Many laboratories in the Department of Pharmacology and Experimental Therapeutics focus their research on studying the action of known drugs and identifying potential targets for new drugs. However, there is also a research component focusing on the design and discovery of new drugs. Traditionally, drug designers have attempted to derive the entire structure of a novel inhibitor from computational experiments and molecular docking. Today, a combination of rational design and optimization by combinatorial chemistry and in vitro selection is more common. The development of some conceptually new drugs, such as antisense and antigene inhibitors of gene expression, is particularly interesting in the context of drug design and optimization. The principal binding mode of these inhibitors via Watson-Crick and Hoogsteen base pairing is known, allowing us to design the nucleobase recognition elements of potential drugs directly from sequence information. The optimization of the affinity for a given nucleic acid target and, perhaps more importantly, the bioavailability of these DNA-based drugs is more difficult to design, however. This has become clear from recent work on analogs of DNA and RNA whose phosphodiester backbone has been replaced with dimethylenesulfone units to render them resistant against degradation by nucleases. This structural replacement by an isosteric group has dramatic effects on the binding properties of oligonucleotides, even though the molecular replacement occurs at a backbone site remote from the nucleobases, which usually dominate the binding properties of DNA and RNA. In fact, short oligonucleotides with dimethylene sulfone groups form non-Watson-Crick duplexes stabilized by an intramolecular hydrogen bonding pattern more characteristic of folded protein structures. New experimental approaches to optimizing the binding properties and biostability of antisense oligonucleotides have been developed over the last three years. These rely on the combinatorial synthesis of small chemical libraries of modified oligonucleotides and non-natural porphyrins and mass spectrometrically monitored selection experiments. Nuclease protection assays, together with binding assays involving target strands immobilized on solid phases have led to the identification of DNA derivatives with novel and therapeutically useful binding properties.

Dr. Clemens Richert's research focuses on using the intrinsic reactivity and molecular recognition properties of known natural biomolecules to construct analogs that fulfill a new, desired biological function. He has applied this concept to porphyrinoids used as sensitizers for photodynamic therapy of tumors and to oligonucleotides under development as antisense inhibitors of gene expression. His area of current interest is to use the combined DNA and peptide structure space to search for new therapeutic agents that bind to DNA or RNA targets in order to inhibit the expression of proteins on the level of the genetic material. This involves synthesis, selection and structural characterization (by multidimensional NMR and molecular dynamics) of hybrids between single stranded DNA and oligopeptides.