Dynamic generation of G-quadruplex DNA ligands by target-guided combinatorial chemistry on a magnetic nanoplatform

Snehasish Jana, Deepanjan Panda, Puja Saha, Dan Pantos, Jyotirmaee Dash

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 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.
Original languageEnglish
Pages (from-to)762-773
Number of pages12
JournalJournal of Medicinal Chemistry
Volume62
Issue number2
Early online date11 Dec 2018
DOIs
Publication statusPublished - 24 Jan 2019

Cite this