Biological Chemistry, Heterocycles, and Biophysics

Nathan Luedtke was born in the United States in 1973, and attended high school near Seattle, Washington. In 1996 he received his bachelor’s degree from the University of Washington where he worked as a teaching assistant for the Department of Chemistry. During his studies at the University of Washington he conducted original research investigating DNA – small molecule interactions with Paul Hopkins (Organic Chemistry), and DNA origins of replication in S. cerevisiae with Walt Fangman (Genetics). Luedtke received his doctoral degree in 2003 from the University of California, San Diego where he studied small molecule – RNA binding interactions in the laboratory of Yitzhak Tor. During his PhD work he received numerous awards for teaching and research, as well as a doctoral fellowship from the State of California to investigate the anti-HIV potential of RNA ligands. From 2003-2006 Nathan worked as an NIH Postdoctoral Fellow in the Laboratory of Alanna Schepartz (Yale University). During this time he investigated a variety of topics at the interface of chemistry and biology, including the application of small fluorescent molecules to study protein folding in living cells. Since October 2006, Nathan has been an Assistant Professor of Organic Chemistry at the University of Zürich where he is investigating the chemistry and biology of DNA.

Research overview:

We use rational design and synthetic organic chemistry to create compounds with interesting physical properties including fluorescence emission, structure-selective DNA binding, and anti-cancer activity. Our current emphasis is on the development of small molecule ligands that bind to and stabilize non-duplex structures like G-quadruplex and i-motif DNA. Molecules that bind to these structures with high affinity and specificity are used to probe their biological function, and may provide new leads for anti-cancer drugs. In addition to the study of non-covalent binding interactions, we are interested in modified oligonucleotides. One such example is the preparation of well-defined DNA-DNA interstrand cross-links (ICLs) that result from anti-cancer therapies utilizing bi-functional alkylating agents. Our approach to this synthetic challenge involves the incorporation of a stable ICL precursor (as a modified base) into duplex DNA, which can be activated for cross-link formation by oxidation or photolysis. We are also developing modified bases to provide new fluorescent probes for DNA structure and dynamics. In addition to synthesis, our lab uses a variety of biophysical, photophysical, and biological techniques to evaluate the properties of each target molecule.
The following projects are currently being investigated in our lab:
♦ Synthesis and evaluation of structure-selective DNA ligands
♦ Kinetics and thermodynamics of non-covalent DNA binding interactions
♦ Regulation of gene transcription by structure-selective DNA ligands
♦ Synthesis of DNA-DNA interstand cross-links in vitro and in living cells
♦ Fluorescent purines to probe DNA folding and stability