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Progress interrogating TRPMPZQ as the target of praziquantel


The drug praziquantel (PZQ) has served as the long-standing drug therapy for treatment of infections caused by parasitic flatworms. These encompass diseases caused by parasitic blood, lung, and liver flukes, as well as various tapeworm infections. Despite a history of clinical usage spanning over 4 decades, the parasite target of PZQ has long resisted identification. However, a flatworm transient receptor potential ion channel from the melastatin subfamily (TRPMPZQ) was recently identified as a target for PZQ action. Here, recent experimental progress interrogating TRPMPZQ is evaluated, encompassing biochemical, pharmacological, genetic, and comparative phylogenetic data that highlight the properties of this ion channel. Various lines of evidence that support TRPMPZQ being the therapeutic target of PZQ are presented, together with additional priorities for further research into the mechanism of action of this important clinical drug.


The drug praziquantel (PZQ) has served for decades as the key clinical agent for treating diseases caused by parasitic flatworms. Effective against the majority of these infections [1,2], it is recognized as one of 100 essential medications by the World Health Organization [3]. As a cheap, safe, broadly active, and well-scrutinized clinical therapy, PZQ has served as the keystone of mass drug administration campaigns to decrease the intensity and prevalence of schistosome infections in countries where schistosomiasis is endemic.

PZQ is, however, an old drug. The anthelmintic activity of PZQ was first realized during a screening collaboration between Merck KGaA and Bayer AG in the 1970s [1,4,5]. Profiling a series of acylated pyrazinoisoquinoline-like compounds revealed the potent activity of PZQ against various trematode and cestodes. Three effects—(i) rapid cellular and tissue depolarization; (ii) a sustained muscle contraction causing worm paralysis; and (iii) damage to the worm tegument apparent as surface “blebbing”—serve as the cardinal triad of features caused by PZQ in all parasitic flatworms where PZQ displays efficacy (Fig 1). For each of these effects, the (R)-enantiomer of PZQ ((R)-PZQ) acted at lower concentrations than the (S)-enantiomer ((S)-PZQ), evidencing a preference for (R)-PZQ at the parasite target. Unfortunately, the identity of this target has resisted definition throughout subsequent decades of clinical usage, placing PZQ within a small minority of FDA-approved drugs with no elaborated molecular target [6].

Fig 1. Cardinal effects of PZQ on schistosomes.

PZQ treatment of schistosomes is associated with a triad of phenotypic effects: a rapid depolarization of muscle cells, a sustained spastic paralysis of the worm, and broad damage to the tegument manifest as surface blebbing and vesicularization. These effects are most obvious with the (R)-enantiomer of PZQ (center). Data are reproduced with permission from [23].

Nevertheless, PZQ has proved a very effective drug in the clinic. 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. Our understanding of why PZQ efficacy varies in these situations has been hampered by our lack of knowledge of the molecular target of PZQ. This has long proved a frustrating roadblock. Knowledge of the target would catalyze a better understanding of endogenous signaling pathways essential for parasite viability and thereby vulnerabilities to chemotherapeutic attack. This would also enable target-based drug screening efforts to catalyze discovery of new anthelmintics. Finally, a validated target would enable prospective surveillance for sequence variation, occurring naturally or in response to drug pressure, which could be one of many mechanisms that underpin decreased PZQ effectiveness in the field [11].

For all these reasons, the recent identification of a parasite target for PZQ is a significant breakthrough [12]. This target is a parasite ion channel from the transient receptor potential melastatin family, named TRPMPZQ [12]. TRPMPZQ has been prioritized as an appealing target as it displays properties consistent with the known action of PZQ against parasitic flatworms. The purpose of this review is to summarize experimental evidence collated since the discovery of TRPMPZQ [12,13] that has interrogated the candidature of this ion channel as the clinically relevant target of PZQ. Efforts have focused on understanding (i) the key properties of TRPMPZQ; (ii) the impact of variation in TRPMPZQ sequence and expression; and (iii) insight from novel pharmacological tools. Ten pieces of evidence supporting correct target validation of TRPMPZQ are presented, concluding with a discussion of caveats and some future priorities for investigation.

Key properties of Sm.TRPMPZQ

In 2019, Park and colleagues identified a TRP channel from Schistosoma mansoni (named Sm.TRPMPZQ) which when heterologously expressed in mammalian cells mediated robust cellular Ca2+ signals on exposure to PZQ [12]. Consistent with the long-held focus on a “Ca2+ channel hypothesis” for PZQ action [1315], effort to further investigate the properties of this Ca2+-permeable ion channel target held merit.

1. The basic properties of TRPMPZQ replicate the characteristics of PZQ action on schistosomes.

Enticingly, the attributes of the TRPMPZQ response to PZQ were consistent with the well-known features of PZQ action on schistosomes. First, the potency of PZQ at TRPMPZQ was in the hundreds of nanomolar range (EC50 for (R)-PZQ was approximately 150 nM at 37°C), consistent with PZQ action on worms ex vivo [12]. Second, (R)-PZQ was more potent than (S)-PZQ, consistent with the recognized stereoselectivity of the enantiomers versus parasitic flatworms [12]. Third, the kinetics of activation of TRPMPZQ were rapid in onset with little apparent desensitization of the channel toward PZQ, consistent with the sustained profile of schistosome muscle contraction evoked by PZQ [16,17]. Fourth, the response of S. mansoni TRPMPZQ to PZQ was attenuated by Mg2+ and blocked by La3+, consistent with the effects of these metal ions on S. mansoni muscle contractility [16,17]. Overall, the congruence between these basic characteristics of PZQ-evoked TRPMPZQ activation and worm responsivity to PZQ underscored the promising candidature of TRPMPZQ as the elusive parasitic target of PZQ [12,13].

2. An endogenous current activated by PZQ matches the biophysical signature of TRPMPZQ.

While identified on the basis of monitoring Ca2+ permeability, TRPMPZQ is a nonselective cation channel permeable to both monovalent and divalent cations [18]. Again, this is consistent with the ability of PZQ to stimulate the influx of Na+ and Ca2+, and the loss of K+ from intact schistosomes [19]. Membrane depolarization consequent to TRPMPZQ activation can be resolved in Ca2+-free solutions using a fluorescent membrane potential reporter [18] or by recording currents in Ca2+-free media [18,20,21]. TRPMPZQ behaves as a voltage-independent ion channel based on a linear current–voltage relationship with a conductance of 110 to 130 pS for S. mansoni, S. haematobium, and S. japonicum TRPMPZQ (recorded in symmetrical 145 mM NaCl) and an open probability, Popen = 0.4 to 0.6 [18,21]. These characteristics, combined with a lack of desensitization of channel opening toward PZQ, may endow TRPMPZQ with the ability to mediate a long-lasting depolarization in cell types where it is expressed [18].

However, native PZQ-evoked currents have never been recorded from any parasitic flatworm. This is likely due to the technical challenges of performing these measurements, but also because of our not knowing what exactly to look for and where best to look. Recent effort to resolve the single-channel properties of TRPMPZQ in vitro have established a “biophysical signature” for Sm.TRPMPZQ, defining a clear search algorithm as well as the optimal recording conditions to search for a native PZQ-evoked current [18]. Further, RNAseq datasets have revealed that TRPMPZQ is expressed in many excitable cells, present in multiple neuronal cell types [22].

These insights improved the feasibility of a new hunt to find an endogenous PZQ-evoked current. Chulkov and colleagues attempted such analyses using invasive electrophysiology to record currents from a live adult schistosome [23]. Despite the challenges of this approach, single-channel responses evoked by PZQ could be resolved from recordings made in “neuronal” tissues, including the anterior ganglia and main nerve cord of male worms [23]. In contrast, no response to PZQ was evident in recordings from “muscle” tissue, or PZQ-derived tegumental vesicles under similar conditions. The native PZQ-activated ion channel displayed properties (linear I-V, Cs+ permeability, Popen, conductance) consistent with the properties of Sm.TRPMPZQ measured in vitro [18]. Further, the PZQ-evoked current was blocked by a Sm.TRPMPZQ antagonist [23]. That the properties of an endogenous PZQ-activated current in an adult schistosome closely match the characteristics of Sm.TRPMPZQ support correct target identification.

3. TRPMPZQ is present in all flatworms that show sensitivity to PZQ.

TRPMPZQ must be present in all parasites that exhibit sensitivity to PZQ; otherwise, another target must exist to mediate PZQ action in these worms. Bioinformatic analyses have shown this to be the case. Scrutiny of available genomic and transcriptomic resources revealed the revealed the presence of TRPMPZQ orthologs in all available flatworm genomes [12,24]. TRPMPZQ orthologs from 11 of these different species have been functionally profiled in vitro. These encompass TRPMPZQ from schistosomes (S. mansoni, Sm.TRPMPZQ; S. japonicum Sj.TRPMPZQ; and S. haematobium, Sh.TRPMPZQ), Clonorchis sinensis (Cs.TRPMPZQ), Opisthorchis viverrini (Ov.TRPMPZQ), Echinostoma caproni (Ec.TRPMPZQ), Fasciola species (F. hepatica, Fh.TRPMPZQ and F. gigantica, Fg.TRPMPZQ), tapeworms (Echinococcus granulosus, Eg.TRPMPZQ and Mesocestoides corti, Mc.TRPMPZQ) as well as a free-living flatworm representative (Macrostomum lignano, Ml.TRPMPZQ). All these orthologs, with the exception of TRPMPZQ from Fasciola species (Fh.TRPMPZQ and Fg.TRPMPZQ) are sensitive to PZQ, with (R)-PZQ being the more active enantiomer in every case [24,25]. While not a comprehensive analysis, data from these functional profiling efforts to date remain consistent with the known clinical utility of PZQ for treating infections caused by these different parasitic flatworms. Fasciola infections are known to be refractory to PZQ treatment. Our understanding of the molecular basis for this insensitivity is discussed in the next section.

Genetic variation impacting TRPMPZQ function

Additional support for TRPMPZQ as the therapeutically relevant target of PZQ comes from the clear correlation between species- and strain-specific properties of TRPMPZQ and the overall sensitivity of these different parasitic flatworms to PZQ.

4. Fasciola TRPMPZQ provides a clear molecular explanation for the insensitivity of these liver flukes to PZQ.

Liver flukes from the genus Fasciola are insensitive to PZQ and epsiprantel [2,26,27]. Human fascioliasis is refractory to treatment by PZQ [28,29]. An explanation for the lack of PZQ efficacy against these particular parasites has long been lacking. Suggestions have encompassed an impermeability of the liver fluke tegument to PZQ, efficient export of PZQ from Fasciola, or that the target of PZQ is absent in Fasciola spp. [26]. TRPMPZQ is, however, present in Fasciola spp. (see point #3), and functional analysis of TRPMPZQ provided a simple explanation for why PZQ does not work against these particular liver fluke infections.

Park and colleagues identified a single nucleotide variation between Fasciola TRPMPZQ and TRPMPZQ in other trematodes that yields an amino acid change within the binding pocket of Fasciola TRPMPZQ, encoding a threonine residue instead of an asparagine residue (Fig 2A; [25]). This difference occurs at a critical position that is necessary for binding PZQ: The asparagine residue in transmembrane helix 1 (TM1) of schistosome TRPMPZQ is predicted to form a hydrogen bond with the internal carbonyl of PZQ [25] (Fig 2B). This interaction is predicted to be lacking between PZQ and Fasciola sp. TRPMPZQ (Fig 2C). When this residue was mutated to a threonine in Sm.TRPMPZQ, PZQ could no longer activate the ion channel [25]. Reciprocally, mutation of the threonine residue to an asparagine within Fasciola hepatica or Fasciola gigantica TRPMPZQ realized a “gain-of-function,” and PZQ became a potent activator of the Fasciola TRPMPZQ channel [24,25] (Fig 2D). Therefore, even though this variation represents a minimal and conservative amino acid replacement, the change in the TRPMPZQ binding pocket was sufficient to abrogate PZQ activity [24,25].

Fig 2. Genetic determinants of PZQ sensitivity.

(A) A single nucleotide difference occurs at position 2 of the reading frame within an exon of the TRPMPZQ gene that forms part of the PZQ binding pocket in S. mansoni TRPMPZQ (left) and F. hepatica TRPMPZQ (right). This results in different amino acids—asparagine in S. mansoni TRPMPZQ (N1388 in Sm.TRPMPZQ) versus threonine in F. hepatica TRPMPZQ (T1270 in Fh.TRPMPZQ)—at an equivalent position within the VSLD binding pocket in TRPMPZQ of these different flukes. This difference also occurs in F. gigantica TRPMPZQ. (B) Location of this S1 helix reside (N1388 in Sm.TRPMPZQ versus T1270 in Fh.TRPMPZQ) in a homology model Sm.TRPMPZQ relative to the predicted PZQ binding poise (magenta). The availability of N1388 to hydrogen bond with the internal carbonyl group of PZQ is inferred as important for PZQ activation of Sm.TRPMPZQ. T1270 is either unavailable for hydrogen bonding, or this variation impacts binding pocket architecture in a manner deleterious to PZQ efficacy. (C) Concentration response curves comparing activation of wild-type Sm.TRPMPZQ and Fh.TRPMPZQ by PZQ (circles), as well as the effect of the reciprocal binding pocket mutants (Sm.TRPM[N1388T]PZQ and Fh.TRPM[T1270N]PZQ, squares) on responsivity to (±)-PZQ. Data adapted from [25]. Panels in this Figure were created using

The selective pressures, if any, underpinning this change in Fasciola TRPMPZQ are unknown. Possibly, it may relate to the exposure to natural products during the Fasciola lifecycle (for example, compounds in watercress leaves where infective metacercariae are attached [30]) that could adversely activate TRPMPZQ in the absence of such this adaptation within the ligand binding pocket. Many phytochemicals act as TRP channel ligands [31].

Whatever the explanation, elucidation of the molecular basis of Fasciola TRPMPZQ insensitivity toward PZQ enabled a rational approach to develop new fasciocidal agents that are tolerant of this variation. Development of novel TRPMPZQ activators is currently a focus of ongoing investigation. One such chemotype—a benzamidoquinazolinone (BZQ)—which potently activated both Sm.TRPMPZQ and Fh.TRPMPZQ was recently identified [32]. The basis for this dual activation depends on a different binding conformation of BZQ within the TRPMPZQ VSLD binding pocket, such that the variant position on the S1 helix is not important for BZQ binding [32]. BZQ engages the S1 helix through a different interaction, conserved in both Sm.TRPMPZQ and Fh.TRPMPZQ. Exposure of schistosomes to BZQ, like PZQ, caused a rapid and sustained contraction with obvious surface damage. Similarly, application of BZQ to Fasciola hepatica also caused a rapid, spastic contraction and tegumental damage. That a Fasciola TRPMPZQ activator identified by target-based screening is deleterious to liver fluke and phenocopies PZQ action on schistosomes further supports correct target validation of TRPMPZQ.

This molecular insight should prompt wariness given the precedence this explanation establishes for the viability of a PZQ-insensitive TRPMPZQ channel maintained over evolutionary time. It would obviously be concerning if a similar TRPMPZQ variant was found naturally or occurred in response to the selective pressure associated with PZQ exposure during mass drug administrative campaigns. Analysis of TRPMPZQ sequence and/or expression levels as potential routes to PZQ resistance would be worthwhile in scenarios such as persistent “hotspots” after mass drug administration campaigns [33] or obvious losses of PZQ efficacy in veterinary [34,35] or aquaculture treatments [36,37]. Effort to catalogue TRPMPZQ variants, coupled with insight as to the functional consequences of such variation, will be crucial for surveillance of changes underpinning decreases in the clinical effectiveness of PZQ.

5. Schistosomes genetically selected for low PZQ sensitivity show low expression of TRPMPZQ.

A genome-wide association study using a mixed population of PZQ-resistant and PZQ-sensitive S. mansoni worms identified a 4MB region on chromosome 3, which harbored many genes at the highest association peak, including the gene encoding Sm.TRPMPZQ [38]. Marker-assisted selection using a single nucleotide polymorphism (SNP) present in the Sm.TRPMPZQ gene and associated with PZQ responsiveness allowed for the generation of 2 populations of schistosomes that displayed a remarkable >377-fold difference in PZQ sensitivity. These populations were fixed for alternative alleles at a SNP genotyped within Sm.TRPMPZQ, as well as 2 different proximal 150 kb deletions (one quite close to Sm.TRPMPZQ and one near a transcription factor). Of the genes within this locus, Sm.TRPMPZQ uniquely exhibited lower expression in adult male worms that displayed poor PZQ sensitivity [38]. This elegant body of work provides strong evidence that variation within, or near to, the TRPMPZQ locus confers decreased responsivity to PZQ [38,39].

One explanation for this observation is that the lower sensitivity to PZQ results from lower levels of Sm.TRPMPZQ expression, which results in a less robust response or a more facile recovery of cells after PZQ exposure. That differential expression of Sm.TRPMPZQ may result in varied sensitivity to PZQ also chimes with the stronger response to PZQ in adult male versus female schistosomes [40,41], which correlates with the higher levels of Sm.TRPMPZQ expression in male worms [38,42]. Sm.TRPMPZQ shows lower expression in male or female worms that display low sensitivity to PZQ [38]. However, TRPMPZQ mRNA levels in juvenile schistosomes are equivalent or higher than those found in adults [38,42], so other explanations must underpin the lower sensitivity of immature worms to PZQ. Again, this may be caused by a less robust response (unique regulation of TRPMPZQ activity or ion channel expression in this specific lifecycle stage) or a more facile recovery to drug exposure (stronger tissue repair in juvenile worms). Overall, resolution of the regulatory mechanisms that control TRPMPZQ expression and correlating TRPMPZQ expression in parasitic flatworms with the effectiveness of PZQ treatment will be priorities for future study.

6. The differential sensitivity of various parasites to PZQ correlates with the differential PZQ sensitivity of TRPMPZQ orthologs in these different flatworms.

The sensitivity of different parasitic flatworms toward PZQ is not the same; for example, while PZQ was originally recognized as effective against trematodes and cestodes [1,43], the sensitivity of cestodes to PZQ is highest. Sensitivity to PZQ is manifest at low nanomolar concentrations against some cestodes [44,45]. Blood flukes typically respond to PZQ in the hundreds of nanomolar range [2], and free-living flatworms show responses in the micromolar range [24]. Fasciola spp. represent an extreme example showing lack of sensitivity toward PZQ.

Efforts to measure the sensitivity of TRPMPZQ orthologs from representatives of each of these groups demonstrated that TRPMPZQ sensitivity to PZQ aligns well with the observed worm sensitivity to PZQ. Two cyclophyllidean cestode TRPMPZQ channels—Mesocestoides corti TRPMPZQ (Mc.TRPMPZQ) and Echinococcus granulosus TRPMPZQ (Eg.TRPMPZQ)—were potently activated by (R)-PZQ (EC50 = 82 ± 3 nM for Mc.TRPMPZQ, EC50 = 55 ± 6 nM for Eg.TRPMPZQ; [24]), consistent with the high sensitivity of this group of cestodes to PZQ. In contrast, TRPMPZQ from a free-living flatworm representative, Macrostomum lignano (Ml.TRPMPZQ), was activated by (R)-PZQ with approximately 300-fold lower potency (EC50 = 18 ± 0.8 μM; [24]), consistent with the concentration range of PZQ activity against free-living flatworms. Variation in the amino acids residues that line the orthosteric binding pocket of the different TRPMPZQ orthologs likely contributes to this differential sensitivity. Functionally impactful residues include (i) a histidine residue in cestode TRPMPZQ orthologs found at the same S1 helix position, which dictates the PZQ insensitivity of Fasciola, and (ii) an acidic amino acid residue found within the TRP helix. This latter residue, represented by an aspartic acid residue in the high sensitivity TRPMPZQ orthologs of trematodes and cyclophyllidean cestodes, is a glutamic acid residue in other parasitic TRPMPZQ orthologs and TRPM paralogs [24]. The presence of the glutamic acid variant confers lower sensitivity to PZQ in these channels, with application of molecular dynamics and metadynamic modelling methods suggesting the glutamic acid residue projects into the PZQ binding pocket ablating a critical receptor–ligand interaction required for high affinity PZQ binding [24]. Identification of this acidic “gatekeeper” residue provides an explanation for the lower observed clinical sensitivity to PZQ in parasitic flatworm infections that harbor a glutamate at this position, while parasites that carry an aspartate at this position (trematodes and cyclophyllidean cestodes) uniquely display high sensitivity to PZQ [2,46]. The properties of TRPMPZQ orthologs from different flatworms, therefore, show a consistent correlation between worm sensitivity to PZQ and TRPMPZQ ortholog sensitivity to PZQ.

Pharmacology of TRPMPZQ

With a candidate parasite target for PZQ identified, target-based drug screening approaches become feasible. Such efforts have realized additional insight into the properties of TRPMPZQ.

7. The structural–activity relationship of drugs causing Sm.TRPMPZQ activation and worm contraction are similar.

Functional profiling of a series of 43 PZQ analogs and nonobvious derivatives against Sm.TRPMPZQ ranked the potency of all these analogs in terms of TRPMPZQ activation [25]. The same analogs were then examined for their potency in causing spastic contraction of adult schistosome worms [25]. The structure–activity fingerprint for these analogs was almost identical in both assays. The “tightness” of the structure–activity relationship (SAR) of PZQ analogs at causing paralysis was also mirrored by the same strict SAR for efficacy at Sm.TRPMPZQ. Such stringency around the pharmacophore of PZQ has long been recognized [1]. Retrospective analysis of data from over 250 PZQ analogs revealed only 4% of synthesized PZQ derivatives displayed equivalent activity to PZQ [47]. Such congruence between the SAR of the contractile response and the pharmacological profile of this ion channel in vitro is again consistent with Sm.TRPMPZQ acting as the mediator of PZQ action.

8. The different structure–activity relationship of TRPMPZQ between parasitic flatworms varies in line with worm sensitivity to different analogs.

When the SAR of PZQ was elaborated [1], it became evident that particular PZQ analogs displayed differential activities against different types of parasite. For example, some PZQ analogs—3-pyridine analogs and certain modifications of the cyclohexyl ring—showed considerably greater activity toward cestodes than against schistosomes [1]. Is this differential bioactivity mirrored by different structure activity relationships at schistosome and cestode TRPMPZQ? The answer is yes, with good alignment between analog activity against different parasites and the underlying selectivity of TRPMPZQ orthologs in these different species [48]. The SAR of TRPMPZQ in different parasites is, therefore, not identical. Differences in the amino acids lining the transmembrane TRPMPZQ ligand binding pocket likely underpin these effects, highlighting future potential for developing drugs tailored toward specific TRPMPZQ targets and problematic clinical infections that are more refractory toward PZQ treatment. That the distinct pharmacological signatures of parasites toward PZQ analogs mirrors the properties of TRPMPZQ in the different parasites further supports TRPMPZQ as the therapeutically relevant target.

9. Other agonists of TRPMPZQ phenocopy PZQ. If TRPMPZQ is the target of PZQ, other activators of TRPMPZQ should mimic PZQ action.

If such TRPMPZQ activators do not phenocopy PZQ action, then PZQ must also engage other targets that contribute to the drug’s therapeutic activity. To develop this line of enquiry, alternative activators of TRPMPZQ needed to be found. Chulkov and colleagues executed a target-based screen of approximately 16,000 compounds against Sm.TRPMPZQ using a miniaturized fluorescence reporter assay [49]. This screen resulted in the identification of a single TRPMPZQ agonist “hit” that surpassed triage criteria. This low hit rate (0.06%) in this screen was again consistent with the known stringent SAR of PZQ and TRPMPZQ. The Sm.TRPMPZQ activator was named AG1 (agonist-1) and was less potent than PZQ (EC50 approximately 9 μM; [49]). Nevertheless, AG1 activated Sm.TRPMPZQ similarly to PZQ, eliciting non-desensitizing, ohmic currents when profiled electrophysiologically [49]. Further, a VSLD binding pocket mutant ablated both PZQ and AG1 activation of Sm.TRPMPZQ, suggesting a similar action of both ligands through engagement of the transmembrane VSLD ligand binding site. While this does not prove that AG1 is selective for Sm.TRPMPZQ, a novel Sm.TRPMPZQ activator was found from this screening effort. Notably, AG1 represented a different chemotype to PZQ. Whereas PZQ has a pyrazinoisoquinoline core, AG1 is a triazolopyridine derivative. Their common activation of TRPMPZQ highlighted the druggability of this novel target. Interestingly, AG1 was a known compound (MV688313, LSHTM-1945) previously identified as a high priority “hit” in a large, phenotypic screen (approximately 300,000 compounds) against different schistosome life cycle stages [50]. That a phenotypic screen and a target-based screen completed by independent groups converged on the same ligand, unmasked as a Sm.TRPMPZQ activator, provided further reassurance of correct target identification.

10. Antagonists of Sm.TRPMPZQ decrease parasite sensitivity toward PZQ.

The same target-based screen against Sm.TRPMPZQ also yielded many potential blockers of this channel [49]. These candidate blockers have yet to be studied and appraised as to their mode of action, for example, whether they function as competitive inhibitors of PZQ within the same VSLD binding pocket, pore blockers, or noncompetitive inhibitors of the TRPMPZQ complex. Only the effects of one compound, ANT1 (“antagonist-1”), have been evaluated to date. ANT1, a substituted pyrazine, blocked the effects of PZQ measured in either a metabolic or a motility assay, such that ANT1 application recovered normal worm movement and viability in the presence of PZQ [38,49]. That a Sm.TRPMPZQ antagonist blocks the action of PZQ on schistosomes again supports the candidacy of TRPMPZQ as the relevant in vivo target of PZQ. ANT1 also blocked the native current evoked by PZQ in schistosomes [23]. The utility of TRPMPZQ blockers (as opposed to TRPMPZQ activators) as potential anthelmintics has not yet been explored. However, further study of these chemotypes is important as these efforts will provide useful tools for inhibiting the function of TRPMPZQ to unmask the endogenous role of this ion channel throughout the parasite lifecycle.

Caveats and future directions

Collectively, these 10 lines of evidence provide strong support for TRPMPZQ acting as the therapeutic target of PZQ, with the experimental data discussed above proving consistent with correct target validation. However, caution is always merited, and further questions remain. One wryly notes that even for cancer drugs undergoing clinical trials in humans, their assumed targets have often retrospectively been shown to be false [51,52]. This underscores the importance of coalescing multiple lines of evidence to underpin target validation [52,53]. In this regard, 3 areas merit further attention [13].

Validation through genetic loss of function analyses.

Insight from functional genetic approaches is needed. Results from knockdown or knockout analyses, to ablate TRPMPZQ expression in parasites, have yet to be reported. Neither of these approaches are trivial to execute: Knockdown by RNA interference (RNAi) can be finicky depending on the target, how abundant it is and where it is expressed in the worm. Stable transgenesis in schistosomes is also an active focus for optimization. TRPMPZQ is not abundantly expressed at the surface of the worm but is found within excitable cells. The large cation flux mediated by TRPMPZQ would likely necessitate a highly penetrant knockdown of TRPMPZQ for RNAi data to be interpretable, as residual expression of TRPMPZQ could still support a robust depolarization response to PZQ. Challenges related to off-target effects with RNAi, and the adequacy of controls for many commonly scored phenotypes, also persist [54]. But provided TRPMPZQ is not crucial for parasite viability, these genetic loss-of-function approaches will provide critical insight as to the essentiality of TRPMPZQ for PZQ action. The availability of small molecule blockers of TRPMPZQ (see point #10) will complement these genetic loss-of-function approaches as pharmacological blockade of TRPMPZQ should phenocopy and thereby validate RNAi effects. Clearly, if PZQ-evoked depolarization, contraction, and surface damage phenotypes persist in the absence of TRPMPZQ, then other targets must mediate these effects. TRPMPZQ, despite the aforementioned evidence, would then be a “false” target in relation to the anthelmintic activity of PZQ.

Other targets?

PZQ inevitably has more than one target, consistent with the polypharmacological profile expected with any small molecule [55,56]. Many of these will be “secondary” targets, with these interactions not recapitulating the high sensitivity and stereoselectivity displayed by TRPMPZQ (the “primary” target). For example, in humans, where the process of target identification is more facile, PZQ has been shown to regulate multiple TRP channels [57,58] and several GPCRs [59]. However, these interactions exhibit lower sensitivities (micromolar at best) and often different stereochemistry (for example, hTRPM8 is only activated by (S)-PZQ [58]). For the human 5-HT2B receptor, where a (R)-PZQ binding pose has been defined and validated, the lower sensitivity of 5-HT2B toward PZQ (EC50 in low micromolar range [59,60]) can be explained by the loss of specific binding interactions that been shown to anchor PZQ within the schistosome TRPMPZQ binding pocket. For example, whereas hydrogen-bonding interactions occur in TRPMPZQ to both the carbonyl groups of PZQ, only a single hydrogen-bond interaction is predicted in the human 5-HT2B binding pocket [60]. Loss of optimal hydrogen-bond interactions will decrease binding affinity [61], likely explaining the shift from the “hundreds of nanomolar” to the “micromolar” sensitivity range, even though “selective” binding (5-HT2B compared with 5-HT2A or 5-HT2C) is still evident. These host targets may be relevant to several side effects associated with PZQ (5-HT2B: smooth muscle contraction underpinning nausea, abdominal pains; TRPM8: poor taste), and, potentially, also therapeutic efficacy (vascular contraction in mesenteric vessels) by aiding the hepatic shift of contracted worms [59,60].

Just as with the discovery of such “secondary” targets in humans, secondary parasite targets for PZQ will be discovered. Indeed, several PZQ-interacting proteins in schistosomes have already been proposed including myosin light chain [62], actin [62,63] (but see [64]), voltage-operated Ca2+ channels [65], multidrug-resistant transporters [66], adenosine transporters [67], glutathione S-transferase (GST) [68], and several members of the tegumental allergen (TAL) family of proteins [69]. However, for the majority of these candidates, quantitative characterization of PZQ binding and the selectivity of the ligand binding site is lacking. Also, acknowledging the tight SAR of PZQ and the reciprocally tight SAR of the TRPMPZQ binding pocket, it is worth pointing out that many conjugated PZQ analogs utilized in prior target discovery strategies would poorly interact with TRPMPZQ, if at all. Whether any of these reported interactions contribute to the therapeutic efficacy of PZQ remains the critical question, and this will require careful validation. Three fundamental criteria, outlined in the preceding sections for TRPMPZQ, must be met. First, is there reasonable congruence between the affinity for PZQ at the proposed target versus PZQ efficacy against the worm? Second, is there a similar SAR for PZQ analogs at the proposed target versus the parasite? Third, is there a clear functional outcome consequent to PZQ engaging these targets that is consistent with the triad of phenotypic outcomes (depolarization, worm contraction, tegument damage)? For example, with Sm.TAL1, where careful efforts have been made to characterize PZQ binding, the resolved affinity is low (Kd of Sm.TAL1 for PZQ = 140 μM [69]) compared with PZQ action on worms. For schistosome GST, where PZQ was cocrystallized with the enzyme, the binding site lies within an amphipathic groove at the dimer interface, which promiscuously accommodates many hydrophobic chemotypes [21] not reflecting the established SAR. Further, PZQ binding does not affect GST function [70]. Therefore, many of these proposed interactors may not stand up to scrutiny as a “primary” target.

Could there be another “primary” parasite target that matches the sensitivity, SAR, and functional impact of TRPMPZQ? Another “primary” target cannot be excluded, while so many ion channels and GPCRs remain unprofiled in parasitic flatworms. However, one notes the insensitivity of Fasciola toward PZQ: If there is another “primary” target for PZQ, then the effects of engagement of this target should be manifest in Fasciola in the absence of any contribution from TRPMPZQ. However, Fasciola spp. remain insensitive to very high (millimolar) concentrations of PZQ [26], consistent with a single “primary” target model. Notwithstanding this argument, the most likely place to look for additional PZQ targets might be other TRP (and likely TRPM) family members, as many of these channels have yet to be studied. This is a challenge in the absence of known activators to confirm successful heterologous expression of each ion channel candidate, as a negative result is not definitive in the absence of a positive control. However, a second TRPM family member has recently been deorphanized and shown to respond to the benzodiazepine, meclonazepam, an old anthelmintic [71]. This channel, named TRPMMCLZ, did not respond to PZQ as predicted [24,71]. However, the fact that TRPMMCLZ—a cousin of TRPMPZQ—also mediates worm contraction, depolarization, and surface damage is broadly supportive of functional assignment of both anthelmintic targets to the same ion channel subfamily. This underscores the promise of TRPM channels for design and development of new anthelmintics.

What has it got in its pocketses?

It is fair to ask—what endogenous ligands activate TRPMPZQ? TRPMPZQ is a large channel, with each monomer composed of approximately 2,200 amino acids (predicted as approximately 250 kDa). The expected tetramer would be of an exceptionally large size (>1 MDa). Within this quaternary structure, there are likely a multitude of nooks and crannies that could accommodate ligands, lipids, and accessory proteins. For example, as many as 16 unique “ligand” binding sites have been counted in human TRPV channels [72], many of which are conserved in other TRP family members [73,74]. Only the VSLD binding pocket has been mapped so far in TRPMPZQ. Therefore, there is much work to do: This encompasses provision of a structural solution to TRPMPZQ architecture, identification of TRPMPZQ regulators, and then definition of their role in regulating TRPMPZQ responsiveness.

Already TRPMPZQ has emerged as a “polymodal” ion channel, defined as a channel regulated by both chemical as well as physical cues. Chulkov and colleagues demonstrated that membrane stretch activates Sm.TRPMPZQ, a potentially relevant cue for an aquatic parasite that must traverse a pressurized vascular system [20]. Schistosome contraction is known to be regulated by stretch [75]. As there are a multitude of sensory demands across the parasitic life cycle, other environmental cues may emerge as TRPMPZQ regulators, potentially encompassing both parasite-derived and host-derived ligands [76]. Unbiased screening approaches, as well as biased probing of known vertebrate TRP channel regulators will be of value in identifying such ligands. Elaboration of the TRPMPZQ interactome to define interacting proteins will be another priority to identify other regulators of the channel complex. Unravelling the functional consequences of both ligand and accessory protein regulation of TRPMPZQ will surely reveal new targets for chemotherapeutic attack.


TRPMPZQ has recently emerged as a druggable parasite ion channel, with the evidence outlined in this review supportive of this ion channel acting as the relevant parasite target of PZQ. Recent work has elaborated the key properties of this ion channel and identified future experimental priorities. The prospect of identifying novel pharmacological tools for probing the function of TRPMPZQ, as well as for other ion channels within the parasitic flatworm TRPM subfamily [71] and the broader TRP channel superfamily [77], will further our understanding of the roles of these sensory ion channels throughout the parasitic lifecycle. This is currently a very exciting time for anthelmintic drug development, with new broad spectrum oxamniquine derivatives [78], highly potent antischistosomal chemotypes [79], as well as novel TRPMPZQ activators all recently emerging [32,49]. Hopefully, this will yield exciting advances for treating parasitic flatworm infections within the not-too-distant future.

Top Five Papers

  1. Andrews P, Thomas H, Pohlke R, Seubert J. Praziquantel. Med Res Rev. 1983;3(2):147–200. Epub 1983/04/01. doi: 10.1002/med.2610030204. PubMed PMID: 6408323.
  2. Bais S, Churgin MA, Fang-Yen C, Greenberg RM. Evidence for Novel Pharmacological Sensitivities of Transient Receptor Potential (TRP) Channels in Schistosoma mansoni. PLoS Negl Trop Dis. 2015;9(12):e0004295.
  3. Park SK, Gunaratne GS, Chulkov EG, Moehring F, McCusker P, Dosa PI, et al. The anthelmintic drug praziquantel activates a schistosome transient receptor potential channel. J Biol Chem. 2019;294(49):18873–18880.
  4. Park SK, Friedrich L, Yahya NA, Rohr CM, Chulkov EG, Maillard D, et al. Mechanism of praziquantel action at a parasitic flatworm ion channel. Sci Transl Med. 2021;13(625):eabj5832. Epub 2021/12/23. doi: 10.1126/scitranslmed.abj5832
  5. Le Clec’h W, Chevalier FD, Mattos ACA, Strickland A, Diaz R, McDew-White M, et al. Genetic analysis of praziquantel response in schistosome parasites implicates a transient receptor potential channel. Sci Transl Med. 2021;13(625):eabj9114.

Key Learning Points

  • Outline the key properties of the parasitic flatworm ion channel, TRPMPZQ.
  • Collate current evidence supporting TRPMPZQ as the target of the clinical drug, praziquantel.
  • Suggest directions for future experimental work.


  1. 1. Andrews P, Thomas H, Pohlke R, Seubert J. Praziquantel. Med Res Rev. 1983;3(2):147–200. Epub 1983/04/01. pmid:6408323
  2. 2. Chai JY. Praziquantel treatment in trematode and cestode infections: an update. Infect Chemother. 2013;45(1):32–43. Epub 2013/11/23. pmid:24265948
  3. 3. World Health Organization model list of essential medicines: 21st list 2019. Geneva.
  4. 4. Gonnert R, Andrews P. Praziquantel, a new board-spectrum antischistosomal agent. Z Parasitenkd. 1977;52(2):129–150. Epub 1977/07/21. pmid:410178
  5. 5. Thomas H, Gonnert R. The efficacy of praziquantel against cestodes in animals. Z Parasitenkd. 1977;52(2):117–127. Epub 1977/07/21. pmid:906623
  6. 6. Drews J. Drug discovery: a historical perspective. Science. 2000;287(5460):1960–1964. Epub 2000/03/17. pmid:10720314
  7. 7. Friedrich L, Park SK, Ballard P, Ho Baeurle TH, Maillard D, Bodding M, et al. Metabolism of (R)-Praziquantel versus the Activation of a Parasite Transient Receptor Potential Melastatin Ion Channel. ChemMedChem. 2023;18(18):e202300140. Epub 2023/06/05. pmid:37272317
  8. 8. Kovac J, Vargas M, Keiser J. In vitro and in vivo activity of R- and S- praziquantel enantiomers and the main human metabolite trans-4-hydroxy-praziquantel against Schistosoma haematobium. Parasit Vectors. 2017;10(1):365. Epub 2017/08/03. pmid:28764732
  9. 9. Meyer T, Sekljic H, Fuchs S, Bothe H, Schollmeyer D, Miculka C. Taste, a new incentive to switch to (R)-praziquantel in schistosomiasis treatment. PLoS Negl Trop Dis. 2009;3(1):e357. Epub 2009/01/23. pmid:19159015
  10. 10. N’Goran EK, Odiere MR, Assande Aka R, Ouattara M, Aka NAD, Ogutu B, et al. Efficacy, safety, and palatability of arpraziquantel (L-praziquantel) orodispersible tablets in children aged 3 months to 6 years infected with Schistosoma in Cote d’Ivoire and Kenya: an open-label, partly randomised, phase 3 trial. Lancet Infect Dis. 2023;23(7):867–876. Epub 2023/03/10. pmid:36893784
  11. 11. Cotton JA, Doyle SR. A genetic TRP down the channel to praziquantel resistance. Trends Parasitol. 2022;38(5):351–352. Epub 2022/03/06. pmid:35246385
  12. 12. Park SK, Gunaratne GS, Chulkov EG, Moehring F, McCusker P, Dosa PI, et al. The anthelmintic drug praziquantel activates a schistosome transient receptor potential channel. J Biol Chem. 2019;294(49):18873–18880. Epub 2019/10/28. pmid:31653697
  13. 13. Park SK, Marchant JS. The Journey to Discovering a Flatworm Target of Praziquantel: A Long TRP. Trends Parasitol. 2020;36(2):182–194. Epub 2019/12/04. pmid:31787521
  14. 14. Jeziorski MC, Greenberg RM. Voltage-gated calcium channel subunits from platyhelminths: potential role in praziquantel action. Int J Parasitol. 2006;36(6):625–632. Epub 2006/03/21. pmid:16545816
  15. 15. Chan JD, Zarowiecki M, Marchant JS. Ca(2)(+) channels and praziquantel: a view from the free world. Parasitol Int. 2013;62(6):619–628. Epub 2012/12/19. pmid:23246536
  16. 16. Fetterer RH, Pax RA, Bennett JL. Praziquantel, potassium and 2,4-dinitrophenol: analysis of their action on the musculature of Schistosoma mansoni. Eur J Pharmacol. 1980;64(1):31–38. Epub 1980/05/30. pmid:7449814
  17. 17. Blair KL, Bennett JL, Pax RA. Praziquantel: physiological evidence for its site(s) of action in magnesium-paralysed Schistosoma mansoni. Parasitology. 1992;104(Pt 1):59–66. Epub 1992/02/01. pmid:1614741
  18. 18. Chulkov EG, Palygin O, Yahya NA, Park SK, Marchant JS. Electrophysiological characterization of a schistosome transient receptor potential channel activated by praziquantel. Int J Parasitol. 2023;53(8):415–425. Epub 2023/01/08. pmid:36610556
  19. 19. Pax R, Bennett JL, Fetterer R. A benzodiazepine derivative and praziquantel: effects on musculature of Schistosoma mansoni and Schistosoma japonicum. Naunyn Schmiedebergs Arch Pharmacol. 1978;304(3):309–315. Epub 1978/10/16. pmid:714190
  20. 20. Chulkov EG, Isaeva E, Stucky CL, Marchant JS. Use the force, fluke: Ligand-independent gating of Schistosoma mansoni ion channel TRPM(PZQ). Int J Parasitol. 2023;53(8):427–434. Epub 2023/01/08. pmid:36610555
  21. 21. Sluis-Cremer N, Naidoo NN, Kaplan WH, Manoharan TH, Fahl WE, Dirr HW. Determination of a binding site for a non-substrate ligand in mammalian cytosolic glutathione S-transferases by means of fluorescence-resonance energy transfer. Eur J Biochem. 1996;241(2):484–488. Epub 1996/10/15. pmid:8917446
  22. 22. Wendt G, Zhao L, Chen R, Liu C, O’Donoghue AJ, Caffrey CR, et al. A single-cell RNA-seq atlas of Schistosoma mansoni identifies a key regulator of blood feeding. Science. 2020;369(6511):1644–1649. Epub 2020/09/26. pmid:32973030
  23. 23. Chulkov EG, Rohr CM, Marchant JS. Praziquantel activates a native cation current in Schistosoma mansoni. Front Parasitol. 2023;2.
  24. 24. Rohr CM, Sprague DJ, Park SK, Malcolm NJ, Marchant JS. Natural variation in the binding pocket of a parasitic flatworm TRPM channel resolves the basis for praziquantel sensitivity. Proc Natl Acad Sci U S A. 2023;120(1):e2217732120. Epub 2022/12/28. pmid:36574686
  25. 25. Park SK, Friedrich L, Yahya NA, Rohr CM, Chulkov EG, Maillard D, et al. Mechanism of praziquantel action at a parasitic flatworm ion channel. Sci Transl Med. 2021;13(625):eabj5832. Epub 2021/12/23. pmid:34936384
  26. 26. Becker B, Mehlhorn H, Andrews P, Thomas H, Eckert J. Light and electron microscopic studies on the effect of praziquantel on Schistosoma mansoni, Dicrocoelium dendriticum, and Fasciola hepatica (Trematoda) in vitro. Z Parasitenkd. 1980;63(2):113–128. Epub 1980/01/01. pmid:7456640
  27. 27. Manger BR, Brewer MD. Epsiprantel, a new tapeworm remedy. Preliminary efficacy studies in dogs and cats. Br Vet J. 1989;145(4):384–388. Epub 1989/07/01. pmid:2775987
  28. 28. Farid Z, Trabolsi B, Boctor F, Hafez A. Unsuccessful use of praziquantel to treat acute fascioliasis in children. J Infect Dis. 1986;154(5):920–921. Epub 1986/11/01. pmid:2877032
  29. 29. Farid Z, Kamal M, Mansour N. Praziquantel and Fasciola hepatica infection. Trans R Soc Trop Med Hyg. 1989;83(6):813. Epub 1989/11/01. pmid:2617651
  30. 30. Mas-Coma S, Bargues MD, Valero MA. Human fascioliasis infection sources, their diversity, incidence factors, analytical methods and prevention measures. Parasitology. 2018;145(13):1665–1699. Epub 2018/07/12. pmid:29991363
  31. 31. Premkumar LS. Transient receptor potential channels as targets for phytochemicals. ACS Chem Neurosci. 2014;5(11):1117–1130. Epub 2014/06/14. pmid:24926802
  32. 32. Sprague DJ, Park SK, Gramberg S, Bauer L, Rohr CM, Chulkov EG, et al. Target-based discovery of a broad spectrum flukicide. bioRxiv. 2023:2023.09.22.559026. Epub 2023/10/04. pmid:37790347
  33. 33. Wiegand RE, Mwinzi PNM, Montgomery SP, Chan YL, Andiego K, Omedo M, et al. A Persistent Hotspot of Schistosoma mansoni Infection in a Five-Year Randomized Trial of Praziquantel Preventative Chemotherapy Strategies. J Infect Dis. 2017;216(11):1425–1433. Epub 2017/10/03. pmid:28968877
  34. 34. Jesudoss Chelladurai J, Kifleyohannes T, Scott J, Brewer MT. Praziquantel Resistance in the Zoonotic Cestode Dipylidium caninum. Am J Trop Med Hyg. 2018;99(5):1201–1205. Epub 2018/09/19. pmid:30226153
  35. 35. Nielsen MK. Apparent treatment failure of praziquantel and pyrantel pamoate against anoplocephalid tapeworms. Int J Parasitol Drugs Drug Resist. 2023;22:96–101. Epub 2023/06/25. pmid:37354849
  36. 36. Bader C, Starling DE, Jones DE, Brewer MT. Use of praziquantel to control platyhelminth parasites of fish. J Vet Pharmacol Ther. 2019;42(2):139–153. Epub 2018/12/18. pmid:30556228
  37. 37. Norbury LJ, Shirakashi S, Power C, Nowak BF, Bott NJ. Praziquantel use in aquaculture—Current status and emerging issues. Int J Parasitol Drugs Drug Resist. 2022;18:87–102. Epub 2022/02/28. pmid:35220160
  38. 38. Le Clec’h W, Chevalier FD, Mattos ACA, Strickland A, Diaz R, McDew-White M, et al. Genetic analysis of praziquantel response in schistosome parasites implicates a transient receptor potential channel. Sci Transl Med. 2021;13(625):eabj9114. Epub 2021/12/23. pmid:34936381
  39. 39. Chevalier FD, Clec’h WL, Berriman M, Anderson TJC. A single locus determines praziquantel response in Schistosoma mansoni. bioRxiv. 2023. Epub 2023/11/14. pmid:37961217
  40. 40. Pica-Mattoccia L, Cioli D. Sex- and age-related sensitivity of Schistosoma mansoni to in vivo and in vitro praziquantel treatment. Int J Parasitol. 2004;34:527–33.
  41. 41. Pica-Mattoccia L, Ruppel A, Xia CM, Cioli D. Praziquantel and the benzodiazepine Ro 11–3218 do not compete for the same binding sites in schistosomes. Parasitology. 2008;135:47–54.
  42. 42. Lu Z, Zhang Y, Berriman M. A web portal for gene expression across all life stages of Schistosoma mansoni. bioRxiv. 2018:308213.
  43. 43. Thomas H, Andrews P. Praziquantel—New Cestocide. Pestic Sci. 1977;8(5):556–560.
  44. 44. Andrews P, Thomas H. The effect of praziquantel on Hymenolepis diminuta in vitro. Tropenmed Parasitol. 1979;30(3):391–400. Epub 1979/09/01.
  45. 45. Terada M, Ishii AI, Kino H, Fujiu Y, Sano M. Studies on chemotherapy of parasitic helminths (IX). Effects of praziquantel on the motility of various parasitic helminths and isolated host tissues. Experientia. 1982;38(5):549–553. Epub 1982/05/15. pmid:7095089
  46. 46. Gemmell MA, Johnstone PD. Cestodes. Antibiot Chemother (1971). 1981;30:54–114. Epub 1981/01/01. pmid:7259135
  47. 47. da Silva VBR, Boucherle B, El-Methni J, Hoffmann B, da Silva AL, Fortune A, et al. Could we expect new praziquantel derivatives? A meta pharmacometrics/pharmacoinformatics analysis of all antischistosomal praziquantel derivatives found in the literature. SAR QSAR Environ Res. 2019;30(6):383–401. Epub 2019/05/31. pmid:31144535
  48. 48. Sprague DJ, Kaethner M, Park SK, Rohr CM, Harris JL, Maillard D, et al. The Anthelmintic Activity of Praziquantel Analogs Correlates with Structure-Activity Relationships at TRPM(PZQ) Orthologs. ACS Med Chem Lett. 2023;14(11):1537–1543. Epub 2023/11/16. pmid:37970586
  49. 49. Chulkov EG, Smith E, Rohr CM, Yahya NA, Park SK, Scampavia L, et al. Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel. PLoS Negl Trop Dis. 2021;15(11):e0009898. Epub 2021/11/04. pmid:34731172
  50. 50. Mansour NR, Paveley R, Gardner JM, Bell AS, Parkinson T, Bickle Q. High Throughput Screening Identifies Novel Lead Compounds with Activity against Larval, Juvenile and Adult Schistosoma mansoni. PLoS Negl Trop Dis. 2016;10(4):e0004659. Epub 2016/04/30. pmid:27128493
  51. 51. Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med. 2019;11(509). Epub 2019/09/13. pmid:31511426
  52. 52. Settleman J, Sawyers CL, Hunter T. Challenges in validating candidate therapeutic targets in cancer. eLife. 2018;7:10.7554/eLife.32402. Epub 2018/02/09. pmid:29417929
  53. 53. Davis RL. Mechanism of Action and Target Identification: A Matter of Timing in Drug Discovery. iScience. 2020;23(9):101487. Epub 2020/09/06. pmid:32891054
  54. 54. Moescheid MF, Puckelwaldt O, Beutler M, Haeberlein S, Grevelding CG. Defining an optimal control for RNAi experiments with adult Schistosoma mansoni. Sci Rep. 2023;13(1):9766. Epub 2023/06/17. pmid:37328492
  55. 55. Brodie JS, Di Marzo V, Guy GW. Polypharmacology Shakes Hands with Complex Aetiopathology. Trends Pharmacol Sci. 2015;36(12):802–821. Epub 2015/10/06. pmid:26434643
  56. 56. Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas AI, Hufeisen SJ, et al. Predicting new molecular targets for known drugs. Nature. 2009;462(7270):175–181. Epub 2009/11/03. pmid:19881490
  57. 57. Babes RM, Selescu T, Domocos D, Babes A. The anthelminthic drug praziquantel is a selective agonist of the sensory transient receptor potential melastatin type 8 channel. Toxicol Appl Pharmacol. 2017;336:55–65. Epub 2017/10/22. pmid:29054683
  58. 58. Gunaratne GS, Yahya NA, Dosa PI, Marchant JS. Activation of host transient receptor potential (TRP) channels by praziquantel stereoisomers. PLoS Negl Trop Dis. 2018;12(4):e0006420. Epub 2018/04/19. pmid:29668703
  59. 59. Chan JD, Cupit PM, Gunaratne GS, McCorvy JD, Yang Y, Stoltz K, et al. The anthelmintic praziquantel is a human serotoninergic G-protein-coupled receptor ligand. Nat Commun. 2017;8(1):1910. Epub 2017/12/07. pmid:29208933
  60. 60. Yahya NA, Lanham JK, Sprague DJ, Palygin O, McCorvy JD, Marchant JS. Molecular and cellular basis of praziquantel action in the cardiovascular system. Am J Physiol Cell Physiol. 2023;324(2):C573–C587. Epub 2023/01/10. pmid:36622066
  61. 61. Chen D, Oezguen N, Urvil P, Ferguson C, Dann SM, Savidge TC. Regulation of protein-ligand binding affinity by hydrogen bond pairing. Sci Adv. 2016;2(3):e1501240. Epub 2016/04/07. pmid:27051863
  62. 62. Gnanasekar M, Salunkhe AM, Mallia AK, He YX, Kalyanasundaram R. Praziquantel affects the regulatory myosin light chain of Schistosoma mansoni. Antimicrob Agents Chemother. 2009;53(3):1054–1060. Epub 2008/12/24. pmid:19104008
  63. 63. Tallima H, El Ridi R. Praziquantel binds Schistosoma mansoni adult worm actin. Int J Antimicrob Agents. 2007;29(5):570–575. Epub 2007/03/08. pmid:17341443
  64. 64. Troianin AR, Pica-Mattoccia L, Valle C, Cioli D, Mignogna G, Ronketti F, et al. Is actin the praziquantel receptor? Int J Antimicrob Agents. 2007;30:274–285.
  65. 65. Kohn AB, Anderson PA, Roberts-Misterly JM, Greenberg RM. Schistosome calcium channel beta subunits. Unusual modulatory effects and potential role in the action of the antischistosomal drug praziquantel. J Biol Chem. 2001;276(40):36873–36876. Epub 2001/08/14. pmid:11500482
  66. 66. Kasinathan RS, Goronga T, Messerli SM, Webb TR, Greenberg RM. Modulation of a Schistosoma mansoni multidrug transporter by the antischistosomal drug praziquantel. FASEB J. 2010;24(1):128–135. Epub 2009/09/04. pmid:19726755
  67. 67. Angelucci F, Basso A, Bellelli A, Brunori M, Pica Mattoccia L, Valle C. The anti-schistosomal drug praziquantel is an adenosine antagonist. Parasitology. 2007;134(Pt 9):1215–1221. Epub 2007/04/13. pmid:17428352
  68. 68. McTigue MA, Williams DR, Tainer JA. Crystal structures of a schistosomal drug and vaccine target: glutathione S-transferase from Schistosoma japonica and its complex with the leading antischistosomal drug praziquantel. J Mol Biol. 1995;246(1):21–27. Epub 1995/02/10. pmid:7853399
  69. 69. Thomas CM, Timson DJ. The Schistosoma mansoni tegumental allergen protein, SmTAL1: Binding to an IQ-motif from a voltage-gated ion channel and effects of praziquantel. Cell Calcium. 2020;86:102161. Epub 2020/01/26. pmid:31981914
  70. 70. Walker J, Crowley P, Moreman AD, Barrett J. Biochemical properties of cloned glutathione S-transferases from Schistosoma mansoni and Schistosoma japonicum. Mol Biochem Parasitol. 1993;61(2):255–264. Epub 1993/10/01. pmid:8264729
  71. 71. Park S-K, Sprague DJ, Chulkov EG, Rohr CM, Petrow I, Kumar S, et al. The anthelmintic drug meclonazepam activates a schistosome transient receptor potential channel. J Biol Chem. 2023. pmid:38043794
  72. 72. Yelshanskaya MV, Sobolevsky AI. Ligand-Binding Sites in Vanilloid-Subtype TRP Channels. Front Pharmacol. 2022;13:900623. Epub 2022/06/03. pmid:35652046
  73. 73. Cao E. Structural mechanisms of transient receptor potential ion channels. J Gen Physiol. 2020;152(3). Epub 2020/01/24. pmid:31972006
  74. 74. Zhao Y, McVeigh BM, Moiseenkova-Bell VY. Structural Pharmacology of TRP Channels. J Mol Biol. 2021;433(17):166914. Epub 2021/03/08. pmid:33676926
  75. 75. Fetterer RH, Pax RA, Bennett JL. Schistosoma mansoni: direct method for simultaneous recording of electrical and motor activity. Exp Parasitol. 1977;43(1):286–294. Epub 1977/10/01. pmid:891712
  76. 76. Bais S, Berry CT, Liu X, Ruthel G, Freedman BD, Greenberg RM. Atypical pharmacology of schistosome TRPA1-like ion channels. PLoS Negl Trop Dis. 2018;12(5):e0006495. Epub 2018/05/11. pmid:29746471
  77. 77. Bais S, Churgin MA, Fang-Yen C, Greenberg RM. Evidence for Novel Pharmacological Sensitivities of Transient Receptor Potential (TRP) Channels in Schistosoma mansoni. PLoS Negl Trop Dis. 2015;9(12):e0004295. Epub 2015/12/15. pmid:26655809
  78. 78. Alwan SN, Taylor AB, Rhodes J, Tidwell M, McHardy SF, LoVerde PT. Oxamniquine derivatives overcome Praziquantel treatment limitations for Schistosomiasis. PLoS Pathog. 2023;19(7):e1011018. Epub 2023/07/10. pmid:37428793
  79. 79. Gardner JMF, Mansour NR, Bell AS, Helmby H, Bickle Q. The discovery of a novel series of compounds with single-dose efficacy against juvenile and adult Schistosoma species. PLoS Negl Trop Dis. 2021;15(7):e0009490. Epub 2021/07/20. pmid:34280206