The anthelmintic meclonazepam activates a schistosome transient receptor potential channel
Sang-Kyu Park, Daniel J. Sprague, Claudia M. Rohr, Evgeny G. Chulkov, Ian Petrow, Sushil Kumar, Jonathan S. Marchant
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 VSLD 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 target-based resistance emerging in response to current mass drug administration campaigns centered around PZQ.