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Erythropoietin mimetic peptide, and preparation method and application thereof

An erythropoietin and peptide-mimicking technology, applied in the field of biomedicine, can solve the problems of low EC50, limit the clinical application of recombinant human EPO, reduce the efficacy of drugs, etc., and achieve the effect of prolonging the half-life

Active Publication Date: 2017-01-11
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, drugs with this type of mechanism will cross-react with EPO antibodies in vivo, reducing the efficacy of this type of drug
Moreover, the EC50 of existing recombinant human EPO drugs that can stimulate the proliferation and differentiation of erythrocytes is very low, only between 20nM and 250nM, which severely limits the clinical application of recombinant human EPO

Method used

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  • Erythropoietin mimetic peptide, and preparation method and application thereof
  • Erythropoietin mimetic peptide, and preparation method and application thereof
  • Erythropoietin mimetic peptide, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Synthesis of SEQ ID NO:1

[0037] The direction of solid-phase synthesis is from C-terminal to N-terminal, starting with the C-terminal lysine of the peptide shown in SEQ ID NO: 1, extending the first amino acid of the sequence (glycine or acetylated glycine), and then simultaneously or The ε-amino protecting group of the linker lysine is successively removed to continue the synthesis of the second branched chain.

[0038] The steps are as follows: soak the resin, remove the amino protecting group of the resin, wash and monitor

[0039] The removal of α-amino protecting group and resin amino protecting group Fmoc is selected from piperidine (PIP), the concentration is 20-25% (PIP: DMF), and the time is 20-50min. The solvent used in the synthesis process is selected from dimethylformamide (DMF) or dichloromethane (DCM), the coupling reagent is selected from a carbodiimide type reagent or a benzotriazolium salt type reagent, and 1-hydroxybenzotriazole (HOBt) o...

Embodiment 2

[0040] Example 2 Increased production of endogenous erythropoietin in vitro

[0041] The sequence selected in the present invention is: SEQ ID NO: 1, and the zinc ion concentration is 0.0001, 0.01, 0.1, 1, 10, 100 mM.

[0042] Human cells derived from liver cancer (Hep3B) were inoculated into 35mm culture dishes and kept at 37°C, 20% O 2 , 5%CO 2 In minimum essential medium (MEM),

[0043] Growth was in Earle's balanced salt solution (Mediatech Inc., Herndon VA), 2 mM L-glutamine, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, and 1% FBS. When the cell layer was confluent, the original medium was replaced with OPTI-MEM medium (Invitrogen Life Technologies, Carlsbad CA), and then incubated at 37°C, 20% O 2 , 5%CO 2 Incubate the cell layer for about 24 hours under the above conditions. Then, the compound of the present invention mixed with different concentrations of zinc ions or different concentrations of zinc ions (negative control) was added to the current cu...

Embodiment 3

[0044] Example 3 Effects of erythropoietin mimetic peptide on mice

[0045] Mice were used to evaluate and compare the effects of erythropoietin mimetic peptide and erythropoietin protein on mouse erythropoiesis under different zinc ion concentrations.

[0046] The sequence selected in the present invention is: SEQ ID NO: 1, and the concentration of zinc ions is 0.0001, 0.001, 0.01, 0.1, 1, 10, 100 mM of zinc ions per milligram of polypeptide.

[0047] Among them, EPO drugs were purchased from Shenyang Sansheng Pharmaceutical Co., Ltd.;

[0048] Kunming mice were purchased from the Shanghai Experimental Animal Center of the Chinese Academy of Sciences, weighing 20-30 g, all male mice, and the number of animals in each group in the experiment: 10, divided into 10 groups.

[0049] Among them, the mice in the positive control group were injected with erythropoietin protein, and the mice in the negative control group were blank controls. The mice were subcutaneously injected w...

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Abstract

The invention provides an erythropoietin mimetic peptide with an amino acid sequence represented by SEQ ID NO:1. The SEQ ID NO:1 is GGLYACHMGPITX1HCQP LRX2K, wherein X1 is 3-(1-naphthyl)-L-alanine (Nal), and X2 is sarcosine (Sar). The amino terminals of the amino acid sequence are modified by acetic anhydride. The mimetic peptide can form a compound with zinc ions. The invention also provides pharmaceutically acceptable salts of the memetic peptide. The invention also provides applications of the memetic peptide and the pharmaceutically acceptable salts in preparing drugs used for treating diseases characterized in erythrocyte deficiency, erythropoietin deficiency or red blood cell group deficiency or defect. The erythropoietin mimetic peptide and the compounds thereof can significantly promote erythrocyte formation. Drug in-vivo half-life period can be significantly prolonged.

Description

technical field [0001] The invention belongs to the field of biomedicine and relates to an erythropoietin mimic peptide obtained by modifying the structure of erythropoietin. Background technique [0002] Erythropoietin is an active glycoprotein synthesized and secreted by the kidney, which can bind to the erythropoietin receptor (EPOR) on the surface of red blood cells to stimulate the proliferation, differentiation and maturation of red blood cells, thereby increasing the number of red blood cells in patients with anemia. To improve the condition of anemia. The molecular weight is about 34kD. The erythropoietin present in the plasma is composed of 165 amino acids, with a high degree of glycosylation, and the main sugar component is sialic acid. According to different carbohydrate content, naturally occurring erythropoietin is divided into two types, α-type and β-type, of which α-type contains 34% carbohydrates, and β-type contains 26% carbohydrates. The two types are id...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/505A61K38/18A61P13/12A61P7/06A61P37/02A61P35/00A61P25/00
CPCA61K38/00C07K14/505
Inventor 郑学敏魏群超周植星孔维苓龚珉徐为人汤立达
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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