Despite being one of the most commonly used drugs, the molecular mechanism of action of the anthelmintic praziquantel remains unknown. There are some unusual features of this drug. Critically, widespread resistance to praziquantel has not developed despite decades of use. Here, we set out some challenges in praziquantel research and propose some provocative hypotheses to address these. We suggest that praziquantel may have multiple pharmacologically relevant targets and the effects on these may synergise to produce an overall, detrimental effect on the parasite. Praziquantel also acts on a number of host proteins and we propose that these actions are important in the drug's overall mechanism. Although the drug is largely used in the treatment of human and domestic animal worm infections, there is a considerable "grey literature" along with some academic studies which may have been overlooked. It appears that praziquantel may be effective against hydra. It may also be effective against some unicellular parasites such as Giardia spp. Further, scientific work on these understudied areas may be useful in understanding the molecular mechanism in Trematoda. The lack of widespread resistance suggests that praziquantel may act, at least in part, on a protein-protein interaction. Altered drug metabolism or enhanced drug efflux are the most likely ways resistance may arise. There is a critical need to understand the biochemical pharmacology of this drug in order to inform the discovery of the next generation of anthelmintic drugs.

/pdf/the-mechanism-of-action-of-praziquantel-six-hypotheses-3gx6413ela.pdf

The Mechanism of Action of Praziquantel: Six Hypotheses

Schistosomiasis remains a public health concern across sub-Saharan Africa; current control programmes rely on accurate mapping and high mass drug administration (MDA) coverage to attempt disease elimination. Inter-species hybridisation can occur between certain species, changing epidemiological dynamics within endemic regions, which has the potential to confound control interventions. The impact of hybridisation on disease dynamics is well illustrated in areas of Cameroon where urogenital schistosomiasis, primarily due to Schistosoma haematobium and hybrid infections, now predominate over intestinal schistosomiasis caused by Schistosoma guineensis. Genetic markers have shown the ability to identify hybrids, however the underlying genomic architecture of divergence and introgression between these species has yet to be established. In this study, restriction site associated DNA sequencing (RADseq) was used on archived adult worms initially identified as; Schistosoma bovis (n = 4), S. haematobium (n = 9), S. guineensis (n = 3) and S. guineensis x S. haematobium hybrids (n = 4) from Mali, Senegal, Niger, São Tomé and Cameroon. Genome-wide evidence supports the existence of S. guineensis and S. haematobium hybrid populations across Cameroon. The hybridisation of S. guineensis x S. haematobium has not been demonstrated on the island of São Tomé, where all samples showed no introgression with S. haematobium. Additionally, all S. haematobium isolates from Nigeria, Mali and Cameroon indicated signatures of genomic introgression from S. bovis. Adaptive loci across the S. haematobium group showed that voltage-gated calcium ion channels (Cav) could play a key role in the ability to increase the survivability of species, particularly in host systems. Where admixture has occurred between S. guineensis and S. haematobium, the excess introgressive influx of tegumental (outer helminth body) and antigenic genes from S. haematobium has increased the adaptive response in hybrids, leading to increased hybrid population fitness and viability.

/pdf/genome-wide-insights-into-adaptive-hybridisation-across-the-21ivuee2.pdf

Genome-wide insights into adaptive hybridisation across the Schistosoma haematobium group in West and Central Africa

Praziquantel leads to increase Ca2+ influx and disrupts Ca2+ homeostasis in adult Schistosoma However, calcium influx is only one component in a series of molecular events leading to the drug effect and some downstream constituents of the cascade that is initiated by this interaction differ between worms with different degrees of susceptibility to praziquantel Extensive use of the drug raises the concern regarding the selection of drug resistant parasites SERCA participates in maintenance of Ca2+ homeostasis Up-regulation of SERCA has been found in Schistosoma mansoni worms with reduced sensitivity to praziquantel This could be due to increase cytosolic Ca2+, activation of calmodulin kinase II or may be due to SR/ER stress generated from oxidative stress that leads to impaired protein degradation The significance of SERCA up-regulation is related to counter action of the drug effect by increasing the worm capacity to restore Ca2+ homeostasis, reducing cytosolic Ca2+ followed by lowering mitochondria Ca2+ and consequently inhibition of apoptosis beside its relation to P-glycoprotein In schistosomes with reduced sensitivity to praziquantel, the agitations produced by Ca2+ influx and the downstream component of the cascade that is initiated by this interaction may be opposed by up-regulation of SERCA and possibly by certain elements of Ca2+ signaling which modulate the process determining cells entrance in the apoptotic state Revealing the principal mechanisms of up-regulation of SERCA and its significance in reducing the effect of the drug could lead to possible strategies to reverse drug resistance or develop alternative therapies

Schistosoma mansoni sarco/endoplasmic reticulum Ca 2+ ATPases (SERCA): role in reduced sensitivity to praziquantel

https://cris.brighton.ac.uk/ws/files/500766/CECA_2018_56_Revision%201_accepted%20ms%20version.pdf

Calmodulins from Schistosoma mansoni: Biochemical analysis and interaction with IQ-motifs from voltage-gated calcium channels.

Control of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction. However, conditions worms are exposed to in vivo may vary considerably from in vitro experiments given the short half-life of PZQ and the importance of host immune system engagement for drug efficacy in animal models. Here, we investigated the effects of in vivo PZQ exposure on Schistosoma mansoni. Measurement of pro-apoptotic caspase activation revealed that worm death occurs only after parasites shift from the mesenteric vasculature to the liver, peaking 24 hours after drug treatment. This indicates that PZQ is not directly schistocidal, since PZQ's half-life is ~2 hours in humans and ~30 minutes in mice, and focuses attention on parasite interactions with the host immune system following the shift of worms to the liver. RNA-Seq of worms harvested from mouse livers following sub-lethal PZQ treatment revealed drug-evoked changes in the expression of putative immunomodulatory and anticoagulant gene products. Several of these gene products localized to the schistosome esophagus and may be secreted into the host circulation. These include several Kunitz-type protease inhibitors, which are also found in the secretomes of other blood feeding animals. These transcriptional changes may reflect mechanisms of parasite immune-evasion in response to chemotherapy, given the role of complement-mediated attack and the host innate/humoral immune response in parasite elimination. One of these isoforms, SmKI-1, has been shown to exhibit immunomodulatory and anti-coagulant properties. These data provide insight into the effect of in vivo PZQ exposure on S. mansoni, and the transcriptional response of parasites to the stress of chemotherapy.

/pdf/schistosoma-mansoni-alter-transcription-of-immunomodulatory-9e5c3v0j97.pdf

Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure.

https://cris.brighton.ac.uk/ws/files/479539/MOLBIO-D-17-00103-accepted%20ms.pdf

The tegumental allergen-like proteins of Schistosoma mansoni: a biochemical study of SmTAL4-TAL13

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The tegumental allergen-like proteins of Schistosoma mansoni: a biochemical study of SmTAL4-TAL13