Dynamic Generation of G-Quadruplex DNA Ligands by Target-Guided Combinatorial Chemistry on a Magnetic Nanoplatform

Abstract

Dynamic combinatorial chemistry (DCC) has emerged as a promising strategy for template-driven selection of high-affinity ligands for biological targets from equilibrating combinatorial libraries. However, only a few examples using disulphide exchange based DCC are reported for nucleic acid targets. Herein, we have demonstrated that gold-coated magnetic nanoparticle conjugated DNA targets can be used as templates for dynamic selection of ligands from an imine-based combinatorial library. The implementation of dynamic combinatorial chemistry using DNA-nanotemplates enables efficient identification of the lead compounds, from the DCL via magnetic decantation. It further allows quick separation of DNA-nanotemplates for reuse in DCC reactions. The identified lead compound exhibits significant quadruplex-vs.-duplex DNA selectivity and suppresses promoter activity of c-MYC gene that contains G-quadruplex DNA forming sequence in the upstream promoter region. Further cellular experiments indicated that the lead compound is able to permeate into cell nuclei and trigger a DNA-damage response in cancer cells.