Phen‐DC 3 Induces Refolding of Human Telomeric DNA into a Chair‐Type Antiparallel G‐Quadruplex through Ligand Intercalation

Anirban Ghosh (1) , Marko Trajkovski (2, 3) , Marie‐paule Teulade-Fichou (4) , Valérie Gabelica (1, 5) , Janez Plavec (2, 3, 6, 7)

1 ARNA - Acides Nucléiques : Régulations Naturelle et Artificielle
2 Slovenian NMR Centre
3 KI - National Institute of Chemistry [Llubljana]
4 CMBC - Chimie et modélisation pour la biologie du cancer
5 IECB - Institut Européen de Chimie et Biologie
6 University of Ljubljana
7 Centre of Excelence EN-FIST [Ljubljana]

Human telomeric G-quadruplex DNA structures are attractive anticancer drug targets, but the target’s polymorphism complicates the drug design: different ligands prefer different folds, and very few complexes have been solved at high resolution. Here we report that Phen-DC3, one of the most prominent G-quadruplex ligands in terms of high binding affinity and selectivity, causes dTAGGG(TTAGGG)3 to completely change its fold in KCl solution from a hybrid-1 to an antiparallel chair-type structure, wherein the ligand intercalates between a two-quartet unit and a pseudo-quartet, thereby ejecting one potassium ion. This unprecedented high-resolution NMR structure shows for the first time a true ligand intercalation into an intramolecular G-quadruplex.

Domaines: Chimie; Biologie structurale [q-bio.BM]

Anirban Ghosh, Marko Trajkovski, Marie‐paule Teulade-Fichou, Valérie Gabelica, Janez Plavec. Phen‐DC 3 Induces Refolding of Human Telomeric DNA into a Chair‐Type Antiparallel G‐Quadruplex through Ligand Intercalation. Angewandte Chemie International Edition, 2022, 61 (40), pp.e202207384. ⟨10.1002/anie.202207384⟩. ⟨hal-04119339⟩