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Sequence-specific and Selective Recognition of Double-stranded RNAs over Single-stranded RNAs by Chemically Modified Peptide Nucleic Acids
Published on: September 21, 2017
RNA G-quadruplex structure recognition by chimeric peptides
Xi Mou1, Jiuming Wang2, Yanruisheng Shao2
1Department of Chemistry and State Key Laboratory of Marine Environmental Health, City University of Hong Kong, Hong Kong, SAR 999077, China.
Nucleic Acids Research
|July 30, 2026
Summary
Researchers designed chimeric peptides targeting RNA G-quadruplexes (rG4s). These peptides show enhanced binding affinity and selectivity, inhibiting telomerase and gene translation in cells, offering a new strategy for rG4-based therapeutics.
Area of Science:
- Molecular Biology
- Biochemistry
- Drug Discovery
Background:
- G-quadruplexes (G4s) are non-canonical nucleic acid structures implicated in gene regulation.
- Developing selective ligands for G4 structures, particularly RNA G-quadruplexes (rG4s), is crucial for therapeutic applications but remains challenging.
Purpose of the Study:
- To rationally design chimeric peptides combining de novo selected and native peptides for enhanced rG4 targeting.
- To evaluate the binding affinity, selectivity, and functional effects of these chimeric peptides on rG4s.
- To investigate the structural basis for the enhanced binding using molecular dynamics simulations.
Main Methods:
- Rational design and synthesis of chimeric peptides (Pep11-Rhau18).
- Biochemical assays to determine binding affinity and selectivity for rG4s versus DNA G-quadruplexes (dG4s) and non-G4 RNA.
- In vitro telomerase inhibition assays.
- Cell-based reporter gene assays and live-cell imaging to assess functional effects and cellular uptake.
- Molecular dynamics (MD) simulations of peptide-rG4 complexes.
Main Results:
- Chimeric peptides exhibited nanomolar affinity for rG4s, a 10-fold improvement over individual peptide modules.
- The designed peptides demonstrated high selectivity for rG4s over dG4s and non-G4 RNA structures.
- Chimeric peptides effectively inhibited telomerase activity in vitro and suppressed rG4-containing reporter gene translation in living cells.
- MD simulations revealed an enhanced and persistent peptide-rG4 interface, explaining the improved binding.
Conclusions:
- Chimeric peptide design is a viable strategy for creating potent and selective rG4-targeting ligands.
- These novel peptides can modulate G4 structure functions, offering potential therapeutic avenues for diseases involving G4s.
- The findings provide a structural rationale for enhanced binding and pave the way for developing new G4-based therapeutic agents.
