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Exploring the G-Quadruplex Formation of AS1411 Derivatives.

Pedro Lourenço1, David Moreira2, André Miranda2

  • 1RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal.

Molecules (Basel, Switzerland)
|May 7, 2025
PubMed
Summary
This summary is machine-generated.

Modified AS1411 aptamers show reduced polymorphism and enhanced binding to nucleolin (NCL), improving cellular uptake for potential anticancer applications. These G-quadruplex (G4) aptamer derivatives offer a more stable and effective therapeutic option.

Keywords:
AS1411 derivativesDNAG-quadruplexaptamersnucleolin

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Nanotechnology

Background:

  • AS1411 is a G-quadruplex (G4) aptamer targeting cell surface nucleolin (NCL) with demonstrated anticancer activity.
  • The therapeutic potential of AS1411 is limited by its high G4 polymorphism, affecting its preclinical applications.

Purpose of the Study:

  • To design and evaluate AS1411 aptamer derivatives with reduced G4 polymorphism.
  • To assess the impact of structural modifications on G4 formation, stability, NCL binding, and cellular uptake.

Main Methods:

  • Synthesis of six AS1411 derivatives with thymine substitutions and modifications.
  • Biophysical characterization using SEC, CD spectroscopy, and melting experiments.
  • NCL binding affinity assays (K_D values), in silico structural studies, and cellular uptake experiments in lung cancer cells.

Main Results:

  • Modified AS1411 derivatives exhibited decreased G4 polymorphism compared to the parent aptamer.
  • Derivatives lacking thymines at sequence ends and with central core thymine deletions showed enhanced G4 formation and stability.
  • High-affinity NCL binding (10^-9 M range) was observed, particularly for derivatives with central linker thymine modifications.
  • In silico and cellular studies confirmed NCL interaction and superior internalization of specific derivatives.

Conclusions:

  • AS1411 derivatives with optimized thymine modifications offer reduced G4 polymorphism and improved NCL binding and cellular uptake.
  • These findings support the development of modified AS1411 aptamers as more effective anticancer therapeutics.