Curation of the Fasciola hepatica kinome as a resource for drug target discovery

Fascioliasis is a zoonosis and neglected tropical disease with worldwide distribution and significant economic impact. The search for anthelmintic compounds against Fasciola hepatica, one of the parasitic liver flukes responsible for this disease, has become important due to widespread resistances against existing drugs. To facilitate drug discovery, a useful strategy is the identification of proteins that are vital for the parasite. Protein kinases (PKs) emerged as potential targets in several parasites, given their critical role in many biological processes. To date, knowledge of the PKs present in F. hepatica is fragmentary.

We curated and classified the kinome of F. hepatica using a refined bioinformatics pipeline and found 245 PKs, which represented 2.14% of the parasite's proteome. Classification of all PKs into their families and sub-families revealed the CMGC group as the largest PK group. A comparison of the kinomes of F. hepatica with medically important Schistosoma species and the human host revealed key similarities and differences. Based on orthology to human sequences, KEGG functional annotation predicted that 25% of 110 annotated PKs in F. hepatica are involved in cancer pathways. We prioritized a panel of related, small-molecule PK inhibitors to assess their efficacy against different F. hepatica life stages in vitro. Among these, vandetanib and ruboxistaurin showed lethal effects on immature flukes in vitro at 50 µM concentration, and ruboxistaurin significantly reduced the motility of adult liver flukes.

These findings suggest that repurposing small-molecule PK inhibitors could be a good strategy for obtaining compounds to combat fascioliasis. The newly established F. hepatica kinome represents a resource for future target discovery.