CN106554395A - A kind of long acting erythropoietin simulating peptide and its preparation method and application - Google Patents
A kind of long acting erythropoietin simulating peptide and its preparation method and application Download PDFInfo
- Publication number
- CN106554395A CN106554395A CN201510638945.0A CN201510638945A CN106554395A CN 106554395 A CN106554395 A CN 106554395A CN 201510638945 A CN201510638945 A CN 201510638945A CN 106554395 A CN106554395 A CN 106554395A
- Authority
- CN
- China
- Prior art keywords
- erythropoietin
- acid
- sodium
- mimetic peptide
- anemia
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 102000003951 Erythropoietin Human genes 0.000 title claims abstract description 111
- 108090000394 Erythropoietin Proteins 0.000 title claims abstract description 111
- 229940105423 erythropoietin Drugs 0.000 title claims abstract description 104
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 title claims abstract description 103
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 32
- 210000003743 erythrocyte Anatomy 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 230000007547 defect Effects 0.000 claims abstract description 10
- 235000018417 cysteine Nutrition 0.000 claims abstract description 3
- 208000007502 anemia Diseases 0.000 claims description 19
- 230000003278 mimic effect Effects 0.000 claims description 19
- 230000007812 deficiency Effects 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 150000001413 amino acids Chemical group 0.000 claims description 9
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 229940024606 amino acid Drugs 0.000 claims description 7
- 235000001014 amino acid Nutrition 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 7
- 239000008280 blood Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000004475 Arginine Substances 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 208000020832 chronic kidney disease Diseases 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 230000003204 osmotic effect Effects 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- 239000007790 solid phase Substances 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 208000030507 AIDS Diseases 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 5
- 150000007514 bases Chemical class 0.000 claims description 5
- -1 pyrosulfate Chemical compound 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 206010036590 Premature baby Diseases 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
- 230000002159 abnormal effect Effects 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
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- 230000032683 aging Effects 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 239000000908 ammonium hydroxide Substances 0.000 claims description 4
- 208000037976 chronic inflammation Diseases 0.000 claims description 4
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims description 4
- 238000000502 dialysis Methods 0.000 claims description 4
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- 208000028208 end stage renal disease Diseases 0.000 claims description 4
- 201000000523 end stage renal failure Diseases 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000036210 malignancy Effects 0.000 claims description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 230000001613 neoplastic effect Effects 0.000 claims description 4
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical group C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 claims description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- 208000020431 spinal cord injury Diseases 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 239000008215 water for injection Substances 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 3
- 238000011033 desalting Methods 0.000 claims description 3
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 235000011007 phosphoric acid Nutrition 0.000 claims description 3
- 238000011894 semi-preparative HPLC Methods 0.000 claims description 3
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 3
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 claims description 2
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical compound OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 claims description 2
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical class [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 2
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- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 claims description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a kind of Erythropoietin mimetic peptide derivant with long-acting promoting erythrocyte systematic function and its officinal salt.Present invention also offers the preparation method of above-mentioned Erythropoietin mimetic peptide derivant and its for prepare treatment with lack erythropoietin or the medicine of red blood cell mass lacks or defect is characterized disease in purposes.Wherein, the Erythropoietin mimetic peptide derivant that the present invention is provided is by SEQ ID NO:Polypeptide shown in 1GGLYACHMGPITNalVCQPLRSarKVPGPGVPGPGVPGPGVPGPG, wherein, two cysteine of the polypeptide form disulfide bond, N-terminal acetylation.
Description
Technical Field
The invention belongs to the field of biomedicine, and relates to an erythropoietin mimic peptide. In particular, the invention relates to an erythropoietin mimic peptide which can be combined with an erythropoietin receptor and activate the erythropoietin receptor or can play an erythropoietin stimulating role, a preparation method thereof, and application of the mimic peptide in preparing a medicament for treating diseases characterized by lack of erythropoietin or lack or defect of erythrocyte groups.
Background
Erythropoietin (EPO) is a glycoprotein hormone with a molecular weight of about 34 kD. Erythropoietin present in plasma consists of 165 amino acids, is glycosylated to a high degree, and the sugar component is predominantly sialic acid. Naturally occurring erythropoietin is classified into two types, alpha and beta, depending on the carbohydrate content, wherein the alpha form contains 34% carbohydrate and the beta form contains 26% carbohydrate. The two types are identical in biological characteristics, antigenicity and clinical application effect. The human erythropoietin gene is located in chromosome 7, region 22. In 1985, cDNA was successfully cloned, and large-scale production of recombinant human erythropoietin (rHuEPO) was started by gene recombination technology, and widely used in clinic. Erythropoietin (Egrie, JC, Strickland, TW, Lane, J, etc. (986), immunobiology (Immunobiol)72:213-224), which is the product of a cloned human erythropoietin gene inserted and expressed in ovarian tissue cells (CHO cells) of the Chinese hamster, has been biosynthesized using recombinant DNA techniques. Naturally occurring human erythropoietin is first translated into a polypeptide chain containing 166 amino acids with arginine at position 166. In post-translational modifications, arginine 166 is cleaved by a hydroxypeptidase. The molecular weight of the polypeptide chain of human EPO without the sugar group is 18236Da, and in the complete erythropoietin molecule, the sugar group accounts for about 40% of the total molecular weight (J.biol.chem.262: 12059).
Erythropoietin plays an important role in regulating and controlling the oxygen supply condition of the organism as an endocrine hormone which acts on bone marrow hematopoietic cells and promotes the proliferation and differentiation of erythroid progenitor cells and the final maturation. Erythropoietin is produced by the liver in the early embryonic stage and then gradually migrates to the kidney and is secreted mainly by tubular interstitial cells after birth.
During the process of erythropoietin-induced erythroid differentiation, globins are induced, which enable the cells to take up more iron to synthesize functional hemoglobin, which can bind with the oxygen in mature red blood cells, and thus, red blood cells and hemoglobin play an extremely important role in providing body oxygen. This process is caused by the interaction between erythropoietin and surface receptors of the erythroid cells.
When a person is in a healthy state, the tissue can absorb enough oxygen from the existing red blood cells, and the body's erythropoietin concentration is low, and this normal low erythropoietin concentration can fully stimulate red blood cells that are normally lost due to age problems. When the level of oxygen transport by red blood cells in the circulatory system is reduced and hypoxia occurs, the amount of erythropoietin in the body will increase and the hypoxic state of the body can be caused by: excessive radiation, decreased oxygen intake due to high altitude or long-term coma, various types of anemia, and the like. In response to the tissue being subjected to hypoxic pressure, an increase in erythropoietin levels stimulates the differentiation of the red blood cells to the point of increasing erythropoiesis. When the number of red blood cells in the body is greater than that required by normal tissue, the levels of erythropoietin in the circulatory system are reduced. Because erythropoietin plays a crucial role in erythropoiesis, this class of hormones holds great promise for the treatment and diagnosis of hematological disorders characterized by poor and defective erythropoiesis. Recent studies have provided the basis for the speculation of the utility of erythropoietin therapy in a variety of diseases, disorders and hematological abnormalities, including: the use of Erythropoietin in the treatment of anemia in patients with Chronic Renal Failure (CRF) and Erythropoietin in the treatment of anemia in AIDS and cancer patients undergoing chemotherapy (Danna, RP, Rudnick, SA, Abels, RI, in: MB, Garnic eds., Erythropoietin in clinical applications-International patent application. Marcel Dekker; 1990: p 301-324).
Some of the biological effects of erythropoietin can be modulated by intrinsic interactions with receptors on the cell membrane surface. Initially, when immature red blood cells isolated from the spleen of a mouse were used to study cell surface bound erythropoietin protein, it was found that this protein is composed of two polypeptides with molecular weights of approximately 85000-100000 KD (Sawyer, et al (1987) Proc. Natl. Acad. Sci. USA 84: 3690-. The number of binding sites for erythropoietin was also calculated, approximately 800-1000 sites per cell membrane. Of these binding sites, approximately 300 have Kd levels of 90pM, while the remaining binding sites have weaker binding, approximately 570 pM. Studies have shown that about 400 binding sites are found in response to EPO from spleen erythrocytes of mice infected with an anemia strain of friend virus, with a high Kd level of 100pM and a low Kd level of 800 pM.
The subsequent work is to transcribe the two erythropoietin receptors from a single gene, which has been cloned. For example, the DNA sequences of the mouse and human erythropoietin receptors and the sequences encoding the peptides have been described in WO 90/08822. Current models indicate that binding of erythropoietin to the erythropoietin receptor results in activation and dimerization of the two erythropoietin receptors, which further results in the initiation of signaling.
Erythropoietin is the first cytokine to be used clinically and is the hemoglobin-increasing preparation which has the single action and is safe and reliable to date. Has certain curative effect on renal anemia, aplastic anemia, multiple myeloma, paroxysmal nocturnal hematuria and the like; in addition, the application of erythropoietin can reduce the blood transfusion amount in operation and can correct anemia caused by malignant tumor, chemotherapy and rheumatoid arthritis to a certain extent. Since erythropoietin is mainly produced by tubular endothelial cells, anemia caused by renal disorders is the first indication for erythropoietin; erythropoietin has almost 100% efficacy in correcting renal anemia, but does not improve renal function. The treatment of the erythropoietin is safe and effective, is suitable for long-term treatment and can also avoid the blood source tension. In the world biotech drug market in 2006, erythropoietin-like recombinant drugs account for $ 119 billion, and have huge market capacity.
As early as 1989, the U.S. FDA approved recombinant human erythropoietin (EPOGEN) for the treatment of renal anemia, but it was not marketed in China until 1992. The annual incidence rate of chronic nephritis in China is about 0.25%, a considerable number of patients can be finally converted into renal failure, and about 50-60 ten thousand of patients with annual renal anemia are treated. According to the conservative drug consumption estimation, if the drug is taken by other patients with 30-40 yuan per patient according to the current price and cancer-related anemia and the like, the domestic market volume is about 12-16 million yuan or more (the average weight of the patients is calculated by 50 Kg). Since the later 90 s in the 20 th century, erythropoietin has entered the popular drug line in hospitals in key cities in China, and in 2003, the sample hospitals in key cities in China had a medication amount of 6213 ten thousand yuan, and the rank was 56. In 2004, the medicine purchase amount of sample hospitals in key cities in China is increased to 8049 ten thousand yuan, which is increased by 30% on year-on-year basis.
The use of the erythropoietin cloning gene further aids in the search for agonists and antagonists of these important receptors. Peptides that are capable of acting to some extent on the erythropoietin receptor have been identified and described. In particular, a group of peptides containing a major peptide segment has been identified which bind to the erythropoietin receptor and stimulate differentiation and proliferation of erythropoietin cells. However, the peptides capable of stimulating proliferation and differentiation of erythrocytes have a very low EC50, between 20nM and 250nM, and thus have a major limitation in clinical application.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides an erythropoietin mimic peptide or a medicinal salt thereof with better biological activity and higher bioavailability and a preparation method thereof.
In one aspect, the present invention is directed to an erythropoietin mimetic peptide or a pharmaceutically acceptable salt thereof having a long acting erythropoiesis stimulating activity.
In a further aspect, the invention also provides a process for the preparation of an erythropoietin mimetic peptide of the invention or a pharmaceutically acceptable salt thereof and its use in the manufacture of a medicament for the treatment of a condition characterised by a deficiency in erythropoietin or a deficiency or defect in the red blood cell population.
In yet another aspect, the present invention provides a pharmaceutical composition comprising the erythropoietin mimetic peptide of the present invention or a pharmaceutically acceptable salt thereof.
Preferably, the pharmaceutical composition of the present invention is an injection; more preferably, the pharmaceutical composition of the present invention is a lyophilized powder injection or a solution injection.
In a preferred embodiment, the pharmaceutical composition of the invention further comprises a pharmaceutically acceptable adjuvant component.
The invention provides an erythropoietin mimic peptide with in vivo biological activity or a pharmaceutically acceptable salt thereof, wherein the amino acid of the mimic peptide is represented by a general formula shown in SEQ ID NO. 1:
GGLYACHMGPITNalVCQPLRSarKVPGPGVPGPGVPGPGVPGPG(SEQ IDNO:1)
wherein,
nal is 3- (1-naphthyl) -L-alanine, the structural formula of which is as follows:
sar is sarcosine, the structural formula of which is as follows:
the two cysteines (C) form an intramolecular disulfide bond, with the N-terminus acetylated.
The invention also provides a preparation method of the erythropoietin mimic peptide or the pharmaceutically acceptable salt thereof, and the method comprises the following steps:
selecting amino acids according to SEQ ID NO 1, and synthesizing the mimic peptide by using Fmoc solid phase polypeptide synthesis;
optionally, the mimetic peptide is formulated into a pharmaceutically acceptable salt.
Preferably, the mimetic is achieved by a method comprising the steps of:
the Fmoc solid-phase polypeptide synthesis method provided by the invention is a synthesis method for synthesizing polypeptide by using polymer resin as a solid-phase reaction substrate and sequentially condensing amino acid protected by amino terminal Fmoc in the presence of a coupling reagent.
Preferably, the preparation method further comprises purifying, desalting and freeze-drying the prepared mimic peptide or the medicinal salt thereof to obtain freeze-dried powder; preferably, the purification is carried out using a semi-preparative HPLC C18 column with acetonitrile as the mobile phase.
The erythropoietin mimetic peptide provided by the invention can be reacted with an acidic or basic compound to form a salt by a known technology, and the acid forming an acid addition salt is generally adopted as follows: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid.
Preferably, the pharmaceutically acceptable salt of the erythropoietin mimetic peptide derivative is selected from the group consisting of sulfate, pyrosulfate, trifluoroacetate, sulfite, bisulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, bromide, iodide, acetate, propionate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, fumarate, maleate, butyne-l, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, gamma-isovalerate, or gamma-isovalerate, Glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate, mandelate and the like, preferably trifluoroacetate.
Basic compounds, including ammonium, alkali or alkaline earth metal hydroxides, and carbonates, bicarbonates, typically sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, and the like, may also be salified with the erythropoietin mimetic peptides.
The invention also provides the application of the erythropoietin mimic peptide in preparing a medicament for treating diseases characterized by the deficiency of erythropoietin or the deficiency or defect of erythrocyte groups.
Preferably, the disease characterized by a deficiency of erythropoietin or a deficiency or defect in the red blood cell population is selected from end-stage renal failure or dialysis; AIDS-related anemia, autoimmune disease, or malignancy; cystic fibrosis; early stage prematurity anemia; anemia associated with chronic inflammatory disease; spinal cord injury; acute blood loss; aging and neoplastic diseases accompanied by abnormal red blood cell production.
The invention also provides a pharmaceutical composition comprising the erythropoietin mimetic peptide or the pharmaceutically acceptable salt thereof for treating diseases characterized by a deficiency of erythropoietin or a deficiency or defect in the red blood cell population.
The pharmaceutical composition comprises one or more pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials are selected from one or more of water-soluble fillers, pH regulators, stabilizers, water for injection and osmotic pressure regulators.
The water-soluble filler auxiliary material is selected from one or more of the following materials: mannitol, low molecular dextran, sorbitol, polyethylene glycol, glucose, lactose and galactose.
The pH adjusting agent is selected from one or more of the following: non-volatile acids such as citric acid, phosphoric acid, lactic acid, tartaric acid, and hydrochloric acid, and physiologically acceptable organic or inorganic acids, bases, and salts such as potassium hydroxide, sodium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate salts, sodium bicarbonate, potassium bicarbonate, or ammonium bicarbonate salts.
The stabilizer is selected from one or more of the following: EDTA-2Na, sodium thiosulfate, sodium pyrosulfite, sodium sulfite, dipotassium hydrogen phosphate, sodium bicarbonate, sodium carbonate, arginine, glutamic acid, polyethylene glycol 6000, polyethylene glycol 4000, sodium dodecyl sulfate or tris (hydroxymethyl) aminomethane. Sodium metabisulfite, dipotassium hydrogen phosphate, arginine, polyethylene glycol 6000 and tris are preferred.
The osmotic pressure regulator is sodium chloride and/or potassium chloride.
The pharmaceutical composition can be administered through intramuscular, intravenous and subcutaneous injection routes, and the preferable preparation formulation is freeze-dried powder or solution injection.
The preparation method of the freeze-dried injection comprises the following steps: taking a proper amount of erythropoietin mimetic peptide solution, adding a water-soluble filler, a stabilizer, an osmotic pressure regulator and the like, adding a proper amount of water for injection, regulating the pH value to 4-8 to dissolve the erythropoietin mimetic peptide solution, adding water to dilute the solution to a proper concentration, adding 0.1-0.5% of activated carbon, stirring the solution for 10-20 minutes at 0-10 ℃, decarbonizing, filtering and sterilizing by adopting a microporous filter membrane, subpackaging the filtrate, preparing a white loose block by adopting a freeze-drying method, and sealing the block to obtain the erythropoietin mimetic peptide containing 5 mu g, 100 mu g and 1mg of erythropoietin mimetic peptide in each specification.
The preparation method of the injection comprises the following steps: taking a proper amount of erythropoietin mimetic peptide solution or freeze-dried powder, adding a water-soluble filler, a stabilizer, an osmotic pressure regulator and the like, adding a proper amount of water for injection, regulating the pH value to 4-8 to dissolve the erythropoietin mimetic peptide solution or freeze-dried powder, adding water to dilute the solution to a proper concentration, adding 0.1-0.5% of activated carbon, stirring the solution for 10-20 minutes at the temperature of 0-10 ℃, decarburizing the solution, filtering and sterilizing the solution by adopting a microporous filter membrane, subpackaging the filtrate, and sealing the filtrate to obtain the erythropoietin mimetic peptide derivatives with the content of 5 mu g, 100 mu g and 1mg in each specification.
The pharmaceutical composition can be administered through intramuscular, intravenous and subcutaneous injection routes, and the preferable preparation formulation is freeze-dried powder or solution injection. Although the dosage may vary depending on the subject to be treated, the mode of administration, the symptoms and other factors, the composition of the present invention is effective over a relatively wide dosage range. In adult treatment, the dose ranges from 50 μ g/person to 10 mg/person, administered once daily or once every few days. The actual dosage should be determined by a physician in the light of the relevant circumstances, including the physical condition of the subject, the route of administration, the age, weight, individual response of the patient to the drug, the severity of the patient's symptoms, and the like, and therefore the above dosage range is not intended to limit the scope of the present invention in any way.
Compared with the prior art, the erythropoietin mimic peptide or the medicinal salt thereof can obviously stimulate the increase of the mouse peripheral blood reticulocyte count, which shows that the erythropoietin mimic peptide or the medicinal salt thereof can stimulate erythropoiesis and can greatly prolong the half-life period of the medicament in vivo. The erythropoietin mimetic peptide derivatives and erythropoietin protein have no significant effect on mature red blood cells, hematocrit, hemoglobin content, nor on peripheral blood leukocyte counts. The increase in mouse peripheral blood reticulocyte count can be significantly stimulated at the same dose compared to commercially available EPO. And greater stimulation of rat reticulocyte production following the same days of administration.
Drawings
Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 shows HPLC validation results of erythropoietin mimetic peptides synthesized in example 1;
FIG. 2 shows the MS-verified results of the erythropoietin mimetic peptides synthesized in example 1.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1 Synthesis of erythropoietin mimetic peptides
The present invention will be described in further detail with reference to specific examples.
The erythropoietin mimic peptide is polypeptide, and the sequence of the polypeptide is selected from SEQ ID NO. 1. The synthesis of the polypeptide of the present invention was carried out by Fmoc solid-phase polypeptide synthesis using a model CS 336X instrument manufactured by CSBio. The synthetic method was performed according to the manufacturer's instructions. The Fmoc solid-phase polypeptide synthesis method is a synthesis method for synthesizing polypeptide by using polymer resin as a solid-phase reaction substrate and sequentially condensing amino acids protected by Fmoc at an amino terminal in the presence of a coupling reagent. The specific method is described in Fmoc solid phase peptide synthesis, a practical proproach, 2000, Oxford University Press. And disulfide bonds in monomers are formed by oxidation methods, such as 20% DMSO oxidation and iodonium oxidation. The prepared polypeptide was purified using a semi-preparative HPLC C18 column with acetonitrile as the mobile phase. Desalting and freeze-drying to obtain polypeptide lyophilized powder.
The resulting products were verified by HPLC and MS, respectively, and the results are shown in fig. 1 and fig. 2, respectively.
Example 2 Effect of erythropoietin mimetic peptides on mice
The effect of erythropoietin mimetic peptides and erythropoietin proteins on mouse erythropoiesis was evaluated and compared using mice.
Wherein, EPO (recombinant human erythropoietin injection, batch No. 201405YC12) medicine is purchased from Shenyang Sansheng pharmaceutical company Limited;
kunming mouse, purchased from Shanghai laboratory animal center of Chinese academy of sciences, weighing 25-30g, is female mouse, and the number of animals in each group in the test: 10, divided into 3 groups.
Among them, a group of mice were injected with the erythropoietin mimetic peptide derivatives synthesized in example 1, a group of mice were injected with erythropoietin protein, a group of mice were blank control, and were injected with PBS buffer (25mM/l) at a dose of 4.5mg/kg for three consecutive days, and then the mice were sacrificed, and whole blood was taken for peripheral blood cell and reticulocyte counting, and the blood cell counting was performed by a full-automatic blood cell counter.
As shown in Table 1, it was found that both the erythropoietin mimetic peptide derivatives and the erythropoietin protein significantly stimulate the increase of mouse peripheral blood reticulocyte count, indicating that they stimulate erythropoiesis. In addition, the mimetic peptide of example 1 significantly stimulates an increase in mouse peripheral blood reticulocyte count at the same dose as compared to commercially available EPO (see table 1).
TABLE 1 Effect of erythropoietin mimetic peptide derivatives on mouse reticulocyte production
| Name (R) | Dosage form | Number of reticulocytes |
| Blank space | PBS buffer | 113.65±2.75 |
| Example 1 mimetic peptides | 4.5mg/kg | 678.75±1.12 |
| EPO | 4.5mg/kg | 647.19±1.17 |
Example 3: effect of erythropoietin mimetic peptides on macaques
The macaque is used for evaluating the influence of the erythropoietin mimic peptide on erythropoiesis, and the weight of the macaque is 5.5-5 kg, and the macaque is not limited in sex and purchased from the Hainan experimental animal center. The macaques are divided into two groups according to basic hemoglobin, and each group comprises three macaques. One group was administered 4.5mg/kg intravenously weekly using the mimetic peptide synthesized in example 1; one group was administered EPO three times per week at 240 μ/kg for five weeks with 1 hematological indicator measured weekly, as shown in table 2.
Table 2: effect of erythropoietin mimetic peptide derivatives on Kiwi reticulocyte production
| Name (R) | Dosage form | Number of reticulocytes |
| Blank space | PBS buffer | 223.12±1.26 |
| SEQ ID NO:1 | 4.5mg/kg | 729.34±2.10 |
| EPO | 4.5mg/kg | 536.28±1.86 |
As a result, a single intravenous injection of the mimic peptide is found to result in the increase of peripheral blood hemoglobin content (33%) of macaques, and the increase of hematocrit indicates that the mimic peptide stimulates the generation of hemoglobin. The positive control erythropoietin also increased the peripheral blood hemoglobin content of macaques (34%), increased hematocrit, but apparently did not have long-term efficacy and required three injections per week.
Example 4 Effect of erythropoietin mimetic peptides on rats
The effect of erythropoietin mimetic peptides and erythropoietin proteins on rat erythropoiesis was evaluated and compared in rats.
Wherein, the EPO drug is purchased from Shenyang Sansheng pharmaceutical Limited liability company;
SD rats purchased from Shanghai laboratory animal center of Chinese academy of sciences, weighing 25-30g, are female rats, and the number of animals in each group in the test is as follows: 10, divided into 3 groups.
Among them, a group of rats injected with the erythropoietin mimetic peptide synthesized in example 1, a group of rats injected with erythropoietin protein, a group of rats as a blank control, injected with PBS buffer (25mM/l) at a dose of 4.5mg/kg, continuously sampled three days after a single administration for peripheral blood cell and reticulocyte counting, counted by a full-automatic blood cell counter, and calculated for the long-term stability of the derivative, and the result found that the derivative 1 still has the effect of stimulating erythropoiesis within 2 weeks after a single administration, and the results are shown in table 2. Also, the mimetic peptides of example 1 showed greater stimulation of rat reticulocyte production at days 7, 14, and 21 compared to commercially available EPO.
TABLE 3 Effect of erythropoietin mimetic peptide derivatives on rat reticulocyte production
Although the present invention has been described to a certain extent, it is apparent that appropriate changes in the respective conditions may be made without departing from the spirit and scope of the present invention. It is to be understood that the invention is not limited to the described embodiments, but is to be accorded the scope consistent with the claims, including equivalents of each element described.
Claims (8)
1. An erythropoietin mimetic peptide, wherein the amino acid sequence of the mimetic peptide is represented by SEQ ID NO: 1:
GGLYACHMGPITNalVCQPLRSarKVPGPGVPGPGVPGPGVPGPG；
wherein Nal is 3- (1-naphthyl) -L-alanine, and the structural formula is as follows:
sar is sarcosine, the structural formula of which is as follows:
the two cysteines (C) form an intramolecular disulfide bond, with the N-terminus acetylated.
2. The method of claim 1, wherein the method comprises:
1) selecting amino acids according to the amino acid sequence shown in SEQ ID NO. 1;
2) the mimetic peptides were synthesized by Fmoc solid phase peptide synthesis.
3. The method of claim 2, further comprising: 3) purifying the mimic peptide obtained in the step 2), desalting and freeze-drying to obtain mimic peptide dry powder; preferably, the purification is carried out by means of a semi-preparative HPLC C18 column with acetonitrile as mobile phase.
4. A pharmaceutically acceptable salt of an erythropoietin mimetic peptide, which is a salt produced by reacting the erythropoietin mimetic peptide according to claim 1 with an acidic compound or a basic compound;
preferably, the acidic compound is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, or acetic acid;
preferably, the basic compound is selected from the group consisting of ammonium, alkali or alkaline earth metal hydroxides, and carbonates, bicarbonates; more preferably, the basic compound is selected from sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate or potassium carbonate;
more preferably, the pharmaceutically acceptable salt of the erythropoietin mimetic peptide is selected from the group consisting of sulfate, pyrosulfate, trifluoroacetate, sulfite, bisulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, bromide, iodide, acetate, propionate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, fumarate, maleate, butyn-l, 4-dioate, hexyn-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, gamma-isovalerate, and mixtures thereof, Glycolate, tartrate, mesylate, propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate or mandelate, preferably trifluoroacetate.
5. A pharmaceutical composition comprising the erythropoietin mimetic peptide according to claim 1 or the pharmaceutically acceptable salt of the erythropoietin mimetic peptide according to claim 4,
preferably, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients selected from one or more of water-soluble fillers, pH regulators, stabilizers, water for injection and osmotic pressure regulators;
preferably, the water-soluble filler adjuvant is one or more selected from the group consisting of: mannitol, low molecular dextran, sorbitol, polyethylene glycol, glucose, lactose and galactose;
the pH adjusting agent is selected from one or more of the following: non-volatile acids such as citric acid, phosphoric acid, lactic acid, tartaric acid, hydrochloric acid, and the like, and potassium hydroxide, sodium hydroxide or ammonium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate salts, sodium bicarbonate, potassium bicarbonate, and ammonium bicarbonate salts;
the stabilizer is selected from one or more of the following: EDTA-2Na, sodium thiosulfate, sodium metabisulfite, sodium sulfite, dipotassium hydrogen phosphate, sodium bicarbonate, sodium carbonate, arginine, glutamic acid, polyethylene glycol 6000, polyethylene glycol 4000, sodium dodecyl sulfate and tris (hydroxymethyl) aminomethane; preferably selected from one or more of the following: sodium metabisulfite, dipotassium hydrogen phosphate, arginine, polyethylene glycol 6000 and tris (hydroxymethyl) aminomethane;
the osmotic pressure regulator is sodium chloride and/or potassium chloride.
6. Use of a pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment of a disease characterized by a deficiency of erythropoietin or a deficiency or defect in a population of red blood cells, preferably selected from the group consisting of end stage renal failure or dialysis; AIDS-related anemia, autoimmune diseases, or malignancies; cystic fibrosis; early stage prematurity anemia; anemia associated with chronic inflammatory disease; spinal cord injury; acute blood loss; aging and neoplastic diseases accompanied by abnormal red blood cell production.
7. Use of an erythropoietin mimetic peptide according to claim 1 for the manufacture of a medicament for the treatment of a disease characterized by a deficiency of erythropoietin or a deficiency or defect in a population of red blood cells, preferably selected from the group consisting of end stage renal failure or dialysis; AIDS-related anemia, autoimmune diseases, or malignancies; cystic fibrosis; early stage prematurity anemia; anemia associated with chronic inflammatory disease; spinal cord injury; acute blood loss; aging and neoplastic diseases accompanied by abnormal red blood cell production.
8. Use of a pharmaceutically acceptable salt of an erythropoietin mimetic peptide according to claim 4 for the manufacture of a medicament for the treatment of a disease characterized by a deficiency of erythropoietin or a deficiency or defect in a population of red blood cells, preferably selected from the group consisting of end-stage renal failure or dialysis; AIDS-related anemia, autoimmune diseases, or malignancies; cystic fibrosis; early stage prematurity anemia; anemia associated with chronic inflammatory disease; spinal cord injury; acute blood loss; aging and neoplastic diseases accompanied by abnormal red blood cell production.
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| EP1527094A2 (en) * | 2002-08-09 | 2005-05-04 | MERCK PATENT GmbH | T-cell epitopes in erythropoietin |
| CN103450348A (en) * | 2012-05-29 | 2013-12-18 | 中国人民解放军军事医学科学院毒物药物研究所 | Mimetic peptide of erythropoietin, preparation method and applications thereof |
| CN103570834A (en) * | 2012-07-19 | 2014-02-12 | 江苏豪森药业股份有限公司 | Methoxy polyethylene glycol-modified erythropoietin mimic peptide derivative |
| CN104231067A (en) * | 2013-06-07 | 2014-12-24 | 中国人民解放军军事医学科学院毒物药物研究所 | Erythropoietin mimetic peptide chemical dimer and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1527094A2 (en) * | 2002-08-09 | 2005-05-04 | MERCK PATENT GmbH | T-cell epitopes in erythropoietin |
| CN103450348A (en) * | 2012-05-29 | 2013-12-18 | 中国人民解放军军事医学科学院毒物药物研究所 | Mimetic peptide of erythropoietin, preparation method and applications thereof |
| CN103570834A (en) * | 2012-07-19 | 2014-02-12 | 江苏豪森药业股份有限公司 | Methoxy polyethylene glycol-modified erythropoietin mimic peptide derivative |
| CN104231067A (en) * | 2013-06-07 | 2014-12-24 | 中国人民解放军军事医学科学院毒物药物研究所 | Erythropoietin mimetic peptide chemical dimer and use thereof |
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