The Effect of Multiple N-Methylation on Intestinal Permeability of Cyclic Hexapeptides
| Autor: | Amnon Hoffman, Sarit Greenberg, Horst Kessler, Florian Opperer, Chaim Gilon, Burkhardt Laufer, Jayanta Chatterjee, Oded Ovadia |
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| Rok vydání: | 2011 |
| Předmět: |
Cell Membrane Permeability
Synthetic membrane Pharmaceutical Science Peptide Methylation Peptides Cyclic chemistry.chemical_compound Drug Discovery medicine Peptide synthesis Animals Humans Transcellular chemistry.chemical_classification Intestinal permeability Facilitated diffusion Chemistry Biological Transport medicine.disease In vitro Rats Intestines Intestinal Absorption Biochemistry Cyclization Permeability (electromagnetism) Molecular Medicine Caco-2 Cells Oligopeptides |
| Zdroj: | Molecular Pharmaceutics. 8:479-487 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/mp1003306 |
| Popis: | Recent progress in peptide synthesis simplified the synthesis of multiple N-methylation of peptides. To evaluate how multiple N-methylation affects the bioavailability of peptides, a poly alanine cyclic hexapeptide library (n = 54), varying in the number of N-methyl (N-Me) groups (1-5 groups) and their position, was synthesized. The peptides were evaluated for their intestinal permeability in vitro using the Caco-2 model. Further evaluation of the transport route of chosen analogues was performed using rat excised viable intestinal tissue, a novel colorimetric liposomal model and the parallel artificial membrane permeability assay (PAMPA). While most members were found to have poor permeability (permeability coefficient, P(app)1 x 10⁻⁶ cm/s, lower than mannitol, the marker for paracellular permeability), 10 analogues were found to have high Caco-2 permeability, (P(app)1 x 10⁻⁵ cm/s, similar to testosterone, a marker of transcellular permeability). No correlation was found between the number of N-methylated groups and the enhanced permeability. However, 9/10 permeable peptides in the Caco-2 model included an N-Me placed adjacently to the D-Ala position. While the exact transport route was not fully characterized, the data suggests a facilitated diffusion. It can be concluded that multiple N-methylation of peptides may improve intestinal permeability, and therefore can be utilized in the design of orally available peptide-based therapeutics. |
| Databáze: | OpenAIRE |
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