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1,2,3-tricarballylic acid coupled EPO peptoid derivative and preparation method and application thereof

A technology of glyceric acid coupling and peptide derivatives, applied in 1, can solve the problems of low and limited EC50, and achieve the effect of prolonging the half-life

Active Publication Date: 2017-05-03
天津天诚新药评价有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the EC50 of peptides that can stimulate erythrocyte proliferation and differentiation is very low, between 20nM and 250nM, so the clinical application of these peptides is greatly limited

Method used

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  • 1,2,3-tricarballylic acid coupled EPO peptoid derivative and preparation method and application thereof
  • 1,2,3-tricarballylic acid coupled EPO peptoid derivative and preparation method and application thereof
  • 1,2,3-tricarballylic acid coupled EPO peptoid derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1 Synthesis of Dimers of Erythropoietin Peptidomimetic Derivatives

[0046] The erythropoietin peptidomimetic of the present invention is a polypeptide, which can be prepared by using the Fmoc solid-phase polypeptide synthesis method, and the CS 336X instrument produced by CSBio Company to synthesize the polypeptide of the present invention. The method of synthesis was carried out according to the manufacturer's instruction manual. The Fmoc solid-phase polypeptide synthesis method described herein refers to a synthetic method in which a polymer resin is used as a solid-phase reaction matrix to sequentially condense amino-terminal Fmoc-protected amino acids in the presence of a coupling reagent to synthesize a polypeptide. x 3 The carboxyl group is attached to the polymer resin, X 3 The amino group is condensed with the 2-position carboxyl group of 1,2,3-propanetriacic acid, and the 1- and 3-position carboxyl groups are respectively condensed with the side ch...

Embodiment 2

[0047] Example 2 Effects of dimers of erythropoietin peptidomimetic derivatives on mice

[0048] Using mice to evaluate and compare the effects of 1, 2, 3-propanetrilic acid-coupled erythropoietin peptidomimetic dimers and erythropoietin protein on mouse erythropoiesis.

[0049] Among them, EPO drugs were purchased from Shenyang Sansheng Pharmaceutical Co., Ltd.;

[0050] Kunming mice, purchased from Shanghai Experimental Animal Center of Chinese Academy of Sciences, weighing 25-30 g, are all female mice. The number of animals in each group in the experiment: 10, divided into 4 groups.

[0051] Among them, the mice in group 1 were injected with erythropoietin peptidomimetic derivative dimer coupled with 1, 2, 3 glyceric acid at a dose of 4.5 mg / kg, and the mice in group 1 were injected with erythropoietin protein at a dose of 4.5 mg / kg. 4.5mg / kg, the mice in group 1 were blank control, injected with PBS buffer solution for seven consecutive days, then sacrificed the mice, t...

Embodiment 3

[0055] Example 3 : Effects of dimers of erythropoietin peptidomimetic derivatives on rhesus monkeys

[0056] The EPO drug used in the present invention was purchased from Shenyang Sansheng Pharmaceutical Co., Ltd.

[0057] Rhesus monkeys were used to evaluate the effect of dimers of erythropoietin peptidomimetic derivatives on erythropoiesis. Rhesus monkeys, weighing 5.5-8.5 kg, male or female, were purchased from Hainan Experimental Animal Center. The macaques were divided into two groups according to the basic hemoglobin, with three monkeys in each group. One group uses the dimer of the peptidomimetic derivatives of the present invention, intravenous injection once a week, 4.5 mg / kg each time; the other group uses EPO as the positive control group, three times / week, 1.5 mg / kg each time, continuously The drug was given for five weeks, and hematological indicators were measured once a week.

[0058] It was found that a single intravenous injection of the peptidomimetic d...

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Abstract

Disclosed are a 1,2,3-tricarballylic acid coupled EPO peptoid derivative and a preparation method and application thereof. The invention relates to a 1,2,3-tricarballylic acid coupled erythropoietin (EPO) peptoid derivative and a dimer thereof. The peptoid derivative is monomer peptide having a sequence shown as SEQ ID NO:1 of GGLYAC6HMGPITX<1>VC15QPLRX<2>K, wherein X<1> is 3-(1-naphthyl)-L-alanine (Na1), X<2> is sarcosine (Sar), cysteine (C) at the sixth site and the fifteenth site forms an intramolecular disulfide bond, and the N terminal is acetylized. The general formula of the dimer is shown as the formula I in the description. The invention further provides a preparation method and pharmaceutically-acceptable salt of the peptoid derivative and the dimer. The invention further provides a pharmaceutical composition containing the peptoid derivative or the dimer or pharmaceutically-acceptable salt thereof. The EPO peptoid derivative, the dimer and the pharmaceutically-acceptable salt thereof can stimulate erythropoiesis and obviously prolong the half-life period of the medicine in the body.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a 1,2,3-propanetriacid-coupled erythropoietin peptide derivative, specifically, the invention relates to a erythropoietin receptor-binding and 1,2,3-propanetriacid-coupled erythropoietin peptidomimetic derivatives that activate erythropoietin receptors or can act as erythropoietin agonists and preparation methods thereof, and the present invention also relates to said peptoids Use of the derivative in the preparation of a medicament for treating diseases characterized by the lack of erythropoietin or the absence or defect of red blood cell populations. Background technique [0002] Erythropoietin (hereinafter referred to as EPO) is an active glycoprotein synthesized and secreted by the kidney. It acts on bone marrow hematopoietic cells, promotes the proliferation and differentiation of erythroid progenitor cells, and finally matures endocrine hormones. Oxygen status plays an important r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/505C07K1/04A61K38/18A61P7/06A61P37/06A61P35/00
CPCA61K38/00C07K14/505
Inventor 魏群超郑学敏龚珉周植星徐为人汤立达
Owner 天津天诚新药评价有限公司
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