Abstract
The anthelmintic drug praziquantel (PZQ) is used to treat schistosomiasis, a neglected tropical disease that affects over 200 million people worldwide. PZQ causes Ca2+ influx and spastic paralysis of adult worms and rapid vacuolization of the worm surface. However, the mechanism of action of PZQ remains unknown even after 40 years of clinical use. Here, we demonstrate that PZQ activates a schistosome transient receptor potential (TRP) channel, christened Sm.TRPMPZQ, present in parasitic schistosomes and other PZQ-sensitive parasites. Several properties of Sm.TRPMPZQ were consistent with known effects of PZQ on schistosomes, including (i) nanomolar sensitivity to PZQ; (ii) stereoselectivity toward (R)-PZQ; (iii) mediation of sustained Ca2+ signals in response to PZQ; and (iv) a pharmacological profile that mirrors the well-known effects of PZQ on muscle contraction and tegumental disruption. We anticipate that these findings will spur development of novel therapeutic interventions to manage schistosome infections and broader interest in PZQ, which is finally unmasked as a potent flatworm TRP channel activator.
Highlights
The anthelmintic drug praziquantel (PZQ) is used to treat schistosomiasis, a neglected tropical disease that affects over 200 million people worldwide
No binding site(s) for these enantiomers has been identified in parasitic flatworms, there has been considerable recent progress in identifying targets for (R)-PZQ and (S)-PZQ in the human host [9]. (R)-PZQ is a partial agonist of the human 5-hydroxytryptamine 2B receptor (5HT2BR [10]), and (S)-PZQ is a partial agonist of the human transient receptor potential melastatin-8 channel (hTRPM8 [11])
We searched for flatworm TRP channels exhibiting sequence homology to hTRPM8
Summary
The anthelmintic drug praziquantel (PZQ) is used to treat schistosomiasis, a neglected tropical disease that affects over 200 million people worldwide. Several properties of Sm.TRPMPZQ were consistent with known effects of PZQ on schistosomes, including (i) nanomolar sensitivity to PZQ; (ii) stereoselectivity toward (R)-PZQ; (iii) mediation of sustained Ca2؉ signals in response to PZQ; and (iv) a pharmacological profile that mirrors the well-known effects of PZQ on muscle contraction and tegumental disruption We anticipate that these findings will spur development of novel therapeutic interventions to manage schistosome infections and broader interest in PZQ, which is unmasked as a potent flatworm TRP channel activator. It is problematic that despite decades of clinical usage, as well as demonstration of strains with lower sensitivity to PZQ in both laboratory and field, the flatworm target(s) of PZQ remains unknown [7, 8]. We demonstrate that (R)-PZQ activates a Ca2ϩ-permeable transient receptor potential (TRP) channel expressed in PZQ-sensitive flatworms
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