DNA G-Quadruplexes as Targets for Natural Product Drug Discovery

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• DNA guanine (G)-quadruplexes (G4s) are unique G-rich secondary structures.
• G4s are crucial in highly transcribed genes, particularly cancer-related oncogenes.
• Targeting oncogene promoter G4s offers a strategy against undruggable proteins like MYC, BCL2, KRAS, and EGFR.

Purpose of the Study:

• To summarize and evaluate recent advancements in natural and nature-derived DNA G4 binders.
• To understand the structural recognition of DNA G4s by natural small molecules.
• To discuss challenges and opportunities in developing G4-targeting drugs.

Main Methods:

• Literature review of natural products targeting DNA G4s.
• Analysis of structural recognition mechanisms between G4s and small molecules.
• Evaluation of identified natural G4 binders and their therapeutic potential.

Main Results:

• Numerous DNA G4s (e.g., MYC-G4, BCL2-G4, KRAS-G4) are targeted by natural products (e.g., berberine, telomestatin).
• Natural products like berberine, telomestatin, quindoline, sanguinarine, and isaindigotone show potential as G4 binders.
• Progress has been made in discovering naturally occurring DNA G4-targeting drugs.

Conclusions:

• Natural products represent a valuable source for developing novel DNA G4-targeting cancer therapeutics.
• Understanding G4-small molecule interactions is key to designing effective drugs.
• Further research into natural G4 binders presents opportunities for overcoming drug resistance.