Locking up G-Quadruplexes with Light-Triggered Staples Leads to Increased Topological, Thermodynamic, and Metabolic Stability.

Autor: Barr J; Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000, Gent, Belgium., Cadoni E; Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000, Gent, Belgium., Schellinck S; NMR and Structure Analysis Unit, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000, Gent, Belgium., Laudadio E; Department of Science and Engineering of Matter, Environment and Urban Planning, Polytechnic University of Marche, Via Brecce Bianche 12, 60131, Ancona, Italy., Martins JC; NMR and Structure Analysis Unit, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000, Gent, Belgium., Madder A; Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000, Gent, Belgium.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Nov 25, pp. e202420592. Date of Electronic Publication: 2024 Nov 25.
DOI: 10.1002/anie.202420592
Abstrakt: G-quadruplexes (G4 s) are secondary, tetraplexed DNA structures abundant in non-coding regions of the genome, implicated in gene transcription processes and currently firmly recognised as important potential therapeutic targets. Given their affinity for human proteins, G4 structures are investigated as potential decoys and aptamers. However, G4 s tend to adopt different conformations depending on the exact environmental conditions, and often only one displays the specifically desired biological activity. Their less intensively studied counterparts, the elusive tetraplexed intercalated-motifs (IMs) are typically unstable at neutral pH, hampering the investigation of their potential involvement in a biological context. We herein report on a photochemical method for "stapling" such tetraplexed-structures, to increase their stability, lock their topology and enhance their enzymatic resistance, while maintaining biological activity. The chemical structure and topology of the stapled Thrombin Binding Aptamer (TBA) was spectroscopically characterised and rationalised in silico. The method was then extended to other biologically relevant G4- and IM-prone sequences, hinting towards potential application of such stapled structures in a therapeutic context.
(© 2024 Wiley-VCH GmbH.)
Databáze: MEDLINE
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