Tetrad-binding ligands do not bind specifically to left-handed G-quadruplexes

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• G-quadruplexes (G4s) are increasingly recognized as promising anticancer targets.
• While right-handed G4s are well-studied, the discovery of left-handed G4s presents new therapeutic avenues.
• Existing ligands often target the structural features of right-handed G4s.

Purpose of the Study:

• To investigate the binding specificity of known right-handed G4 ligands to newly discovered left-handed G4s.
• To elucidate the structural basis for differential ligand binding between right-handed and left-handed G4s.
• To inform the development of novel G4-targeting anticancer agents.

Main Methods:

• Ligand binding assays using Phen-DC3 and RHAU peptide.
• Structural analysis of right-handed and left-handed G-quadruplexes.
• Computational modeling to assess ligand-G4 interactions.

Main Results:

• Ligands specific for right-handed G4s, including Phen-DC3 and RHAU peptide, showed no specific binding to left-handed G4s.
• In right-handed G4s, ligands displaced capping overhangs/loops to stack on terminal tetrads.
• Tight T-capping in left-handed G4s sterically hindered ligand access to the tetrad core.

Conclusions:

• Structural differences, particularly T-capping, dictate ligand specificity for G-quadruplexes.
• Right-handed G4 ligands are not suitable for targeting left-handed G4s.
• Further research is needed to develop ligands that specifically target left-handed G4 structures.