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Stearic acid-modified cell penetrating peptide and its preparation and application

A technology of stearic acid and penetrating peptide, which is applied in the directions of non-active ingredients medical preparations, medical preparations containing active ingredients, and polypeptides containing positioning/targeting motifs, etc. Polypeptide structure, permeability limitations and other problems, to improve the ability to enter cells, overcome the inability to enter cells, and achieve the effect of high stability

Inactive Publication Date: 2017-12-08
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although some polypeptides can enter cells through receptor-mediated endocytosis, the polypeptides that enter cells are eventually swallowed by lysosomes, and the biological activity of polypeptides is destroyed by enzymes in lysosomes, resulting in only a small part of the Peptides can enter the cytoplasm to play a role, so although many peptides have a good effect in vitro, they cannot be used in vivo due to bioavailability problems
In addition, peptide drugs are not stable in vivo, and various internal factors can lead to inactivation of peptides: temperature, pH, high salt concentration, or surface activity affect its activity, non-covalent ionic compounds, low molecular or high molecular weight Compounds also affect the structure of peptides, etc.
Due to the short half-life of the polypeptide, continuous injection administration makes the patient's compliance poor, and the physicochemical properties and low permeability of the polypeptide itself also limit its non-invasive nasal, skin, lung and oral administration routes[3] Applications

Method used

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  • Stearic acid-modified cell penetrating peptide and its preparation and application
  • Stearic acid-modified cell penetrating peptide and its preparation and application
  • Stearic acid-modified cell penetrating peptide and its preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 Preparation and acquisition of cell penetrating peptide CPP-SA

[0056] 1.1 The polypeptide CPP is prepared and obtained by chemical synthesis, the amino acid sequence of the CPP is shown in SEQ ID NO.1, specifically: Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Lys (GRKKRRQRRRK). Then stearic acid is modified on the C-terminal Lys of the CPP, specifically, the carboxyl group on the C-terminal Lys of the CPP can be amidated, and then the carboxyl group of stearic acid and the C-terminal Lys of the CPP can be The amino group of the side chain was subjected to condensation reaction to prepare a cell-penetrating peptide whose C-terminus of CPP was modified with stearic acid, which was named CPP-SA. After verification and characterization, the structural formula of CPP-SA is correct, as shown in formula (1), specifically:

[0057] 1.2 Prepare and obtain the polypeptide CPP-MMP by chemical synthesis, the amino acid sequence of the CPP-MMP is shown in SEQ ID NO.2, sp...

Embodiment 2

[0062] Embodiment 2 fusion peptide Gaegurins5-CPP-SA and liposome preparation thereof

[0063] (1) The C-terminus of Gaegurins5 is connected to the N-terminus of CPP-SA by chemical synthesis method to prepare and obtain the fusion peptide Gaegurins5-CPP-SA. The amino sequence of Gaegurins5 is shown in SEQ ID NO.3, specifically: Phe-Leu-Gly-Ala-Leu-Phe-Lys-Val-Ala-Ser-Lys-Val-Leu-Pro-Ser-Val-Lys- Cys-Ala-Ile-Thr-Lys-Lys-Cys.

[0064] (2) Surfactant dialysis method prepares liposome preparation:

[0065] a) Preparation of liposome suspension: get each liposome component HSPC, Chol according to the ratio, mix well, N 2 Blow dry to obtain a lipid film, add 5% glucose, ultrasonically hydrate at 40°C with a power of 80% for 30 min, and pass through an 80 nm film 21 times with an Extruder to obtain a liposome suspension;

[0066] b) Preparation of fusion peptide surfactant solution: take fusion peptide Gaegurins5-CPP-SA and surfactant OG according to the ratio, and mix them unifor...

Embodiment 3

[0118] Embodiment 3 fusion peptide HNPs1-CPP-SA and liposome preparation thereof

[0119] (1) The C-terminus of human neutrophil peptide-1 (HNPs1) was connected to the N-terminus of CPP-SA by chemical synthesis method to prepare and obtain the fusion peptide HNPs1-CPP-SA. The amino sequence of HNPs1 is shown in SEQ ID NO.4, specifically: Ala-Cys-Tyr-Cys-Arg-Ile-Pro-Ala-Cys-Ile-Ala-Gly-Glu-Arg-Arg-Tyr-Gly- Thr-Cys-Ile-Tyr-Gln-Gly-Arg-Leu-Trp-Ala-Phe-Cys-Cys.

[0120] (2) Surfactant dialysis method prepares liposome preparation:

[0121] a) Preparation of liposome suspension: get each liposome component EPC, Chol by proportioning, mix well, N 2 Blow dry to obtain a lipid film, add 5% glucose, ultrasonically hydrate at 40°C with a power of 80% for 30 min, and pass through an 80 nm film 21 times with an Extruder to obtain a liposome suspension;

[0122] b) Preparation of fusion peptide surfactant solution: take fusion peptide HNPs1-CPP-SA and surfactant n-nonyl-β-D-glucopyranos...

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Abstract

The invention specifically relates to a stearic acid-modified cell penetrating peptide and the preparation and application thereof, belonging to the field of research and development on biological drugs. Results of extensive and in-depth study show that a fusion peptide formed by fusion of the novel stearic acid-modified cell-penetrating peptide and a polypeptide can effectively assist the polypeptide in entering cells. A liposome preparation prepared from the fusion peptide by using a surfactant method has the advantages of uniform particle size, good entrapment efficiency and high stability, can further improve the cell-entering ability of the fusion peptide and overcomes the problem that many polypeptides including functional peptides cannot enter cells.

Description

technical field [0001] The invention belongs to the field of biopharmaceutical research and development, and specifically relates to a stearic acid-modified cell-penetrating peptide and its preparation and application. Background technique [0002] Most of the therapeutic targets of peptide drugs are in cells, such as cytoplasm, nucleus or other special organelles such as mitochondria, etc. Therefore, the key to the efficacy of peptide drugs is to deliver biologically active peptides into cells. In the delivery process of peptide drugs, there are many limitations. First of all, the large molecular weight of the polypeptide itself makes the polypeptide foreign to the recipient organism. In addition to some small molecular polypeptides entering the cell through active transport, the lipophilic biomembrane also prevents the polypeptide molecule from entering the cell spontaneously. Although some polypeptides can enter cells through receptor-mediated endocytosis, the polypeptid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K7/08C07K14/00C07K19/00A61K9/127A61K47/28A61K38/08A61K38/10A61K38/16
CPCA61K9/127A61K38/00A61K47/28C07K7/06C07K7/08C07K14/00C07K19/00C07K2319/10
Inventor 徐宇虹李秩举彭金良魏晓慧陈晓龙
Owner SHANGHAI JIAO TONG UNIV
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