  • sufficient oxygen can inhibit the production of erythropoietin in the liver and the production of erythropoietin in the kidneys, thus regulating the production of red blood cells.
  • EPO is a sialoglycoprotein hormone. It was first discovered in 1906. It is an endogenous compound with a molecular weight of 34,000 and consists of 165 amino acids. It mainly comes from the kidney (a small amount comes from the liver) and is synthesized by the interstitial cells surrounding the cortical tube.
  • the rhEPO synthesized by gene recombination technology has a molecular weight of 30,400, and its physical and chemical properties and biological activities are the same as those of natural endogenous erythropoietin. The difference is that the gene locus on chromosome 7 is a glycoprotein.
  • EPO erythrocyte-shaped colony-forming unit
  • BFuE early-stage erythrocyte burst-forming unit
  • RBC red blood cells
  • EPO Although natural EPO has many advantages in the treatment of anemic diseases, related products that have been marketed include erythropoietin and so on. Due to the nature of peptide drugs and the various barriers created by the human body, injection has always been the main route of their conventional administration. EPO also achieves oral administration through a special preparation method, and the present invention fusion expresses EPO and transferrin, and also achieves oral administration, reducing the pain caused by long-term frequent injections of patients.
  • the present invention provides an application for plant production of oral EPO and transferrin fusion protein capsules.
  • the present invention reforms and modifies the structure of erythropoietin (EOP) with anemia treatment effect, so that it can be absorbed through the intestinal tract and reach an effective therapeutic concentration in the body, and the active substance is produced by plants.
  • EOP erythropoietin
  • the invention uses plants, especially lettuce, as an efficient platform technology for recombinant protein production, and expresses the fusion protein of EPO and transferrin. And made into oral anemia treatment capsules.
  • the present invention provides a fusion protein of EPO and transferrin, which has:
  • the present invention also provides nucleotides encoding the fusion protein, having
  • (III) A nucleotide sequence that encodes the same protein as the nucleotide sequence of (I) or (II), but is different from the nucleotide sequence of (I) or (II) due to the degeneracy of the genetic code; or
  • nucleotide sequence obtained by substituting, deleting or adding one or more nucleotide sequences to the nucleotide sequence shown in (I), (II) or (III), and with (I), (II) or (III) nucleotide sequences with the same or similar functions; or
  • (V) a nucleotide sequence that has at least 80% homology with the nucleotide sequence described in (I), (II), (III) or (IV).
  • the present invention also provides an expression vector, including the nucleotide and the vector to be transformed.
  • the vector to be transformed is a chloroplast expression vector.
  • the present invention also provides the construction method of the expression vector, which is characterized in that it comprises the following steps:
  • Step 1 The codons of the fusion protein of EPO and transferrin are optimized to plant-preferred codons, and the nucleotide sequence is shown in SEQ ID No. 2;
  • Step 2 Cloning the nucleotide sequence into the pUC57 vector to obtain pEPO.
  • the present invention also provides the application of the expression vector or plant in expressing the fusion protein of EPO and transferrin or preparing a medicine containing the fusion protein;
  • the plant is selected from lettuce, spinach, tomato, radish, cabbage, Corn, soybean, wheat or tobacco;
  • the organs of the plant are selected from seeds, leaves, rhizomes or whole plants.
  • the drug is an oral preparation for treating anemia.
  • the present invention also provides a host, a plant or microorganism transformed with the expression vector; the plant is selected from lettuce, spinach, tomato, radish, cabbage, corn, soybean, wheat or tobacco; the organ of the plant is selected from seeds, Leaves, rhizomes or whole plants.
  • the invention also provides medicines, including the fusion protein and pharmaceutically acceptable excipients.
  • the drug is an oral preparation for treating anemia.
  • the present invention also provides a method for expressing the fusion protein of EPO and transferrin by a plant as a host.
  • the expression vector is bombarded with a gene gun on the leaves, and the regenerated plants are obtained after expression in the chloroplasts of the plants, and the leaves are freeze-dried and crushed , Extract to obtain the fusion protein of EPO and transferrin.
  • the gene gun bombardment includes the following steps:
  • Step 1 Prepare vector for transformation
  • Step 2 Prepare particle bullets
  • Step 3 Gene gun bombardment
  • Step 4 After conversion, cultivate and regenerate into plants.
  • the present invention also provides a method for preparing a medicine for treating anemia by using a plant as a host.
  • the expression vector is bombarded with a gene gun to the leaves and expressed in plant chloroplasts to obtain regenerated plants.
  • the plant leaves are freeze-dried, crushed, and extracted to obtain EPO and transferrin fusion protein, filling.
  • the gene gun bombardment includes the following steps:
  • Step 1 Prepare vector for transformation
  • Step 2 Prepare particle bullets
  • Step 3 Gene gun bombardment
  • Step 4 After conversion, cultivate and regenerate into plants.
  • Plant chloroplast expression technology is the use of gene gun bombardment and homologous recombination to transfer a plasmid containing the target protein to plant chloroplasts to obtain high-efficiency expression of the gene in plant chloroplasts. Compared with animal cell expression systems, the cost of plant expression systems is very low, only one thousandth to two thousandths.
  • the invention uses plant leaves to produce oral anemia treatment capsules.
  • the anemia treatment product does not require injection, which reduces the suffering of patients. Lettuce does not contain plant toxic substances, and this product does not require a protein purification process, which can greatly shorten the production cycle and production costs.
  • the present invention found through experiments that the plant system, especially the lettuce system, is a more economical and efficient expression platform, and the chloroplast can efficiently express active proteins. Because lettuce is easy to grow and can be produced in large quantities commercially, it is easier to obtain and cheaper than other plants, such as tobacco, and because it does not require complex special production equipment, the cost can be significantly reduced. In summary, the present invention can utilize the lettuce system to produce the fusion protein of EPO and transferrin on a large scale.
  • Figure 1 shows a schematic diagram of the vector pEPO
  • FIG. 1 shows the western-blot results.
  • the invention discloses an application of a plant for producing oral EPO and transferrin fusion protein capsules.
  • Those skilled in the art can learn from the content of this article and appropriately improve the process parameters.
  • all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
  • the method and application of the present invention have been described through the preferred embodiments. It is obvious that relevant personnel can modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.
  • the present invention provides the application of plants as hosts to express the fusion protein of EPO and transferrin.
  • the plant is selected from lettuce, spinach, tomato, radish, cabbage, corn, soybean, wheat or tobacco; and the organ of the plant is selected from seeds, leaves, rhizomes or whole plants.
  • the present invention also provides an expression vector, including the fusion protein sequence of EPO and transferrin and the vector.
  • the codons of the fusion protein of EPO and transferrin are optimized to plant-preferred codons.
  • the optimized EPO and transferrin fusion protein sequence is shown in SEQ ID No. 1; the optimized EPO and transferrin fusion protein sequence is shown in SEQ ID No.2.
  • the vector is a plant chloroplast vector.
  • the method for constructing the expression vector includes the following steps:
  • Step 1 Optimize the codons of the fusion protein of EPO and transferrin to plant-preferred codons
  • Step 2 Gene synthesis and cloning into pUC57 vector by GenScript to obtain pEPO vector
  • the present invention uses the amino acid sequence of the fusion protein of EPO and transferrin using reverse translation software (https://www.ebi.ac.uk/Tools/st/emboss_backtranseq /) Obtain the nucleotide sequence and optimize its codons to plant-preferred codons, synthesized by GenScript (Nanjing, China). And cloned into the pUC57 vector from GenScript to obtain the pEPO vector ( Figure 1).
  • the invention also provides the application of the expression vector in expressing the fusion protein of EPO and transferrin.
  • the expression vector provided by the present invention is bombarded with a gene gun to plant leaves, regenerated into plants, and the plant leaves are harvested and made into oral anemia treatment capsules.
  • the invention uses plant leaves to produce oral anemia treatment capsules.
  • the anemia treatment product does not require injection, which reduces the suffering of patients. Lettuce does not contain plant toxic substances, and this product does not require a protein purification process, which can greatly shorten the production cycle and production costs.
  • the present invention found through experiments that the plant system, especially the lettuce system, is a more economical and efficient expression platform, and the chloroplast can efficiently express active proteins. Because lettuce is easy to grow and can be produced in large quantities commercially, it is easier to obtain and cheaper than other plants, such as tobacco, and because it does not require complex special production equipment, the cost can be significantly reduced. In summary, the present invention can utilize the lettuce system to produce the fusion protein of EPO and transferrin on a large scale.
  • the raw materials and reagents used in the application of the plant for producing oral EPO and transferrin fusion protein capsules can be purchased from the market.
  • the amino acid sequence of the fusion protein of EPO and transferrin was used to obtain the nucleoside by reverse translation software (https://www.ebi.ac.uk/Tools/st/emboss_backtranseq/) Acid sequence, and optimized its codons to plant-preferred codons, synthesized by GenScript (Nanjing, China).
  • the gold powder suspension in the glycerol state was vortexed for 5 minutes to resuspend the gold powder. Take 50 ⁇ L of gold powder suspension in a sterile 1.5 mL centrifuge tube and vortex for 1 minute. Add 10 ⁇ g plasmid DNA and vortex for 30 seconds. Add 50 ⁇ L of 2.5M CaCl 2 and vortex for 30 seconds. 20 ⁇ L of 0.1M spermidine was added, the mixture was vortexed for 5 minutes, and allowed to stand on ice for 2 minutes. Add 60 ⁇ L of pre-cooled absolute ethanol, flick your fingers to resuspend it, centrifuge at 14,000 rpm for 10 seconds, remove the supernatant, and repeat. Add 50 ⁇ L of absolute ethanol to resuspend and set aside.
  • carrier membranes and splittable membranes, and barrier nets are used according to the number of samples (note: carrier membranes and splittable membranes need to be replaced every gun, and the barrier net can be shared with the same sample) soak in absolute ethanol for 15 minutes, and use sterile Rinse twice with water, let it dry naturally, and set aside. Put the dried carrier film into a sterile iron ring and flatten it. The prepared bullets were vortexed to mix well, and 10 ⁇ L bullets were placed in the center of the carrier film and dried naturally. Move the particle launcher out of the bombardment chamber, unscrew the cover, add the blocking net, install the particle slide in the fixed groove (the side with the particles is facing down), screw on the cover, and put the particle launcher back into the bombardment chamber.
  • Screening culture transfer the materials after dark culture to the screening medium (antibiotic concentration of 50 ⁇ g/mL) for screening culture.
  • Rooting culture transfer buds to rooting medium (antibiotic concentration of 100 ⁇ g/mL) to induce rooting.
  • mice were randomly divided into two treatment groups, each with 10 mice, and received treatment proteins containing anemia (the fusion protein of EPO and transferrin prepared in Example 5 of the present invention) and treatment proteins not containing anemia
  • treatment proteins containing anemia the fusion protein of EPO and transferrin prepared in Example 5 of the present invention
  • treatment proteins not containing anemia One of the two experimental capsules, do the first repetition.
  • the mice were administered for 7 consecutive days, once a day. After the test, blood was collected to determine peripheral red blood cells (RBC), hemoglobin (Hb), and reticulocytes (RET).
  • RhEPO recombinant EPO, Cirolbo, 5000IU/ml, Sihuan Biopharmaceutical Co., Ltd. was used as a positive control.
  • the 7-week-old experimental mice were randomly divided into three treatment groups, each with 10 mice, and received glycoproteins (fed 500ng/g according to body weight) (the fusion protein of EPO and transferrin obtained in the present invention) , And one of the two experimental capsules that do not contain hypoglycemic protein, and receive the same experimental diet. Feeding was continued for 10 days, and observations were made after each feeding. Continuous observation was required for more than 6 hours a day. It did not see whether the mice were excited or inhibited, did not appear to be slow or diarrhea. It proves that the fusion protein of EPO and transferrin has high oral safety.

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Abstract

La présente invention concerne une protéine de fusion de transferrine et d'EPO orale produite par une plante, à l'aide d'une plante telle que la laitue en tant que plateforme d'expression pour la production de protéine recombinante. L'invention concerne en outre une application de la protéine de fusion à la fabrication de capsules orales. Les résultats de test d'activité biologique montrent qu'une capsule de traitement de l'anémie produite par la technique de plateforme augmente significativement le nombre de globules rouges chez les souris.
PCT/CN2020/089980 2019-06-24 2020-05-13 Protéine de fusion de la transferrine et de l'epo produite par des plantes et application de celle-ci Ceased WO2020259109A1 (fr)

Applications Claiming Priority (2)

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CN201910550550.3A CN110229237A (zh) 2019-06-24 2019-06-24 植物生产口服epo与转铁蛋白融合蛋白胶囊的应用
CN201910550550.3 2019-06-24

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WO2020259109A1 true WO2020259109A1 (fr) 2020-12-30

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110229237A (zh) * 2019-06-24 2019-09-13 王跃驹 植物生产口服epo与转铁蛋白融合蛋白胶囊的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005021579A2 (fr) * 2003-08-28 2005-03-10 Biorexis Pharmaceutical Corporation Peptides mimetiques epo et proteines de fusion
CN102936288A (zh) * 2012-06-07 2013-02-20 张海涛 促红细胞生成素模拟肽融合蛋白及突变体
CN107188970A (zh) * 2010-06-04 2017-09-22 株式会社蒂奥姆生物 具有因子vii活性的融合蛋白质
CN110229237A (zh) * 2019-06-24 2019-09-13 王跃驹 植物生产口服epo与转铁蛋白融合蛋白胶囊的应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005021579A2 (fr) * 2003-08-28 2005-03-10 Biorexis Pharmaceutical Corporation Peptides mimetiques epo et proteines de fusion
CN107188970A (zh) * 2010-06-04 2017-09-22 株式会社蒂奥姆生物 具有因子vii活性的融合蛋白质
CN102936288A (zh) * 2012-06-07 2013-02-20 张海涛 促红细胞生成素模拟肽融合蛋白及突变体
CN110229237A (zh) * 2019-06-24 2019-09-13 王跃驹 植物生产口服epo与转铁蛋白融合蛋白胶囊的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEN, KAI: "The Transgenic Plants Express Foreign Medical Protein", JOURNAL OF HANDAN AGRICULTURAL COLLEGE, UNITED STATES, vol. 21, no. 1, 7 January 2005 (2005-01-07), United States, XP055771533 *
DATABASE Protein 27 December 2020 (2020-12-27), ANONYMOUS: "erythropoietin precursor [Homo sapiens]", XP055771535, retrieved from NCBI *

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