Target-Based Design of Praziquantel Analogs at Cestode TRPM_PZQ

The drug praziquantel (PZQ) has been used for decades to treat clinical and veterinary infections caused by parasitic flatworms. Although PZQ is efficacious against many different types of flukes and tapeworms, PZQ activity is lower against certain types of parasites, including pseudophyllidean cestodes. The target of PZQ is a parasitic flatworm transient receptor potential ion channel (TRPM_PZQ), and interrogation of this target affords the opportunity to understand why PZQ efficacy varies between different parasites and how target-based design strategies could help deliver new analogs with improved efficacy against currently hard-to-treat diseases. In this study, we consider natural amino acid variation within cestode TRPM_PZQ binding pockets to design thioamide derivatives of PZQ with greater efficacy at pseudophyllidean cestode TRPM_PZQ. Target-based design across parasite TRPM_PZQ orthologues, as well as at other TRPM paralogues in this ion channel family, provides an opportunity to expand and improve on the current anthelmintic toolbox.