Structural basis for telomeric G-quadruplex targeting by naphthalene diimide ligands

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Human telomeres form G-quadruplex structures at their 3' end, inhibiting telomere maintenance by telomerase.
• Stabilizing these G-quadruplexes with small molecules is a therapeutic strategy against cancer.
• Developing selective ligands for parallel-stranded G-quadruplexes remains challenging due to limited structural data.

Purpose of the Study:

• To employ a structure-based approach for designing high-affinity and selective G-quadruplex-binding ligands.
• To investigate the structural basis for ligand interactions with the human telomeric G-quadruplex.
• To provide a rationale for the observed biological activity of G-quadruplex-targeting compounds.

Main Methods:

• Determined crystal structures of complexes between a human telomeric G-quadruplex and two naphthalene diimide ligands.
• Functionalized ligands with N-methyl-piperazine side-chains to promote parallel-stranded quadruplex topology.
• Analyzed ligand mobility and interactions within the G-quadruplex grooves.

Main Results:

• Two tetra-substituted naphthalene diimide compounds selectively bind to the 3' surface of parallel-stranded human telomeric G-quadruplexes.
• One ligand exhibited reduced mobility and enhanced G-quadruplex stabilization through electrostatic and hydrogen bonding interactions.
• Structural data correlate with biophysical, cellular, and in vivo anti-cancer activity.

Conclusions:

• Structure-based design can yield potent and selective G-quadruplex-binding ligands.
• Ligand-induced stabilization of telomeric G-quadruplexes offers a viable strategy for cancer therapy.
• Further development of small molecules targeting DNA G-quadruplexes holds promise for anti-cancer drug discovery.