the best selectivity. This demonstrates that the conformation
adopted during the interaction is important for the selectivity.
In order to evaluate the site of interaction of these ligands
they were also tested for their affinity toward a fragment of
TAR lacking the bulge (TARab). Our initial hypothesis was
that these compounds should bind preferentially to the junction
between the stem and the bulge, since the nucleobase S is
directed toward the A22ꢁU40 base pair and the amino acid
residues could interact cooperatively with the other bases or
phosphates in proximity (bulge). Interestingly, only compound
3ba retains the activity toward TARab and is non specific.
Compound 3bb is 6 fold more specific and surprisingly, the
mono-Lys derivatives 3ab and 3aa were found to be highly
specific (TAR vs. TARab), demonstrating therefore that their
site of interaction could be the expected stem–bulge junction.
Finally, in order to further elucidate the sites of interactions
of these new RNA ligands we applied the molecular docking
method to TAR RNA in the presence of compounds 3ab and
3bb (see SI for detailed studies). We observed that the TAR
RNA complexed with compounds 3ab or 3bb are more twisted
than without ligand which is in line with the induced fit
effect of TAR RNA. After structural adaptation of the ligand
to the target, the global molecular movements are less loose
than without ligand (3ab and 3bb), thereby evidencing the
TAR–ligand interaction.
introduction of other binding aminoacid and aminosugar
residues not only at the 30- and 50- but also at the 20-position,
with the use of ribose as central scaffold, will allow and guide
the rational design and the discovery of high-affinity and
highly selective ligands for RNAs.
This work was supported by CNRS, University of Nice
Sophia Antipolis, ICSN (Gif-sur-Yvette) and the French
Ministry of Education (PhD fellowship to VM). The authors
thank Professor Jean-Yves Lallemand for his scientific
assistance.
Notes and references
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c
6164 Chem. Commun., 2010, 46, 6162–6164
This journal is The Royal Society of Chemistry 2010