Copper-Induced Topology Switching and Thrombin Inhibition with Telomeric DNA G-Quadruplexes

Abstract

The topological diversity of DNA G-quadruplexes may play a crucial role in its biological function. Reversible control over a specific folding topology was achieved by the synthesis of a chiral, glycol-based pyridine ligand and its fourfold incorporation into human telomeric DNA by solid-phase synthesis. Square-planar coordination to a Cu^II ion led to the formation of a highly stabilizing intramolecular metal-base tetrad, substituting one G-tetrad in the parent unimolecular G-quadruplex. For the Tetrahymena telomeric repeat, Cu^II -triggered switching from a hybrid-dominated conformer mixture to an antiparallel topology was observed. Cu^II -dependent control over a protein-G-quadruplex interaction was shown for the thrombin-tba pair (tba=thrombin-binding aptamer).

Keywords: G-quadruplexes; bioinorganic chemistry; metal-base pairs; supramolecular chemistry; telomeric DNA.