Structural Optimization of Azacryptands for Targeting Three-Way DNA Junctions.
Fiche publication
Date publication
juin 2024
Journal
Angewandte Chemie (International ed. in English)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MONCHAUD David
Tous les auteurs :
Pipier A, Chetot T, Kalamatianou A, Martin N, Caroff M, Britton S, Chéron N, Trantírek L, Granzhan A, Monchaud D
Lien Pubmed
Résumé
Transient melting of the duplex-DNA (B-DNA) during DNA transactions allows repeated sequences to fold into non-B DNA structures, including DNA junctions and G-quadruplexes. These noncanonical structures can act as impediments to DNA polymerase progression along the duplex, thereby triggering DNA damage and ultimately jeopardizing genomic stability. Their stabilization by ad hoc ligands is currently being explored as a putative anticancer strategy since it might represent an efficient way to inflict toxic DNA damage specifically to rapidly dividing cancer cells. The relevance of this strategy is only emerging for three-way DNA junctions (TWJs) and, to date, no molecule has been recognized as a reference TWJ ligand, featuring both high affinity and selectivity. Herein, we characterize such reference ligands through a combination of in vitro techniques comprising affinity and selectivity assays (competitive FRET-melting and TWJ Screen assays), functional tests (qPCR and Taq stop assays), and structural analyses (molecular dynamics and NMR investigations). We identify novel azacryptands TrisNP-amphi and TrisNP-ana as the most promising ligands, interacting with TWJs with high affinity and selectivity. These ligands represent new molecular tools to investigate the cellular roles of TWJs and explore how they can be exploited in innovative anticancer therapies.
Mots clés
DNA junctions, anticancer strategy, azacryptands, in vitro assays, ligands
Référence
Angew Chem Int Ed Engl. 2024 06 14;:e202409780