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Targeting DNA G-quadruplexes with helical small molecules.


Type

Article

Change log

Authors

Müller, Sebastian 
Laxmi-Reddy, Katta 
Jena, Prakrit V 
Baptiste, Benoit 
Dong, Zeyuan 

Abstract

We previously identified quinoline-based oligoamide helical foldamers and a trimeric macrocycle as selective ligands of DNA quadruplexes. Their helical structures might permit targeting of the backbone loops and grooves of G-quadruplexes instead of the G-tetrads. Given the vast array of morphologies G-quadruplex structures can adopt, this might be a way to achieve sequence selective binding. Here, we describe the design and synthesis of molecules based on macrocyclic and helically folded oligoamides. We tested their ability to interact with the human telomeric G-quadruplex and an array of promoter G-quadruplexes by using FRET melting assay and single-molecule FRET. Our results show that they constitute very potent ligands--comparable to the best so far reported. Their modes of interaction differ from those of traditional tetrad binders, thus opening avenues for the development of molecules specific for certain G-quadruplex conformations.

Description

Keywords

DNA structures, FRET, G-quadruplex, foldamers, single-molecule fluorescence, Fluorescence Resonance Energy Transfer, G-Quadruplexes, Ligands, Molecular Structure, Quinolones, Small Molecule Libraries

Journal Title

Chembiochem

Conference Name

Journal ISSN

1439-4227
1439-7633

Volume Title

15

Publisher

Wiley
Sponsorship
We thank the “Cancer Research UK” for doctoral funding (SM) and “Association pour la recherche sur le cancer” for a postdoctoral fellowship (KLR). The Balasubramanian laboratory is core-funded by a programme grant from Cancer Research UK. TH acknowledges the NIH grant GM065367.