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 genus Fasciola. This is due to a single amino acid change within the target of PZQ, a transient receptor potential ion channel (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 damage to the protective tegument of these liver flukes. BZQ also retained activity against Schistosoma mansoni comparable 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.

Single-cell transcriptomics identifies a p21-activated kinase important for survival of the zoonotic parasiteFasciola hepatica

“…We speculate on a role in cell adhesion, as TRPM channels have shown to localize in focal adhesions in humans 69 . Ligands targeting the schistosomal TRPM PZQ (praziquantel) or the Fasciola TRPM PZQ (BZQ) caused tegumental damage 70,71 , which might be related to the destabilization of the attachment of cells to the extracellular matrix, and to the basement membrane in particular.…”

Progress interrogating TRPMPZQ as the target of praziquantel

“…The prospect of identifying novel pharmacological tools for probing the function of TRPM PZQ , as well as for other ion channels within the parasitic flatworm TRPM subfamily [ 71 ] and the broader TRP channel superfamily [ 77 ], will further our understanding of the roles of these sensory ion channels throughout the parasitic lifecycle. This is currently a very exciting time for anthelmintic drug development, with new broad spectrum oxamniquine derivatives [ 78 ], highly potent antischistosomal chemotypes [ 79 ], as well as novel TRPM PZQ activators all recently emerging [ 32 , 49 ]. Hopefully, this will yield exciting advances for treating parasitic flatworm infections within the not-too-distant future.…”

“…Development of novel TRPM PZQ activators is currently a focus of ongoing investigation. One such chemotype—a benzamidoquinazolinone (BZQ)—which potently activated both Sm .TRPM PZQ and Fh .TRPM PZQ was recently identified [ 32 ]. The basis for this dual activation depends on a different binding conformation of BZQ within the TRPM PZQ VSLD binding pocket, such that the variant position on the S1 helix is not important for BZQ binding [ 32 ].…”

“…One such chemotype—a benzamidoquinazolinone (BZQ)—which potently activated both Sm .TRPM PZQ and Fh .TRPM PZQ was recently identified [ 32 ]. The basis for this dual activation depends on a different binding conformation of BZQ within the TRPM PZQ VSLD binding pocket, such that the variant position on the S1 helix is not important for BZQ binding [ 32 ]. BZQ engages the S1 helix through a different interaction, conserved in both Sm .TRPM PZQ and Fh .TRPM PZQ .…”

TRP drop, TRP drop: a steady patter of anti-schistosomal target illumination

“…This binding pocket is formed from the first four transmembrane helices (S1-S4) and the TRP helix of the ion channel, within the voltage-sensor-like domain (VSLD) cavity (Figure 1C). The agonists of both parasitic flatworm TRPM channels retain broadly similar physiochemical properties (size, hydrophobicity, and chemical space) and exploration of their structure-activity relationships has revealed stringent requirements for agonism (Menezes et al, 2012;McCusker et al, 2019;Park et al, 2021;Sprague et al, 2023). These stringent requirements are imposed by architectural determinants of the VSLD binding pocket.…”