Biomedical Engineering Reference
In-Depth Information
Despite controversial studies regarding the capacity of CPPs to penetrate
through lipid bilayers or liposomal membranes (direct translocation), the initial
contact with the cell membrane constitutes an important stage in the internalization
process and has been investigated in depth. This initial interaction might be impor-
tant just to increase the local peptide concentration in the surface before its uptake
by either direct translocation (eventually leading to a deeper peptide penetration
and lipid reorganization) or endocytosis.
Following the initial contact of CPPs with the cell membrane surface mainly
driven by electrostatic interactions and the increase in the local peptide concentra-
tion, both peptide and lipid reorganization take place to allow peptide uptake by
either endocytosis or direct translocation. The mode of action of the peptide in
terms of lipid reorganization is dictated both by the CPP structure and the lipid
composition of cellular or model systems. Taking into account the different peptide
sequences, CPPs have been classified in three major classes:
1. Primary amphipathic such as transportan (Pooga et al. 1998), Pep-1 (Morris
et al.
2001
), they comprise sequentially hydrophobic and cationic domains and
contain more than 20 amino acids, long enough to span the bilayer. They bind
with strong affinities to both zwitterionic and anionic lipids suggesting that
membrane interaction is dominated by hydrophobic interaction (Magzoub et al.
2001
). They penetrate deeper than other CPPs in the membrane but without
spanning the bilayer (Deshayes et al.
2004
), the insertion is often accompanied
by a secondary structure change. They have a tendency to self associate in the
headgroup region. They often have antimicrobial activity and are rather difficult
to distinguish from antimicrobial peptides as they can greatly perturb bilayer
integrity, although less than AMP because they are less deeply inserted.
2. Secondary amphipathic such as penetratin (Derossi et al.
1996
), KLAL (Dathe
et al.
1996
) and RL16 (Lamaziere et al.
2007
), are shorter and display amphipathic
property (evident when their amino acid sequence is depicted on a helical wheel)
only through a change in their secondary structure upon lipid or HSPG contact.
They possess poor affinity to neutral membranes, and their affinity is highly
enhanced when anionic lipids are present due not only to electrostatic interaction
but to a change in the peptide secondary structure (Binder and Lindblom
2003
;
Wieprecht et al.
2002
). Despite the formation of an amphipathic structure by these
peptides, the insertion in the bilayer is not marked and no membrane perturbation
is usually observed at low anionic lipid content. Their binding leads to a change in
the polar lipid headgroup orientation (Kichler et al.
2006
; Roux et al.
1989
). For
tryptophan-containing cell-penetrating peptides, as examplified by pAntp ana-
logues, in-cell studies support the hypothesis that hydrophobic interactions anchor
those peptides in the membrane and might help their translocation into the cytosol
(Le Roux et al.
1993
; Fischer et al.
2002
; Christiaens et al.
2004
)
3. Non-amphipathic are generally shorter and comprise almost exclusively cationic
amino acids such as R9. They do not bind lipid membranes unless they contain
a high fraction of anionic phospholipids. Contrarily to amphipathic CPPs, direct
translocation is not observed at low micromolar concentrations and at low
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