Chemistry Reference
In-Depth Information
DNA cleavage.
39c
DNA-binding experiments of the peptide-functionalized cylinders
indicated that the Fe(II) cylinder retained its ability to coil DNA, albeit to less
extent compared to the unsubstituted analogue, whereas the Cu(I) cylinder cleaved
DNA, with a tendency for double-stranded cleavage.
37
Apparently, this is a promis-
ing strategy for the construction of sequence-specifi c major - groove - binding mole-
cules by attaching peptides able to confer sequence-specifi city upon DNA binding.
12.2.3
Bioactive Peptides
J. Brunner and J.K. Barton have addressed the problem of insuffi cient cellular
uptake of drugs by attaching a cell-penetrating peptide onto the bpy (2,2
-
bipyridine) ligand of the rhodium intercalator [Rh(chrysi)(phen)(bpy)]
3+
(chrysi = chrysenequinone diimine, phen = 1,10 - phenanthroline).
40
D - octaarginine, a
well-known cell-penetrating peptide for delivery to the nucleus,
41
was appended to
the rhodium complex. Rhodium intercalators bearing the sterically demanding
ligand chrysi bind preferentially to single-base mismatched sites and, upon photoac-
tivation, the complexes furthermore promote strand breakage neighbouring the
mismatched site.
42
The presence of the oligoarginines was found to increase the
nonspecifi c binding affi nity (at least two orders of magnitude) of the complexes for
both matched and mismatched DNA, while photocleavage remained selective for
the mismatched site. Confocal microscopy experiments confi rmed the nuclear locali-
zation of the metal-peptide conjugates demonstrating that the delivery properties
of the appended cell-penetrating peptide are not affected by the presence of the
bulky octahedral metal complex.
′
12.2.4
De novo
Designed Peptides
The variety of the different amino acid side chain functionalities offers a great tool
in designing peptides of diverse composition in order to elucidate peptide-DNA
interactions. K.D. Copeland
et al.
used metallointercalator-peptide conjugates as a
model system for studying DNA-protein crosslinking.
43
The ruthenium intercalator,
[Ru - (phen)(bpy
)(dppz)]
2+
(bpy
- bipyridine), binds
with high affi nity to DNA and initiates crosslinking through a fl ash - quench reaction.
Pentamer peptides were designed in order to be long enough to allow interactions
between the peptide and DNA, even when the dppz ligand is intercalated into the
base stack, and short enough to remain unstructured. An Ala was added at the N-
termini intended as a fl exible spacer, and a Gly at the C-termini simplifi ed synthesis
and was intended to adsorb end effects. Finally, the three central residues were
varied. Two types of peptides were considered: peptides with positively charged
residues (Lys or Arg) at positions 2 and 4 and peptides with aliphatic residues (Ala
and Gly) at positions 2 and 4. The outcome of this study was that the peptide com-
position does impact binding and crosslinking. The conjugates bearing lysine resi-
dues generally showed greater affi nity for DNA. Furthermore, the Lys-X-Lys or
Arg-X-Arg peptides gave the highest levels of crosslinking. This difference in
crosslinking activity may be attributed to increased interaction between the DNA
′
′
= 4 - (butyric acid) - 4
′
- methyl - 2,2
′
