Targeting DNA G-quadruplexes with helical small molecules.

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biophysical Chemistry

Background:

• DNA quadruplexes, particularly G-quadruplexes, are increasingly recognized as therapeutic targets.
• Existing ligands often target the G-tetrad core, limiting specificity due to diverse G-quadruplex structures.
• Helical foldamers and macrocycles offer alternative binding modes, potentially targeting loops and grooves.

Purpose of the Study:

• To design and synthesize novel quinoline-based oligoamide helical foldamers and macrocycles.
• To evaluate the binding affinity and selectivity of these compounds for various G-quadruplex DNA structures.
• To investigate the interaction mechanisms of these ligands with G-quadruplexes.

Main Methods:

• Chemical synthesis of macrocyclic and helically folded oligoamide ligands.
• Förster Resonance Energy Transfer (FRET) melting assays to assess binding.
• Single-molecule FRET to study interaction dynamics and mechanisms.

Main Results:

• The synthesized molecules demonstrated potent ligand activity against human telomeric and promoter G-quadruplexes.
• Binding potency was comparable to the most effective G-quadruplex ligands reported to date.
• Ligand-G-quadruplex interactions occurred via novel mechanisms distinct from traditional G-tetrad binders.

Conclusions:

• Macrocyclic and helical oligoamides are highly effective G-quadruplex ligands.
• These ligands interact with G-quadruplexes through unique modes, targeting structures beyond the G-tetrads.
• This work opens new possibilities for developing conformation-specific G-quadruplex-targeting drugs.