Comparison of permeation through phosphatidylcholine bilayers of N-dipicolinyl-alpha- and -beta-oligopeptides.
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.
Gardiner
James
J
Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH-Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich.
Thomae
Anita V
AV
Mathad
Raveendra I
RI
Seebach
Dieter
D
Krämer
Stefanie D
SD
D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D007477:Ions; D008051:Lipid Bilayers / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D009842:Oligopeptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry*; D010848:Picolinic Acids / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry; D013725:Terbium / Q000737:chemistry
D007477:Ions; D008051:Lipid Bilayers; D008081:Liposomes; D009842:Oligopeptides; D010455:Peptides; D010713:Phosphatidylcholines; D010848:Picolinic Acids; D011506:Proteins; D013725:Terbium; C004860:dipicolinic acid