Targeting human telomeric higher-order DNA: dimeric G-quadruplex units serve as preferred binding site

Area of Science:

• Biochemistry
• Chemical Biology
• Structural Biology

Background:

• Long human telomeric fragments form higher-order G-quadruplex structures, recognized as potential therapeutic targets.
• Ligand binding to higher-order G-quadruplexes is scarce, with existing ligands targeting the cleft between structures.

Purpose of the Study:

• To investigate the binding preferences of zinc-finger-like chiral supramolecular complexes with G-quadruplexes.
• To develop ligands with high selectivity for higher-order G-quadruplexes over single G-quadruplexes.

Main Methods:

• Synthesis of nanosized chiral supramolecular complexes.
• Analysis of ligand binding to single and higher-order G-quadruplex structures.
• Determination of binding selectivity using biophysical techniques.

Main Results:

• Chiral supramolecular complexes exhibit approximately 200-fold higher selectivity for higher-order G-quadruplexes compared to single G-quadruplexes.
• This represents the first reported ligand capable of distinguishing higher-order G-quadruplexes from single ones with such high selectivity.
• The complex binds to two G-quadruplex units directly, not in the cleft between them.

Conclusions:

• Nanosized chiral supramolecular complexes offer a novel approach for selective targeting of higher-order G-quadruplexes.
• Dimeric G-quadruplex units can serve as preferred binding sites for specific ligands.
• These findings provide new insights into the development of ligands for higher-order G-quadruplex drug targets.