Target-based discovery of a broad spectrum flukicide

Abstract

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 genusFasciola. This is due to a single amino acid change within the target of PZQ, a transient receptor potential ion channel (TRPMPZQ), inFasciolaspecies. Here we identify benzamidoquinazolinone analogs that are active againstFasciolaTRPMPZQ. Structure-activity studies define an optimized ligand (BZQ) that caused protracted paralysis and damage to the protective tegument of these liver flukes. BZQ also retained activity againstSchistosoma mansonicomparable to PZQ and was active against TRPMPZQorthologs in all profiled species of parasitic fluke. This broad spectrum activity was manifest as BZQ adopts a pose within the binding pocket of TRPMPZQdependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPMPZQand a first-in-class, broad spectrum flukicide.