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Self-assembled tandem penetrating peptide nanoparticle antibacterial agent that can penetrate the blood-brain barrier and its preparation method and application

A nanoparticle and blood-brain barrier technology, applied in the field of tandem penetrating peptides, can solve the problem of restricted use of toxicity, achieve good bacteriostatic effect, increase permeability, and improve amphipathic effect.

Active Publication Date: 2019-06-18
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Only a few antibiotics are clinically available for the treatment of brain infections, but their high toxicity to the central nervous system, liver and kidneys limits their use

Method used

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  • Self-assembled tandem penetrating peptide nanoparticle antibacterial agent that can penetrate the blood-brain barrier and its preparation method and application
  • Self-assembled tandem penetrating peptide nanoparticle antibacterial agent that can penetrate the blood-brain barrier and its preparation method and application
  • Self-assembled tandem penetrating peptide nanoparticle antibacterial agent that can penetrate the blood-brain barrier and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] When X is nona-arginine R 9 , Y is NP2, C n When it is a long chain of palmitic acid, the general structural formula of the self-assembled tandem penetrating peptide nanoparticle antibacterial agent is: C 16 -R-R-R-R-R-R-R-R-R-K-I-K-K-V-K-K-K-G-R-K. Its synthesis method is as follows:

[0038] 1. Materials

[0039] Palmitic acid, Fmoc‐Arg(pbf)‐OH (N‐fluorenylmethoxycarbonyl‐2,2,4,6,7‐pentamethyldihydrobenzofuran‐5‐sulfonylarginine), Fmoc‐ Lys(Boc)‐OH (N‐fluorenylmethoxycarbonyl‐N'‐tert-butoxycarbonyl‐lysine), Fmoc‐Ile‐OH (N‐fluorenylmethoxycarbonyl‐isoleucine), Fmoc ‐Val‐OH (N‐fluorenylmethoxycarbonyl‐valine), Fmoc‐Gly‐OH (N‐fluorenylmethoxycarbonyl‐glycine), Rink Amide-MBHA Resin, DBLK (hexahydropyridine+DMF), HBTU (O-benzotriazol-1-yl-N,N,N,N-tetramethylurine hexafluorophosphate) and HOBT (1-hydroxybenzotriazole); piperidine, acetic anhydride, DMF (N, N-dimethylformamide), TFA (trifluoroacetic acid), NMM (N-methylmorpholine), ether, methanol, DCM (dichloromethan...

Embodiment 2

[0055] Other fatty acid-modified self-assembled tandem penetrating peptide nanoparticle antibacterial agents of the present invention that can penetrate the blood-brain barrier can replace the amino acids and fatty acids in Example 1, and use Fmoc (fluorenylmethyloxycarbonyl) protected solid phase The synthesis method is synthesized and purified according to the preparation method described in Example 1.

[0056] That is, as described in the preparation method (1) of Example 1, swell the resin, then wash it with DMF, add piperidine / DBLK to wash the resin after the shock reaction, and add amino acid raw materials, HBTU, HOBT, NMM, DMF, wash the resin with DMF after the shock reaction, and the ninhydrin test was negative. Then, according to the preparation method (2) of Example 1, according to the amino acid sequences of different tandem penetrating peptides, different amino acid raw materials (from the C-terminal to the N-terminal sequence) were sequentially added, and the shak...

Embodiment 3

[0061] Self-assembled tandem penetrating peptide nanoparticle antibacterial agent C 16 R 9 Molecular dynamics simulation and scanning electron microscope morphology observation of self-assembly of NP2

[0062] 1. Molecular dynamics simulation

[0063] To the self-assembled membrane-penetrating peptide nanoparticle antibacterial agent C in series in embodiment 1 16 R 9 NP2 for molecular dynamics simulations. The software used is Material Studio. Through the coarse-grained model, the Flory-Huggins parameters of its interaction with water are calculated, and the force field is further established for molecular dynamics simulation. Simulation results such as Figure 4 As shown, tandem penetrating peptides self-assemble in aqueous solution to form nanoparticles, in which hydrophobic palmitic acid is inside and tandem penetrating peptides are outside.

[0064] 2. Scanning electron microscope morphology observation

[0065] Using a cold field emission scanning electron microsc...

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Abstract

Disclosed in the present invention are a self-assembled serially-connected cell-penetrating peptide nano-particulate antibacterial agent capable of penetrating the blood brain barrier, a preparation method therefor, and uses thereof. The general structural formula of the antibacterial agent is Cn-X-Y, wherein X and Y are both cell-penetrating peptides and are serially connected to form a hydrophilic portion, and the Cn represents a hydrophobic portion fatty acid chain coupled with the cell-penetrating peptides; the cell-penetrating peptides are L-type amino acids; and the number of carbon atoms of the fatty acid chain is 12-20. The self-assembled serially-connected cell-penetrating peptide nano-particles of the present invention have good resistance to bacteria (including drug-resistant bacteria) and fungus, can penetrate the blood brain barrier, has low hemolytic toxicity, and can be used for researching and developing novel antibacterial agents for treating brain infection and other infectious diseases.

Description

technical field [0001] The present invention relates to a tandem penetrating peptide, in particular to a self-assembled tandem penetrating peptide nanoparticle antibacterial agent capable of penetrating the blood-brain barrier and its preparation method and application. Application in medicine for bacterial or fungal infection diseases. Background technique [0002] Brain infection has long been one of the most important infectious causes of death and can be caused by bacteria such as Staphylococcus aureus, Escherichia coli and fungi such as Candida albicans. In patients with acute meningitis, even when the bacteria are susceptible and antibiotics are given early, high mortality can occur within hours and survivors can suffer permanent visual impairment, hearing loss, neurological impairment, and mobility impairment . Despite major advances in antibiotic therapy, patients with brain infections still suffer from high morbidity and mortality due to the difficulty of drugs cr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00C07K1/06C07K1/04C07K1/30C07K1/16C07K1/14A61K38/10A61P31/04A61P25/00
CPCA61K38/00C07K7/06C07K2319/00Y02A50/30
Inventor 何道航何碧
Owner SOUTH CHINA UNIV OF TECH
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