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 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 ... More
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 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 orthologs, as well as at other TRPM paralogs in this ion channel family, provides opportunity to expand and improve on the current anthelmintic toolbox.Graphical Abstract
