Fine-tuning the physicochemical properties of peptide-based blood–brain barrier shuttles
| Autor: | Morteza Malakoutikhah, Fatemeh Aboutalebi, Somaye Ghasemy, Meritxell Teixidó, Kianoush Dormiani, Júlia García-Pindado |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell Survival Lipid Bilayers Clinical Biochemistry Synthetic membrane Pharmaceutical Science Peptide 010402 general chemistry PC12 Cells 01 natural sciences Biochemistry Permeability 03 medical and health sciences Drug Discovery Animals Humans Amino Acid Sequence Solubility Molecular Biology chemistry.chemical_classification Tetrapeptide Organic Chemistry Rats 0104 chemical sciences Amino acid HEK293 Cells 030104 developmental biology Membrane chemistry Blood-Brain Barrier Permeability (electromagnetism) Lipophilicity Biophysics Molecular Medicine Peptides Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Bioorganic & Medicinal Chemistry. 26:2099-2106 |
| ISSN: | 0968-0896 |
| Popis: | N-methylation is a powerful method to modify the physicochemical properties of peptides. We previously found that a fully N-methylated tetrapeptide, Ac-(N-MePhe)4-CONH2, was more lipophilic than its non-methylated analog Ac-(Phe)4-CONH2. In addition, the former crossed artificial and cell membranes while the latter did not. Here we sought to optimize the physicochemical properties of peptides and address how the number and position of N-methylated amino acids affect these properties. To this end, 15 analogs of Ac-(Phe)4-CONH2 were designed and synthesized in solid-phase. The solubility of the peptides in water and their lipophilicity, as measured by ultra performance liquid chromatography (UPLC) retention times, were determined. To study the permeability of the peptides, the Parallel Artificial Membrane Permeability Assay (PAMPA) was used as an in vitro model of the blood-brain barrier (BBB). Contrary to the parent peptide, the 15 analogs crossed the artificial membrane, thereby showing that N-methylation improved permeability. We also found that N-methylation enhanced lipophilicity but decreased the water solubility of peptides. Our results showed that both the number and position of N-methylated residues are important factors governing the physicochemical properties of peptides. There was no correlation between the number of N-methylated amide bonds and any of the properties measured. However, for the peptides consecutively N-methylated from the N-terminus to the C-terminus (p1, p5, p11, p12 and p16), lipophilicity correlated well with the number of N-methylated amide bonds and the permeability of the peptides. Moreover, the peptides were non-toxic to HEK293T cells, as determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. |
| Databáze: | OpenAIRE |
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