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236 Cell-Penetrating Peptides: Processes and Applications
TABLE 10.2
Sequences of Selected Membrane-Active Peptides
Name Sequence Translocation Lytic/Pore
Melittin GIGAVLKVLTTGLPALISWIKRKRQQ-NH 2 yes yes 33
Magainin 2 GIGKFLHSAKKFGKAFVGEIMNS yes yes 47,48
Mastoparan X INWKGIAAMAKKLL-NH 2 yes yes 47
Buforin 2 TRSSRAGLQWPVGRVHRLLRK yes no 54
Note: Positively charged residues are underlined.
Among the other CPPs included in Table 10.1, the Tat peptide had been discussed
in terms of an amphipathic α-helix, 46 whereas two NLS-chimera seem to adopt βstructures
with phospholipid vesicles, irrespective of the surface charge. 12,13
10.7 POSSIBLE EFFECTS OF PEPTIDES ON MEMBRANES:
COMPARISON WITH OTHER TYPES
OF MEMBRANE-INTERACTING PEPTIDES
There is a vast amount of literature on membrane interactions and membrane effects
by bioactive peptides. Biological effects have been compared with studies of interactions
and structures in membrane model systems. In contrast to the more hydrophobic
peptides, sometimes of an integral type, the highly amphipathic and watersoluble
small peptides are more unpredictable in their biophysical behavior. Here
we will only mention a few examples of the latter type of peptide and discuss various
biological and physico-chemical effects defined for some peptides that may be
relevant for understanding CPPs. We have selected the antimicrobial peptides, a
widespread and much studied class of peptides. 47-51
Antimicrobial and toxic peptides from various sources, exemplified by magainin
(frog skin), melittin (bee venom), and mastoparan X (wasp venom), are examples
of pore-forming peptides which, under certain conditions, cause the cell membrane
to disrupt and lead to lysis of the cell. The sequences and a summary of their
characteristic effects on biological membranes are shown in Table 10.2.
The overall view is that these peptides exert their cytotoxicity by permeabilizing
cell membranes. The positively charged peptides are particularly toxic to bacterial
membranes, which are negatively charged overall. A transmembrane potential (negative
inside) has been found to increase the ability of peptides to induce cell lysis. The exterior
side of the plasma membrane of mammalian cells is more neutral in charge (zwitterionic)
and hence should have a lower affinity for the peptide. This is generally given as
an explanation for the lower biological activity with mammalian cells as compared to
bacterial cells, and thus the selective toxicity and the rescue of the host cells.
Amphiphaticity and aggregational states have been much discussed for the
antimicrobial peptides, mostly in terms of (helical) secondary structures and membrane
topology. The mechanisms of action have been suggested to include dynamic