Comparison of Permeation through Phosphatidylcholine Bilayers ofN-Dipicolinyl-α- and -β-Oligopeptides

Abstract

Cell-membrane permeation of small therapeutic peptides and peptidomimetics is a fundamental issue in pharmaceutical research. Using a Tb(3+)-based permeation assay, we have examined the ability of alpha- and beta-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 beta-hexapeptide was discovered. Significant differences in permeation were observed between the DPA-alpha- and the DPA-beta-peptides, with all beta-peptidic compounds permeating better than their alpha-analogs. Thus, beta-peptides have been shown to interact with lipid bilayers in a manner that is distinctly different from that of alpha-peptides. Together with the fact that beta-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 beta-peptides.

Voltammetric and Electrochemical Impedance Study of Ferrocenyl Containing β-Peptide Monolayers on Gold

“…The CD spectral evidence for AcSC 15 B 6 Fc in TFE indicates this peptide adopts a 10/12-helix, which is typically not favored by these peptides and considered unlikely (however, CD studies are not always accurate, and structural determinations based solely on CD are unwise). 24,25 Finally, ellipsometry on the SAM Fc used in this study gave an average film thickness = 4.3 ((0.3) nm, which compares with 0.8 nm for lipoic acidÀ (β 3 Val-β 3 Ala-β 3 Leu) 2 ÀFc. 10 Long-chain alkyl thiolates are exceptionally good at forming compact and well-ordered SAMs, 26À28 but this ability is offset by any bulkiness in terminal moieties that can reduce the film compactness.…”

Protonation Kinetics Compromise Liposomal Fluorescence Assay of Membrane Permeation

“…Fluorescence spectroscopy has been used to quantify the kinetics of drug permeation through model membranes similar to those studied computationally, i.e., lipid bilayers composed of either a single type of lipid (e.g., phospholipid) or a mixture of two lipids (e.g., phospholipid and cholesterol). These approaches, however, require that the permeant itself is fluorescent or exhibits self-quenching fluorescence. − An alternative approach utilizing the photoluminescence of lanthanides has also been developed. − However, in this case, the permeant is required to both absorb in a convenient wavelength window and chelate the lanthanide ion . Furthermore, there is evidence that some of these latter studies are prone to experimental artifact …”

Lipid‐Bilayer Permeation of Drug‐Like Compounds

“…As discussed above, it is often assumed that the lipid-bilayer permeation of the ionized species of a weak acid or a base is negligible at physiological pH. We found that the anions of several aromatic carboxylic acids controlled permeation across egg phosphatidylcholine bilayers at pH 7 [3] [4] [41]. This was concluded from the fact that the pH -permeation profiles, which perfectly fitted Hendersson -Hasselbalch functions with inflection points at pH ¼ pK a , reached the plateau of ion permeation at pH values < 7.…”