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Switching G-quadruplex to parallel duplex by molecular rotor clustering.

Qiuda Xu1, Mujing Yang1, Yun Chang1

  • 1Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, 321004, China.

Nucleic Acids Research
|September 21, 2022
PubMed
Summary

Researchers achieved G-quadruplex (G4) switching to parallel-stranded duplexes using molecular rotor clustering. This novel method overcomes G4 stability in physiological potassium conditions, enabling new therapeutic strategies.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genomics

Background:

  • G-quadruplex (G4) structures are crucial for genomic regulation and nucleic acid-based applications.
  • Targeting G4s with ligands shows therapeutic potential, but switching G4s in physiological conditions remains challenging.
  • Existing methods for G4 conversion are limited, especially in potassium-rich environments.

Purpose of the Study:

  • To investigate a novel method for switching G-quadruplex structures to non-G4 folding in physiological potassium conditions.
  • To overcome the stability barrier of G4s in the presence of potassium ions.
  • To explore the potential of multimolecular ligand binding for G4 structural transitions.

Main Methods:

  • Utilized molecular rotors (Thioflavin T, Thiazole Orange) as initiators for multimolecular ligand binding.
  • Applied ligand clustering to induce G4 switching in purine-rich sequences, including the KRAS promoter region.
  • Investigated the conversion of G4 structures into dimeric parallel-stranded duplexes (psDNAs).

Main Results:

  • Successfully demonstrated G4 switching to psDNAs via molecular rotor-initiated ligand clustering in potassium solution.
  • The formed psDNAs exhibited enhanced stability compared to the original G4 structures.
  • Ligand clustering on psDNAs created multiple binding sites, stabilizing the new structure.

Conclusions:

  • Multimolecular ligand binding, or ligand clustering, can effectively overcome the G4 switching barrier in physiological potassium conditions.
  • This finding offers a new strategy for designing ligands capable of inducing efficient G4 structural switching.
  • The developed method holds promise for advancing nucleic acid-based constructs and therapeutic applications targeting G4s.