Target-based discovery of a broad-spectrum flukicide

Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases-for example, the parasitic blood fluke infection schistosomiasis-are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola because of a single amino acid change within the target of PZQ, a transient receptor potential ion channel in the melastatin family (TRPM_PZQ), in Fasciola species. Here, we identify benzamidoquinazolinone analogs that are active against Fasciola TRPM_PZQ. Structure-activity studies define an optimized ligand (BZQ) that caused protracted paralysis and tegumental damage to these liver flukes. BZQ also retained activity against Schistosoma mansoni comparable to PZQ and was active against TRPM_PZQ orthologs in all profiled species of parasitic fluke. This broad-spectrum activity manifests as BZQ adopts a pose within the binding pocket of TRPM_PZQ that is dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPM_PZQ and a first-in-class, broad-spectrum flukicide.