Comparison of permeation through phosphatidylcholine bilayers of N-Dipicolinyl-α- and -β-Oligopeptides

Abstract

Cell-membrane permeation of small therapeutic peptides and peptidomimetics is a fundamental issue in pharmaceutical research. Using a Tb³⁺-based permeation assay, we have examined the ability of α- and β-peptides, bearing proteinogenic side chains and an N-terminal dipicolinic acid (DPA) monoamide group, to enter liposomes composed of egg phosphatidylcholine bilayers. A series of 12 DPA–peptides of increasing chain length was prepared and characterized by CD and NMR analysis. An interesting destabilizing effect of the N-terminal DPA group on the helical structure of a β-hexapeptide was discovered. Significant differences in permeation were observed between the DPA-α- and the DPA-β-peptides, with all β-peptidic compounds permeating better than their α-analogs. Thus, β-peptides have been shown to interact with lipid bilayers in a manner that is distinctly different from that of α-peptides. Together with the fact that β-peptides are proteolytically stable in mammalian organisms, and that they fold to form helices and hairpin turns with short chain lengths, the new results further emphasize the biomedical potential of β-peptides.