DNA, being of central importance in biological systems, constitutes a primary target for our studies. Core experimental methodologies of our group include the use of structural and biophysical state-of-the-art instrumentation for UV-VIS absorption spectroscopy, circular dichroism, fluorescence spectroscopy, microcalorimetry (ITC) and biomolecular NMR spectroscopy.
A 600 MHz NMR spectrometer for
high-resolution structural analysis
including a
quadruple-resonance cryoprobe
is solely dedicated
to the group’s research activities. It is specially
equipped with low-temperature devices to enable NMR
measurements at temperatures as low as 103 K appropriate
for the detailed characterization of hydrogen bonds in
small model systems under slow exchange conditions. In
addition, lab and computer equipment for synthetic
chemistry and molecular modeling work complement
available facilities.
Drug interactions
with duplex DNA.
Many antibiotics bind covalently or non-covalently
to double-stranded DNA, thereby artificially
altering or inhibiting the natural flow of genetic
information. To be used as efficient therapeutics or
diagnostics, DNA binding ligands should not only
possess high affinity toward the nucleic acid but
also exhibit a high sequence selectivity that
enables the specific manipulation of predefined
stretches of DNA.
We are engaged in the design,
development and characterization of DNA-binding
ligands that interact with a double helix through
intercalation and insertion into its major or minor
groove.
Ongoing research projects
involve the study of hybrid ligands that are
composed of various covalently linked DNA binding
motifs to achieve a more selective and effective
recognition. Drug binding is examined in both
thermodynamic and structural terms to gain a
comprehensive understanding of the forces that
govern binding, a prerequisite for rational drug
design and for further drug optimization.
Formation of triple-helical DNA.
Whereas most natural and synthetic low
molecular weight antibiotics bind to DNA
through its minor groove or through
intercalation between base pairs, a
single-stranded oligonucleotide may
selectively bind a duplex through
interactions in its major groove by
forming a triple helix.
Research efforts aim
to expand the restricted recognition code
and to enhance stabilities under
physiological conditions for such triple-helical complexes by introducing
modifications in the triplex-forming
oligonucleotide.
In particular, current projects
involve the development of triplex
binding ligands that
selectively stabilize triple- helical
structures in either their free form
or when conjugated to the triplex-forming oligonucleotide and that may
also serve as potential fluorescent
probes for the detection of triple
helical structures.
G-Quadruplexes
as targets for drug design.
Quadruplexes have been shown to form from G-rich DNA
sequences and consist of four-stranded nucleic acid
structures in which guanine bases form stacked
planar tetrads stabilized by hydrogen bonding and
cation coordination. Due to their putative presence
in pivotal genomic regions such as telomeres and
promoters of oncogenes, quadruplex binding compounds
have attracted significant interest as
therapeutically active agents, e.g. by interfering
with telomerase function.
We are currently involved
in the study of quadruplex structures and in the design of quadruplex-selective ligands.
The latter are assessed with respect to their
affinity, selectivity toward different quadruplex
topologies and their mode of binding.
