Dynamic Generation of G-Quadruplex DNA Ligands by Target-Guided Combinatorial Chemistry on a Magnetic Nanoplatform.
Snehasish JanaDeepanjan PandaPuja SahaG Dan PantosJyotirmayee DashPublished in: Journal of medicinal chemistry (2018)
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 disulfide-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 DCC using DNA nanotemplates enables efficient identification of the lead compounds, from the dynamic combinatorial library via magnetic decantation. It further allows quick separation of DNA nanotemplates for reuse in DCC reactions. The identified lead compound exhibits significant quadruplex versus 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.
Keyphrases
- nucleic acid
- circulating tumor
- cell free
- single molecule
- dna damage response
- molecularly imprinted
- gene expression
- healthcare
- signaling pathway
- circulating tumor cells
- photodynamic therapy
- oxidative stress
- high resolution
- dna repair
- drug discovery
- cancer therapy
- wastewater treatment
- copy number
- solid phase extraction
- drug release