Target-based discovery of a broad-spectrum flukicide

Daniel J Sprague; Sang-Kyu Park; Svenja Gramberg; Lisa Bauer; Claudia M Rohr; Evgeny G Chulkov; Emery Smith; Louis Scampavia; Timothy P Spicer; Simone Haeberlein; Jonathan S Marchant

doi:10.1038/s41594-024-01298-3

Target-based discovery of a broad-spectrum flukicide

Nat Struct Mol Biol. 2024 May 7. doi: 10.1038/s41594-024-01298-3. Online ahead of print.

Authors

Affiliations

¹ Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
² Program in Chemical Biology, Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
³ BFS, Institute of Parasitology, Justus Liebig University Giessen, Giessen, Germany.
⁴ The Herbert Wertheim UF Scripps Institute Molecular Screening Center, Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA.
⁵ Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA. JMarchant@mcw.edu.

PMID: 38714890
DOI: 10.1038/s41594-024-01298-3

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 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.