Faculty Collaboration Database

The anthelmintic meclonazepam activates a schistosome transient receptor potential channel. J Biol Chem 2024 Jan;300(1):105528

Date

12/04/2023

Pubmed ID

38043794

Pubmed Central ID

PMC10788528

DOI

10.1016/j.jbc.2023.105528

Scopus ID

2-s2.0-85180267343 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms, which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPM_MCLZ, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPM_MCLZ through engagement of a binding pocket within the voltage-sensor-like domain of the ion channel to cause worm paralysis, tissue depolarization, and surface damage. TRPM_MCLZ reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum, which is explained by a polymorphism within this voltage-sensor-like domain-binding pocket. TRPM_MCLZ is distinct from the TRP channel targeted by PZQ (TRPM_PZQ), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPM_MCLZ as a novel druggable target that could circumvent any target-based resistance emerging in response to current mass drug administration campaigns centered on PZQ.

Author List

Park SK, Sprague DJ, Rohr CM, Chulkov EG, Petrow I, Kumar S, Marchant JS

Authors

Evgenii Chulkov Postdoctoral Fellow in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Sang Kyu Park PhD Research Scientist I 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

MESH terms used to index this publication - Major topics in bold

Animals
Anthelmintics
Benzodiazepines
Benzodiazepinones
Clonazepam
Humans
Praziquantel
Schistosoma mansoni
Schistosomiasis mansoni
TRPM Cation Channels