Faculty Collaboration Database

Target-based discovery of a broad spectrum flukicide. bioRxiv 2023 Sep 22

Date

10/04/2023

Pubmed ID

37790347

Pubmed Central ID

PMC10542552

DOI

10.1101/2023.09.22.559026

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 genus Fasciola. This is due to a single amino acid change within the target of PZQ, a transient receptor potential ion channel (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 damage to the protective tegument of 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 was manifest as BZQ adopts a pose within the binding pocket of TRPM_PZQ 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.

Author List

Sprague DJ, Park SK, Gramberg S, Bauer L, Rohr CM, Chulkov EG, Smith E, Scampavia L, Spicer TP, Haeberlein S, Marchant JS

Authors

Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Daniel J. Sprague PhD Postdoctoral Fellow in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin