General aspects of peptide selectivity towards lipid bilayers and cell membranes studied by variation of the structural parameters of amphipathic helical model peptides.
Model compounds of modified hydrophobicity (Eta), hydrophobic moment (mu) and angle subtended by charged residues (Phi) were synthesized to define the general roles of structural motifs of cationic helical peptides for membrane activity and selectivity. The peptide sets were based on a highly hydrophobic, non-selective KLA model peptide with high antimicrobial and hemolytic activity. Variation of the investigated parameters was found to be a suitable method for modifying peptide selectivity towards either neutral or highly negatively charged lipid bilayers. Eta and mu influenced selectivity preferentially via modification of activity on 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) bilayers, while the size of the polar/hydrophobic angle affected the activity against 1-palmitoyl-2-oleoylphosphatidyl-DL-glycerol (POPG). The influence of the parameters on the activity determining step was modest in both lipid systems and the activity profiles were the result of the parameters' influence on the second less pronounced permeabilization step. Thus, the activity towards POPC vesicles was determined by the high permeabilizing efficiency, however, changes in the structural parameters preferentially influenced the relatively moderate affinity. In contrast, intensive peptide accumulation via electrostatic interactions was sufficient for the destabilization of highly negatively charged POPG lipid membranes, but changes in the activity profile, as revealed by the modification of Phi, seem to be preferentially caused by variation of the low permeabilizing efficiency. The parameters proved very effective also in modifying antimicrobial and hemolytic activity. However, their influence on cell selectivity was limited. A threshold value of hydrophobicity seems to exist which restricted the activity modifying potential of mu and Phi on both lipid bilayers and cell membranes.
Dathe
Margitta
M
Research Institute of Molecular Pharmacology, Berlin, Germany. dathe@fmp-berlin.de
Meyer
Jana
J
Beyermann
Michael
M
Maul
Björn
B
Hoischen
Christian
C
Bienert
Michael
M
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D005452:Fluoresceins; D005456:Fluorescent Dyes; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D011485:Protein Binding; D055672:Static Electricity; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D005452:Fluoresceins; D005456:Fluorescent Dyes; D008051:Lipid Bilayers; D010455:Peptides; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; C028694:1-palmitoyl-2-oleoylphosphatidylcholine; C007740:fluorexon