Selective targeting of G-quadruplex using furan-based cyclic homooligopeptides: effect on c-MYC expression

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biophysics

Background:

• G-quadruplex structures are promising targets in cancer therapy.
• Development of selective ligands for G-quadruplexes is crucial for therapeutic applications.

Purpose of the Study:

• To synthesize and characterize novel furan-based cyclic homooligopeptides.
• To evaluate the G-quadruplex binding affinity, selectivity, and biological activity of these ligands.

Main Methods:

• Circular dichroism (CD) spectroscopy and UV melting for structural analysis.
• Isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) for binding kinetics.
• Real-time PCR, luciferase assays, and flow cytometry for biological evaluation.

Main Results:

• Ligands 1 and 2 effectively induced and stabilized G-quadruplex structures in c-MYC DNA.
• High affinity (K ~ 10^7 M^-1) and selectivity for G-quadruplex over duplex DNA were demonstrated.
• Significant downregulation of c-MYC transcripts and protein levels observed.
• Ligand treatment induced apoptosis, evidenced by cell cycle arrest in the sub-G1 stage.

Conclusions:

• The synthesized furan-based cyclic homooligopeptides are potent and selective G-quadruplex binders.
• These molecules represent a promising scaffold for developing novel quadruplex-targeting cancer therapeutics.