Novel brain-targeted cell-penetrating peptide and application thereof in lipidosome
A brain-targeting and liposome technology, applied in the fields of life science and pharmacy, can solve the problems of small number of amino acids, difficulty in preparation and synthesis, easy to produce immunogenicity, etc., and achieve good drug effect
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Embodiment 1
[0050] Example 1 Design of brain targeting peptide RVGP combined with acetylcholine receptor
[0051] Using RVG29 (YTIWMPENPRLMSCDIFTNSRGKRASKG) as a template, molecular docking and molecular dynamics simulations were carried out between RVGP29 and acetylcholine receptor (α7-nAchR) subunit monomers. By analyzing the dynamic process of RVG29 specific binding to nAChR, the binding regions and The key binding site, and then change the type of amino acid through the method of virtual mutation, design multiple candidate mutant peptides and then perform kinetic simulation, and finally optimize the contribution of amino acid binding energy to obtain a short peptide RVGP that has a stronger interaction with nAChR.
[0052] (1) Selection and construction of molecules
[0053] The three-dimensional structure of α7-nAchR pentamer (PDB ID: 3SQ6) and the sequence information of RVG29 in RVG protein (PDB ID: 3NFK) were obtained from the PDB database. Using the protein docking program onlin...
Embodiment 2
[0064] Example 2 Design of the brain-targeted penetrating peptide PTB
[0065] Taking advantage of the characteristics of the drug transport mode on the blood-brain barrier (BBB), the combination of receptor-mediated and adsorption-mediated is beneficial to the transmembrane transport and lysosome escape of drugs. In addition to the combined use of receptor ligands and cell-penetrating peptides to prepare drug delivery systems such as biligand-modified liposomes, it is also possible to directly couple receptor ligands and cell-penetrating peptides. A novel dual-mediated delivery method. In the present invention, we used polyarginine as a cell penetrating peptide, and used all-atom molecular dynamics simulation to investigate the influence of the number of arginine on the binding ability of RVGP and nAChR, and determined the binding energy of arginine. The optimal number is 9, thus a novel peptide RVGPR9 with brain targeting and membrane penetrating functions was invented, its...
Embodiment 3
[0072] The optimal density of embodiment 3 PTB modified liposomes
[0073] The modification density of PTB on the liposome surface is a key parameter affecting its targeting ability. This patent studies the binding site of PTB and α7-nAchR pentamer complex through the combined use of PatchDock, FireDock and Tox Dock three docking software, and through the comparative analysis of the distance between PTB and liposome surface, it is obtained that PTB is in the The optimal density of liposome surface modification was 2%, and was found to be characterized by the binding of multiple PTBs on liposomes to one AChR protein, rather than the binding of 1 PTB to one receptor protein.
[0074] (1) Molecular docking
[0075] The three-dimensional structure of the α7-nAchR pentamer in Example 1 and the obtained PTB optimal molecular conformation PDB file were used as the initial structure for docking. First, use PatchDock to initially search for the potential binding sites of PTB on the α...
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