Guanine Amine Derivatives Promote Forming a Base-Vacancy-G Quadruplex Structure

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• G-quadruplex (G4) structures play vital roles in biological processes and disease treatment, especially cancer.
• G-vacancy G4 structures, stabilized by guanine or its derivatives, offer therapeutic potential.
• Identifying specific ligands for G4 structures remains a significant challenge in drug development.

Purpose of the Study:

• To investigate the role of guanine derivatives in forming G-vacancy G-quadruplex (G4) structures.
• To evaluate the impact of G-base deficiency on G4 assembly and stabilization.
• To identify specific guanine derivatives that can effectively assist G4 formation in modified sequences.

Main Methods:

• Design and synthesis of EAD2 sequences with one or two missing G bases.
• Circular dichroism (CD) spectroscopy to analyze G4 structure formation and stability.
• Assays using hemin/G4 DNAzyme-catalyzed ABTS to confirm the auxiliary role of guanine derivatives.

Main Results:

• Guanine derivatives showed minimal impact on intact EAD2 sequences but significantly altered single-G-base-deficient sequences.
• G4 formation was challenging in EAD2 sequences lacking two G bases, even with guanine derivative assistance.
• The guanine derivative M2 demonstrated superior auxiliary effects on base-deficient sequences compared to other compounds.
• Hemin/G4 DNAzyme assays confirmed M2's role in promoting G4 formation in G-deficient sequences.

Conclusions:

• G-base deficiency significantly impacts G-quadruplex assembly.
• The guanine derivative M2 effectively facilitates stable G4 formation in G-base-deficient sequences.
• These findings contribute to the development of G4-targeting drugs for therapeutic applications.