G-quadruplexes in helminth parasites

Parasitic helminths infecting humans are highly prevalent infecting similar to 2 billion people worldwide, causing inflammatory responses, malnutrition and anemia that are the primary cause of morbidity. In addition, helminth infections of cattle have a significant economic impact on livestock production, milk yield and fertility. The etiological agents of helminth infections are mainly Nematodes (roundworms) and Platyhelminths (flatworms). G-quadruplexes (G4) are unusual nucleic acid structures formed by G-rich sequences that can be recognized by specific G4 ligands. Here we used the G4Hunter Web Tool to identify and compare potential G4 sequences (PQS) in the nuclear and mitochondrial genomes of various helminths to identify G4 ligand targets. PQS are nonrandomly distributed in these genomes and often located in the proximity of genes. Unexpectedly, a Nematode, Ascaris lumbricoides, was found to be highly enriched in stable PQS. This species can tolerate high-stability G4 structures, which are not counter selected at all, in stark contrast to most other species. We experimentally confirmed G4 formation for sequences found in four different parasitic helminths. Small molecules able to selectively recognize G4 were found to bind to Schistosoma mansoni G4 motifs. Two of these ligands demonstrated potent activity both against larval and adult stages of this parasite.

Automated summary

Parasitic helminths infecting humans and cattle have significant impacts on health and livestock production. This study identified and compared G4 sequences in the genomes of various helminths and found that a Nematode species, Ascaris lumbricoides, had a high enrichment of stable G4 structures. Experimental confirmation of G4 formation and the discovery of small molecules that can selectively recognize and bind G4 motifs in a parasitic helminth demonstrate the potential for targeting G4 structures in the treatment of helminth infections.