Target-based discovery of a broad-spectrum flukicide. Nat Struct Mol Biol 2024 Sep;31(9):1386-1393
Date
05/08/2024Pubmed ID
38714890DOI
10.1038/s41594-024-01298-3Scopus ID
2-s2.0-85192232257 (requires institutional sign-in at Scopus site) 1 CitationAbstract
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 (TRPMPZQ), in Fasciola species. Here, we identify benzamidoquinazolinone analogs that are active against Fasciola TRPMPZQ. 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 TRPMPZQ orthologs in all profiled species of parasitic fluke. This broad-spectrum activity manifests as BZQ adopts a pose within the binding pocket of TRPMPZQ that is dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPMPZQ 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 JSAuthors
Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinSang Kyu Park PhD Research Scientist I in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAnthelmintics
Drug Discovery
Helminth Proteins
Mice
Models, Molecular
Praziquantel
Schistosoma mansoni
Structure-Activity Relationship
