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G-quadruplexes in helminth parasites.

Alessio Cantara1,2, Yu Luo3,4, Michaela Dobrovolná5

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Parasitic helminths harbor unique G-quadruplex (G4) structures. Specific G4-binding molecules show potent activity against Schistosoma mansoni, offering new therapeutic avenues.

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Area of Science:

  • Genomics
  • Parasitology
  • Biochemistry

Background:

  • Parasitic helminths infect billions globally, causing significant human morbidity and economic losses in livestock.
  • Nematodes and Platyhelminths are the primary etiological agents of helminth infections.
  • G-quadruplexes (G4) are unusual nucleic acid structures formed by G-rich sequences, recognized by specific ligands.

Purpose of the Study:

  • To identify and compare potential G4 sequences (PQS) in helminth genomes for potential G4 ligand targets.
  • To investigate the distribution and stability of PQS in helminth genomes.
  • To evaluate the therapeutic potential of G4 ligands against parasitic helminths.

Main Methods:

  • Utilized the G4Hunter Web Tool to identify PQS in nuclear and mitochondrial genomes of various helminths.
  • Experimentally confirmed G4 formation for sequences from four parasitic helminths.
  • Tested small molecules that selectively recognize G4 for binding to Schistosoma mansoni G4 motifs and their activity against parasite stages.

Main Results:

  • PQS were nonrandomly distributed in helminth genomes, often near genes.
  • Ascaris lumbricoides showed an unexpected enrichment of stable PQS, tolerating them unlike most species.
  • G4 formation was experimentally confirmed.
  • G4 ligands bound to Schistosoma mansoni G4 motifs, with two ligands showing potent activity against larval and adult stages.

Conclusions:

  • Helminth genomes contain identifiable G4 structures with potential as drug targets.
  • Ascaris lumbricoides exhibits unique G4 sequence characteristics.
  • G4-binding small molecules demonstrate promising anti-parasitic activity against Schistosoma mansoni, suggesting a novel therapeutic strategy.