Metal-linked Nucleic Acids

Antisense therapy presents a promising avenue for future treatment of genetic-based disease. The antisense approach relies upon the binding of a nucleic acid-derived drug to a gene (or mRNA) target in order to prevent expression of the diseased state. Conventional nucleic acids (i.e., DNA and RNA), however, are not ideal drugs owing to poor cellular transport, low affinity for mRNA targets, and digestion by cellular nucleases. In order to address these shortcomings in antisense therapy, we are preparing a new class of nucleic acids in which metal complexes play structural roles. The phosphate of DNA is transformed into various metal-ligand complexes, thereby imparting unique properties to the drug. After reengineering DNA, we study metal-binding and the influences upon DNA duplex stability.

Experiments in progress include the synthesis of new metal-linked nucleic acids and studies on the effects of these modifications to DNA duplex stabilities, both with and without metals present. Biochemical processing, cellular uptake, and preventing expression of target genes are also in progress.