The Mechanism of Action of Praziquantel: Six Hypotheses

Abstract

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.

Artemether and Praziquantel: Origin, Mode of Action, Impact, and Suggested Application for Effective Control of Human Schistosomiasis

“…Even if the influx of calcium ions into the worm after exposure to PZQ is regularly observed, the molecular mechanism of PZQ’s mode of action is not fully unravelled. The lack of widespread resistance after long-term use may be due to the presence of multiple pharmacologically relevant targets, and Thomas and Timson [71] suggest that PZQ may act, at least in part, on a protein–protein interaction and that altered drug metabolism or enhanced drug efflux are the most likely ways resistance may arise. Additionally, laboratory tests to identify resistance to PZQ have demonstrated a specific region in the parasite genome which might be responsible for reduced drug susceptibility [72].…”

The anthelmintic drug praziquantel activates a schistosome transient receptor potential channel

“…( S )-PZQ is regarded as the less active distomer (6). From a therapeutic perspective, 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). This lack of knowledge is a longstanding roadblock for this field.…”

Avermectins, praziquantel and levamisole have in vitro efficacy against Neoechinorhynchus buttnerae (Neoechinorhynchidae) in Colossoma macropomum: A Serrasalmidae from the Amazon

“…Efficacy of the anthelminthics against Neoechinorhynchus buttnerae of Colossoma macropomum in 6 and 24 hr of exposure of Dactylogyrus vastator Nybelin, 1924 after exposure to praziquantel. Praziquantel has a mechanism of action based on depolarization of the tegument of helminth parasites, thus leading to entry of calcium into the cells, hence causing immobilization, spasmodic contractions and paralysis(Hardy-Smith et al, 2012;Sitja-Bobadilla, Felipe, & Alvarez-Pellitero, 2006;Thomas & Timson, 2018;Williams, Ernst, Chambers, & Whittington, 2007).…”