The Anthelmintic Activity of Praziquantel Analogs Correlates with Structure-Activity Relationships at TRPMPZQ Orthologs

Article Parasitology

Electrophysiological characterization of a schistosome transient receptor potential channel activated by praziquantel

Evgeny G. Chulkov et al.

Summary: Ion channels have been identified as effective targets for anthelmintic chemotherapy, including a recently discovered flatworm ion channel targeted by praziquantel (PZQ) for the treatment of schistosomiasis. This study provides a detailed biophysical characterization of the properties of the PZQ-activated ion channel in various parasitic flatworms, identifying its distinctive features and calcium permeability. The findings contribute to a better understanding of the mechanism of action of PZQ and pave the way for future investigations into the regulation of this novel antiparasitic target.

INTERNATIONAL JOURNAL FOR PARASITOLOGY (2023)

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Article Chemistry, Medicinal

Metabolism of (R)-Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel

Lukas Friedrich et al.

Summary: Praziquantel (PZQ) is an important anthelmintic drug that activates the TRPMPZQ ion channel in trematode worms. Recent findings suggest that the cyclohexyl ring of PZQ is crucial for its activity, as well as its metabolism. In this study, the in vitro and in vivo activities of PZQ analogues with improved metabolic stability were evaluated, along with the contribution of the parent drug and its main metabolite to overall activity in humans.

CHEMMEDCHEM (2023)

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Article Multidisciplinary Sciences

Natural variation in the binding pocket of a parasitic flatworm TRPM channel resolves the basis for praziquantel sensitivity

Claudia M. Rohr et al.

Summary: The drug praziquantel (PZQ) is the key clinical therapy for treating schistosomiasis and other infections caused by parasitic flatworms. A recent study identified a target for PZQ in parasitic flatworms, but little is known about its properties in other flatworms. This study found that the PZQ target is present in all parasitic flatworms and showed different sensitivities to PZQ among different flatworms. The study also identified variations in the binding pocket of the PZQ target, which explains why PZQ is effective against specific infections.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2022)

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Article Cell Biology

Genetic analysis of praziquantel response in schistosome parasites implicates a transient receptor potential channel

Winka Le Clec'h et al.

Summary: Mass drug administration with praziquantel is a key strategy for controlling and eliminating schistosomiasis, but there is variability in parasite response to the drug. A study identified a transient receptor potential channel, Sm.TRPMPZQ, that influences the response of Schistosoma mansoni to praziquantel, providing a potential method for monitoring emerging PZQ-resistant alleles in schistosome elimination programs.

SCIENCE TRANSLATIONAL MEDICINE (2021)

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Article Cell Biology

Mechanism of praziquantel action at a parasitic flatworm ion channel

Sang-Kyu Park et al.

Summary: This study reveals the mechanism of action of PZQ on schistosomes, activating the TRPMPZQ channel to cause calcium entry and worm paralysis. PZQ activates TRPMPZQ homologs in schistosomes, but is ineffective against Fasciola hepatica.

SCIENCE TRANSLATIONAL MEDICINE (2021)

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Article Infectious Diseases

Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel

Evgeny G. Chulkov et al.

Summary: This study optimized a high-throughput screening method for Schistosoma mansoni TRPMPZQ activity, leading to the discovery of a novel activator of Sm.TRPMPZQ and numerous potential blockers. The new activator, though distinct from PZQ, was similar to a known chemical entity identified through phenotypic screening.

PLOS NEGLECTED TROPICAL DISEASES (2021)

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Review Parasitology