Locking up G-Quadruplexes with Light-Triggered Staples Leads to Increased Topological, Thermodynamic, and Metabolic Stability
Jack Barr
Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000 Gent, Belgium
These authors contributed equally to this work.
Search for more papers by this authorCorresponding Author
Dr. Enrico Cadoni
Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000 Gent, Belgium
These authors contributed equally to this work.
Search for more papers by this authorDr. Sofie Schellinck
NMR and Structure Analysis Unit, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000 Gent, Belgium
Search for more papers by this authorDr. Emiliano Laudadio
Department of Science and Engineering of Matter, Environment and Urban Planning, Polytechnic University of Marche, Via Brecce Bianche 12, 60131 Ancona, Italy
Search for more papers by this authorProf. Dr. José C. Martins
NMR and Structure Analysis Unit, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000 Gent, Belgium
Search for more papers by this authorCorresponding Author
Prof. Dr. Annemieke Madder
Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000 Gent, Belgium
Search for more papers by this authorJack Barr
Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000 Gent, Belgium
These authors contributed equally to this work.
Search for more papers by this authorCorresponding Author
Dr. Enrico Cadoni
Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000 Gent, Belgium
These authors contributed equally to this work.
Search for more papers by this authorDr. Sofie Schellinck
NMR and Structure Analysis Unit, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000 Gent, Belgium
Search for more papers by this authorDr. Emiliano Laudadio
Department of Science and Engineering of Matter, Environment and Urban Planning, Polytechnic University of Marche, Via Brecce Bianche 12, 60131 Ancona, Italy
Search for more papers by this authorProf. Dr. José C. Martins
NMR and Structure Analysis Unit, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000 Gent, Belgium
Search for more papers by this authorCorresponding Author
Prof. Dr. Annemieke Madder
Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000 Gent, Belgium
Search for more papers by this authorAbstract
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.
Conflict of Interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
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