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

Abstract

Praziquantel (PZQ) is an essential anthelmintic drug recently established to be an activator of a Transient Receptor Potential Melastatin (TRPMPZQ) ion channel in trematode worms. Bioinformatic, mutagenesis and drug metabolism work indicate that the cyclohexyl ring of PZQ is a key pharmacophore for activation of trematode TRPMPZQ, as well as serving as the primary site of oxidative metabolism which results in PZQ being a short‐lived drug. Based on our recent findings, the hydrophobic cleft in schistosome TRPMPZQ defined by three hydrophobic residues surrounding the cyclohexyl ring has little tolerance for polarity. Here we evaluate the in vitro and in vivo activities of PZQ analogues with improved metabolic stability relative to the challenge of maintaining activity on the channel. Finally, an estimation of the respective contribution to the overall activity of both the parent and the main metabolite of PZQ in humans is reported.

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

“…1 This increased tolerability to modifications of the cyclohexyl group of PZQ, a key part of the pharmacophore at Sm.TRPM PZQ , 7 may provide opportunity to accommodate other cyclohexane ring modifications�notably, more metabolically stable PZQ derivatives�within the cestode TRPM PZQ binding pocket. 15,16 This could potentially enhance the in vivo efficacy of these analogs for treating cestode infections, and these data therefore highlight an opportunity to design drugs that selectively target cestode TRPM PZQ . Whether the absolute potency of such analogs can be further improved over PZQ to yield better treatments for cestode species less sensitive to PZQ (e.g., noncyclophyllidean cestodes 10,17 ) or for cestode life cycle stages that are hard to treat will require further work and a better understanding of the molecular basis by which cestode-selective analogs engage the TRPM PZQ binding pocket.…”

Progress interrogating TRPMPZQ as the target of praziquantel

“…However, opportunities for improvement certainly remain. These include optimization of formulations or derivatives that address the low oral bioavailability and rapid host metabolism of PZQ [ 7 , 8 ], as well as mitigation of other challenges (for example, bitter taste [ 9 ]) that result in poor compliance in the field [ 10 ]. Further opportunities relate to the lower efficacy of PZQ against certain parasites and life cycle stages—most clearly exemplified by the lack of PZQ activity against Fasciola species as well as the poor effectiveness of PZQ against juvenile schistosomes.…”