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Polypeptide having kidney protection effect, and application thereof

A kidney protection and action technology, applied in the field of chemically modified peptides, can solve problems such as limiting clinical application, and achieve the effects of strong scalability, easy drug use, and high biological activity.

Active Publication Date: 2015-07-01
ZHONGSHAN HOSPITAL FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the linear peptide HBSP is easily degraded by peptidases in plasma, and its half-life is only about 2 minutes, which greatly limits its clinical application.

Method used

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  • Polypeptide having kidney protection effect, and application thereof
  • Polypeptide having kidney protection effect, and application thereof
  • Polypeptide having kidney protection effect, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Embodiment 1: Target polypeptide and its preparation:

[0079] 1. Reagents and instruments

[0080] The compound was synthesized using CEM Liberty1 microwave peptide synthesizer and artificial synthesis. The peptide product was separated and purified by reversed-phase high-performance liquid chromatography (RP-HPLC Waters 1525\2489\2707). The structure was identified by mass spectrometry ESI-MS and Finnigan LCQ Deca mass spectrometer assay. The purity of the target compound was all greater than 95%, and the peptide purity analysis was carried out by dual-solvent system high performance liquid chromatography (system 1, solvent composition A: 0.05% TFA aqueous solution, B: 0.05% TFA acetonitrile solution; system 2, solvent composition A: 0.05 % TFA in water, C: 0.05% TFA in methanol). Preparative column model: Vydac C18, 120A (10×250mm); XBridgeTM C18, 5μM, 19×150mm, UV detection at 225nm or 210nm; analytical column model: SunfireTM, C18, 3.5μM, 4.6×150mm, 225nm or 210n...

Embodiment 3

[0125] The plasma half-life measurement of embodiment 3 thioether cyclic peptide and HBSP

[0126] a. Select normal human plasma (from healthy volunteers) containing 0.2 μM and 1 μM concentrations of HBSP and thioethercyclic peptide CHBP, and incubate at 37° C.

[0127] b. After extracting 50ul plasma samples at different time points, add 150ul ethanol to stop the reaction

[0128] e. Using mass spectrometry to detect the content of HBSP and thioether cyclic peptide. Three parallel experiments were set up for this detection.

[0129] Experimental results:

[0130] HBSP was basically degraded after 60 minutes, and its half-life did not exceed 10 minutes, but thioethercyclic peptide still existed in the original form after 5 hours, indicating that it was stable in plasma ( Image 6 ).

Embodiment 4

[0131] Example 4 Half-life determination of thioether cyclic peptide and HBSP in human liver microsomes

[0132] a. Select 100 μl of HBSP with a concentration of 6 μM and 100 μl of thioether cyclic peptide with a concentration of 6 μM respectively with 100 μl of normal human liver cell suspension (purchased from In Vitro Technologies, Victoria, Australia) (2×10 6 cells / ml) were incubated at 37°C.

[0133] b. After extracting samples at different time points, add 200 μl of acetonitrile to terminate the reaction.

[0134] c. Using mass spectrometry to detect the content of HBSP and thioether cyclic peptide. Three parallel experiments were set up for this detection.

[0135] Experimental results:

[0136] The half-life of HBSP is 96.25 minutes, while that of thioether cyclic peptide is 247.5 minutes, indicating that the metabolism of thioether cyclic peptide by liver cells is significantly slower than that of HBSP ( Figure 7 ).

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Abstract

The invention provides a polypeptide having a kidney protection effect. The polypeptide is characterized in that the structural general formula of the sequence of the polypeptide is X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10 and X11 are independently L- or D-type natural alkaline, acidic or aromatic amino acids or derivatives thereof, the above amino acids are selected from Cys, Ser, Asn, Leu, Ala, Arg, Glu and Gln, and R2 is hydrogen or an amino group. The polypeptide can be used for treating the renal ischemia reperfusion injury.

Description

technical field [0001] The present invention relates to five types of chemically modified peptides with renal protective effect, the main functional sequence of which is derived from the surface of erythropoietin (EPO) B helix, and the metabolic stability in vivo is improved through chemical structure modification. Background technique [0002] Renal ischemia and hypoxia lead to insufficient energy metabolism, excessive depletion of adenosine triphosphate (ATP), and a large amount of oxygen free radicals are produced during reperfusion, both of which can lead to apoptosis of renal tubular epithelial cells and severely damage renal function. At the same time, in the process of ischemia, a large number of inflammatory cells are recruited into the renal tubulointerstitium and release various inflammatory mediators, which not only cause direct damage to renal tissue, but also cause damage to renal vascular endothelial cells and enhance immunogenicity, and further lead to immune ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K7/08A61K38/08A61K38/10A61P13/12A61P9/10
Inventor 朱同玉龙亚秋戎瑞明杨橙许忠良李龙
Owner ZHONGSHAN HOSPITAL FUDAN UNIV
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