The anthelmintic praziquantel is a human serotoninergic G-protein-coupled receptor ligand

Abstract

Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. Approximately 260 million people are infected worldwide, underscoring the clinical and socioeconomic impact of this chronic infection. Schistosomiasis is treated with the drug praziquantel (PZQ), which has proved the therapeutic mainstay for over three decades of clinical use. However, the molecular target(s) of PZQ remain undefined. Here we identify a molecular target for the antischistosomal eutomer — (R)-PZQ — which functions as a partial agonist of the human serotoninergic 5HT2B receptor. (R)-PZQ modulation of serotoninergic signaling occurs over a concentration range sufficient to regulate vascular tone of the mesenteric blood vessels where the adult parasites reside within their host. These data establish (R)-PZQ as a G-protein-coupled receptor ligand and suggest that the efficacy of this clinically important anthelmintic is supported by a broad, cross species polypharmacology with PZQ modulating signaling events in both host and parasite.

Chemoenzymatic Approach to (S)‐1,2,3,4‐Tetrahydroisoquinoline Carboxylic Acids Employing D‐Amino Acid Oxidase

“…Chiral 1,2,3,4‐tetrahydroisoquinolines (THIQs) are widely distributed in various natural bioactive alkaloids and also serve as important intermediates in pharmaceutical chemistry . Compounds containing THIQ skeleton exhibit a variety of biological activities, such as antitumor, antimalarial, anthelmintic, antihypertensive, targeting of the central nervous system, and inhibiting Keap1‐Nrf2 protein‐protein interactions . Their biological activities are occasionally stereoselective in terms of their potency, metabolism and bitter taste …”

“…[7] Their biological activities are occasionally stereoselective in terms of their potency, metabolism and bitter taste. [4,8] Considerable effort has been devoted to the enantioselective preparation of chiral THIQs. Chemical asymmetric synthesis method are important and frequent sources of these compounds.…”

The anthelmintic drug praziquantel promotes human Tr1 differentiation

“…We further demonstrated this as supernatants of PZQ‐treated cells strongly suppressed proliferation of bystander T cells, and this was partly restored by blocking IL‐10. Interestingly, a recent study showed that PZQ acted as an agonist for the human serotonin receptor 5‐HT2BR, demonstrating its ability to modulate human cells . T cells express serotonin receptors upon their activation and it is theoretically possible that PZQ may utilize 5‐HT2BR to exert its action on human T cells.…”

“…Importantly, a recent study identified a serotonin receptor as a cellular receptor for PZQ . PZQ bound specifically to the 5‐HT2BR and elicited contraction of mouse mesenteric vasculature.…”

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

“…To date, the mechanism of action remains unknown. Among others, voltage‐operated Ca 2+ channels were discussed as potential targets of PZQ ( 9 ), and recently also a (human) serotoninergic 5‐HT 2B receptor . After treatment, muscle contractions of the parasite are observed first before the worms are swept into the liver and are eliminated by inflammatory reactions .…”