Pro-apoptosis bicyclic polypeptide with stable alpha-helical conformation and a preparation method and application thereof

A technology of helical conformation and apoptosis, applied in the field of pro-apoptotic bicyclic polypeptides and preparation, can solve the problems of weak targeting, low cell penetration ability, poor metabolic stability of polypeptides, etc., and achieves a high degree of α-helix, Improved cyclization efficiency, small effect of normal cell killing ability

Active Publication Date: 2021-05-25
SOUTHWEST JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004]The present invention solves the technical problems of poor metabolic stability of traditional polypeptides, low cell penetration ability and weak targeting

Method used

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  • Pro-apoptosis bicyclic polypeptide with stable alpha-helical conformation and a preparation method and application thereof
  • Pro-apoptosis bicyclic polypeptide with stable alpha-helical conformation and a preparation method and application thereof
  • Pro-apoptosis bicyclic polypeptide with stable alpha-helical conformation and a preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0043] This example provides a pro-apoptotic bicyclic polypeptide with a stable α-helical conformation, comprising a pro-apoptotic peptide functional peptide segment, targeting α v beta 3 Integrin RGD, turn-angle amino acid proline, and thioether-containing molecular backbone, the sequence of the pro-apoptotic peptide functional peptide is KLAKLXKKLAKLKK, which is a linear sequence rich in lysine, and X is a non- The natural amino acid, the pro-apoptotic peptide functional peptide and RGD are connected by proline to reduce the mutual interference between the pro-apoptotic peptide and RGD, and at the same time, it is convenient to turn into a loop and improve the flexibility of the connection. Acids construct bicyclic structures with thioether backbones on linear polypeptides through thiol-alkyne click chemistry reactions.

[0044] The amino acids in the sequence of the pro-apoptotic peptide functional peptide are all L-type amino acids, and have an α-helical conformation, whi...

Embodiment 2

[0056] This example provides a method for preparing a pro-apoptotic bicyclic polypeptide with stable α-helical conformation, as shown in the attached figure 1 As shown, the specific preparation process is as follows:

[0057] S1. Synthesize the linear peptide sequence Fmoc-WRGDfVPKLAKLXKKLAKLK(Alloc)K-Resin containing the allyloxycarbonyl Alloc side chain protection group by Fmoc solid-phase synthesis method, wherein the Alloc side chain protection group is located at the lysine on the right side of the sequence On the above, X is an unnatural amino acid with an alkyne group, and tryptophan is connected to the end of RGD. Tryptophan has an absorption peak at 280nm, and the concentration of the polypeptide can be determined by a microplate reader. The linear peptide sequence Fmoc-WRGDfVPKLAKLXKKLAKLK(Alloc) The specific structure of K-Resin is as follows:

[0058]

[0059] The specific synthesis process is as follows:

[0060] First weigh 400mg of Rink resin, swell it with...

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Abstract

The invention discloses a pro-apoptosis bicyclic polypeptide with stable alpha-helical conformation and a preparation method and application thereof, the pro-apoptosis bicyclic polypeptide comprises a pro-apoptosis functional peptide fragment, a tumor targeting functional peptide fragment, a corner amino acid residue and a thioether-containing molecular skeleton; the pro-apoptosis peptide fragment is an amphiphilic sequence rich in lysine and leucine, the corner amino acid is proline, the thioether-containing molecular skeleton is obtained by adding bimolecular thiohydracrylic acid to an alkynyl-containing non-natural amino acid side chain through sulfydryl-alkynyl click chemistry and carrying out macrocyclic lactamization. The preparation method of the polypeptide is simple and effective, the cyclization efficiency can be remarkably improved by performing double-cyclization on the ith amino acid residue position and the (i + 7) th amino acid residue position of the pro-apoptotic peptide functional peptide fragment, compared with linear polypeptide, the double-ring polypeptide is higher in alpha-helix degree, higher in stability and good in blood stability, and in addition, the bicyclic polypeptide can respectively target a cell surface integrin receptor and intracellular mitochondria, selectively disturbs the membrane potential of the integrin high expression tumor cell mitochondria, and the pro-apoptosis bicyclic polypeptide has a good tumor treatment application prospect.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a pro-apoptotic bicyclic polypeptide with a stable α-helix conformation, a preparation method and application thereof. Background technique [0002] The pro-apoptotic peptide KLA (KLAKLAKKLAKLAK) is an α-helical amphipathic polypeptide with antibacterial activity, which can target mitochondria and damage mitochondrial membranes, resulting in the release of cytochrome C and inducing apoptosis. It has been widely reported that it can be used in malignant Tumor treatment. However, linear KLA polypeptides have problems such as poor stability, poor cell penetration, and poor cell activity. At present, it is reported in the literature that the pro-apoptotic peptide KLA is delivered into cells mainly by coupling ligands and using receptor-mediated endocytosis. For example, by further modifying the cyclic NGR polypeptide ligand in the pro-apoptotic peptide KLA sequence, the AHNP ...

Claims

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Application Information

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IPC IPC(8): C07K19/00C07K1/04A61K38/10A61K47/64A61P35/00
CPCC07K7/08A61K47/64A61P35/00C07K2319/33A61K38/00Y02P20/55
Inventor 田原唐瑞
Owner SOUTHWEST JIAOTONG UNIV
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