Biomedical Engineering Reference
In-Depth Information
Therefore, there is no clear relationship between the structure these peptides
might adopt in solution or in contact with biological membranes and their ability to
enter cells.
3
Binding of Cell-Penetrating Peptides to Membrane
Components
3.1
Role of Proteoglycans
In the majority of cases, and independently of the internalization pathway of the
CPP, the initial contact involves interactions between the CPP and cell-surface
proteoglycans (PGs). Using model systems, the role of heparan sulphate proteogly-
cans (HSPGs) in CPP uptake has been investigated using isothermal titration calo-
rimetry (ITC; Ziegler and Seelig
2004
; Goncalves et al.
2005
), plasmon resonance
methods (Duchardt et al.
2009
; Ram et al.
2008
), ESR spectroscopy (Ghibaudi
et al.
2005
), and affinity chromatography (Fuchs and Raines
2004
). Such studies
point to considerably tight binding of CPPs to HSPGs such as heparan sulphates
(HS), heparin and chondroitin sulfate B (CS) with dissociation constants in the low
micromolar range. A higher affinity was observed for these HSPGs when compar-
ing to anionic lipids. Although, the primary interaction between CPPs and HSPGs
was considered to be electrostatic, it is also likely that hydrogen bonding occurs,
taking into account the ability of the guanidium group (arginines are often present
in CPPs) to form hydrogen bonds with sulfate and carboxylate groups.
3.2
Lipids
Taking into account the nature of CPPs, both electrostatic interactions between the
positively charged amino acids and the lipid headgroups, and hydrophobic interac-
tions between residues such as tryptophan and the lipid fatty acid region are pos-
sible. A strong electrostatic interaction can be established between the peptides and
the lipids due to the large entropy gain that results from the release of counterions
both at the level of the membrane (the Gouy-Chapman layer) (Zimm and Le Bret
1983
) and the peptide (the Manning layer) (Manning 1969). Negative charges in the
lipid can arise from the lipid headgroup itself in case of anionic lipids (phosphati-
dylglycerol, phosphatidylserine and phosphatidic acid) or from the phosphatidic
groups of the fatty acids, which can establish strong ionic interactions with guanid-
ium groups, often present in CPPs (Nakase et al.
2008
). Even if the majority of
the lipids present in the outer layer of eukaryotic cells are zwitterionic, anionic
lipids are also present and their role may become relevant when they cluster in
small domains, a process that is induced by CPPs and antimicrobial peptides
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