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Issue 8, 2020
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In situ formation of transcriptional modulators using non-canonical DNA i-motifs

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Abstract

Non-canonical DNA i-motifs and G-quadruplexes are postulated as genetic switches for the transcriptional regulation of proto-oncogenes. However, in comparison to G-quadruplexes, the therapeutic potential of i-motifs is less explored. The development of i-motif selective ligands by conventional approaches is challenging due to the structural complexity of i-motifs. The target guided synthetic (TGS) approach involving in situ cycloaddition could provide specific ligands for these dynamic DNA structures. Herein, we have used i-motif forming C-rich DNA and their complementary G-quadruplex forming DNA sequences of c-MYC and BCL2 promoter regions as well as a control self-complementary duplex DNA sequence as the templates to generate selective ligands from a pool of reactive azide–alkyne building blocks. In our approach, thiolated DNA targets are immobilized on the surface of gold-coated iron nanoparticles to enable efficient isolation of the newly generated ligands from the solution mixture by simple magnetic decantation. The combinatorial in situ cycloaddition generated cell-membrane permeable triazole leads for respective DNA targets (c-MYC and BCL2 i-motifs and G-quadruplexes) that selectively promote their formation. In vitro cellular studies reveal that the c-MYC i-motif and G-quadruplex leads downregulate c-MYC gene expression whereas the BCL2 i-motif lead upregulates and the BCL2 G-quadruplex lead represses BCL2 gene expression. The TGS strategy using i-motif DNA nanotemplates represents a promising platform for the direct in situ formation of i-motif specific ligands for therapeutic intervention.

Graphical abstract: In situ formation of transcriptional modulators using non-canonical DNA i-motifs

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Supplementary files

Article information


Submitted
04 Sep 2019
Accepted
28 Jan 2020
First published
18 Feb 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 2058-2067
Article type
Edge Article

In situ formation of transcriptional modulators using non-canonical DNA i-motifs

P. Saha, D. Panda, D. Müller, A. Maity, H. Schwalbe and J. Dash, Chem. Sci., 2020, 11, 2058
DOI: 10.1039/D0SC00514B

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