Drug repurposing of farnesyltransferase inhibitors as novel anthelmintics for the treatment of larval cestodiases

Introduction: Larval cestodiases are caused by parasitic helminths of the class Cestoda, whose metacestode larvae infect host tissues and cause neglected diseases such as echinococcosis and cysticercosis. Current treatments are limited because available drugs are mainly parasitostatic and require prolonged administration at high doses, often causing severe side effects. In this context, drug repurposing represents a promising strategy for the development of more effective anthelmintics. The mevalonate pathway, essential for isoprenoid synthesis in eukaryotes, is conserved in cestodes, except for the cholesterol biosynthesis branch. Within this pathway, farnesyltransferase (FTase) emerges as a potential therapeutic drug. Objectives: This study evaluated the potential of the FTase inhibitors Tipifarnib and Lonafarnib for the treatment of larval cestodiases against the model cestode Mesocestoides corti. Methods: amino acid sequences of FTase α and β subunits from parasitic helminths and their hosts were identified and used for phylogenetic analyses. Ab initio 3D models of M. corti FTase subunits were generated, followed by molecular docking analyses with Tipifarnib. In addition, in vitro assays with M. corti larvae were performed to evaluate anthelmintic activity. Results: FTase α and β subunit sequences from 53 helminth species and their hosts were recovered. The β subunit showed greater structural conservation. Structural modeling of M. corti FTase revealed high similarity to the human enzyme. Molecular docking analyses indicated that Tipifarnib binds to catalytic site of FTase, potentially blocking substrate access. In vitro assays demonstrated strong anthelmintic activity. Lonafarnib induced morphological damage in parasites within 24 h, whereas Tipifarnib caused complete parasite mortality within 48 h. Conclusions: These findings support FTase as a promising target for the repurposing of its inhibitors as novel anthelmintic agents. Future studies exposing parasites to Tipifarnib and Lonafarnib will be conducted to generate samples for proteomic analyses and to further investigate their mechanisms of action.