Work

Meclonazepam sensitivity of parasitic flatworms correlates with TRPMMCLZ sensitivity to meclonazepam

Year: 2026

Type: article

Abstract: The ionotropic portfolio of parasitic flatworms affords considerable opportunity for development of new anthelmintics. In this regard, transient receptor potential ion channels (TRP channels), cation channels responsive to various physiochemical cues, have emerged as promising druggable targets. This is based on the recent discovery that two members of a TRP channel subfamily (TRP melastatin or TRPM channels) are selectively activated by the clinical drug praziquantel (TRPM PZQ ), or the anthelmintic benzodiazepine meclonazepam (TRPM MCLZ ). Here, the efficacy of meclonazepam was investigated in a trematode (the liver fluke, Fasciola hepatica ) and a cestode ( Echinococcus multilocularis ) model, in which an observed lack of meclonazepam sensitivity correlated with the lack of efficacy of meclonazepam on TRPM MCLZ in these different parasites. Such correlations support assignment of TRPM MCLZ as the meclonazepam target. Bioinformatic analysis of all available parasitic flatworm genomes allowed prediction of the meclonazepam binding pocket in over sixty different TRPM MCLZ orthologs. Mutagenesis and functional profiling analyses highlighted the importance of a key residue in the S4 transmembrane helix of TRPM MCLZ that impacts meclonazepam potency and efficacy. Variation of this residue and overall binding pocket architecture between different parasitic flatworm TRPM MCLZ orthologs restricts meclonazepam action to a subset of schistosome species. Rohr et al. investigate the engagement of a TRPM channel by a benzodiazepine, meclonazepam. Left , predicted structure of the tetrameric parasite TRPM ion channel, TRPM MCLZ . Transmembrane regions are shown in green, and cytoplasmic regions in orange and red, colored by exon structure. The predicted MCLZ binding site is highlighted (circle). Right , enlargement of predicted binding pose of meclonazepam (magenta), a benzodiazepine, within the transmembrane binding pocket located in the voltage sensing-like domain (VSLD) of TRPM MCLZ viewed from above the membrane. Residue H946, discussed in the manuscript, is shown in blue. • A parasite TRP channel is activated by the anthelmintic benzodiazepine, meclonazepam • Binding pocket variation restricts meclonazepam efficacy against certain parasites • Deciphering key interactions will facilitate the design of new TRP channel ligands

Source: International Journal for Parasitology Drugs and Drug Resistance

DOI: 10.1016/j.ijpddr.2026.100634