In order to improve the buccal absorption of a dipeptide model compound, Tryptophan-Leucine (Trp-Leu), we have synthesised a lipophilic derivative by myristoylation of the N- terminal amino group of Trp-Leu. The acylated peptide (Myr-Trp-Leu) was characterized by HPTLC, purified and isolated by chromatography on a silica gel column. Its structure was confirmed by (13)C and (1)H NMR and mass spectroscopy. The increased lipophilicity of the Myr-Trp-Leu was compared to that of the native peptide by chromatography and by its partition coefficient between n-octanol and saline phosphate buffer. In addition, the sensitivity towards hydrolytic enzymes was studied. The interaction of Trp-Leu with liposomes as model membranes was also studied. The phase transition temperature of dipalmitoylphosphatidylcholine (DPPC) was lowered in the presence of Myr-Trp-Leu, while it was increased in the presence of native parent peptide. Permeation experiments performed in vitro with pig buccal mucosa showed that the Myr-Trp-Leu accumulated in the tissue at the various concentrations tested. In contrast, the native peptide was able to pass through the membrane at all concentrations used. Lipophilic modification of the peptide by acylation drastically changes its behaviour towards tissue systems.
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