# Identification of targets of the antiparasitic drug praziquantel

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $444,538

## Abstract

PROJECT SUMMARY
The parasitic infection schistosomiasis afflicts over 200 million people worldwide and is clinically treated using
a single drug, praziquantel (±PZQ). Although ±PZQ has served as a stalwart anthelmintic for decades, the
molecular basis of action of this drug remains undefined. This lack of mechanistic knowledge impedes rational
design of alternative therapeutics and is worrisome in the face of emergence of schistosome strains exhibiting
refractoriness to ±PZQ exposure given ±PZQ is ineffective against all parasitic life cycle stages. Insight into the
targets of ±PZQ action, and their effectors, is therefore needed to develop improved anthelmintic therapies.
This R01 application is based around preliminary data supporting a premise that PZQ is a serotonin-like ligand
in both the parasite and the human host. Our laboratory has recently identified targets for both R-PZQ and S-
PZQ, the two enantiomers in the clinical formulation of ±PZQ. R-PZQ is a ligand at the human 5-HT2B G protein
coupled receptor (5-HT2B GPCR), and S-PZQ is a serotonergic regulator of the human transient receptor
potential melastatin 8 ion channel (TRPM8). These findings are significant as they (i) provide clues to the likely
targets of PZQ enantiomers in the parasite (5-HT GPCRs & TRP channels) and (ii) demonstrate that PZQ does
not act as a selective antiparasitic, but also is active in the host. Notably ±PZQ acutely changes blood vessel
tone within the mesenteric blood vessels where the adult worms reside. Chronic engagement of 5-HT GPCRs
in hepatic stellate cells inhibited fibrotic changes caused by inflammatory reactions to worm eggs deposited in
host tissues. Coalescing such beneficial host and deleterious parasitic activities provides a novel route to
generating improved antiparasitic therapies that kill worms and prevent the tissue damage they cause.
Based on our discoveries, we will map the binding sites of R-PZQ on 5-HT2BR, and S-PZQ on TRPM8 and use
these binding poses to identify similar binding architectures in schistosome bioaminergic GPCRs (Aim 1) and
TRP channels (Aim 2). Following this strategy, we have recently identified a schistosome TRP channel that is
regulated by PZQ (10) – the first target of PZQ ever identified in a flatworm. Finally, we will address the
clinical significance of host bioactivity of anthelmintics (Aim 3) in terms of acute effects on the vasculature, and
chronic effects on hepatic stellate cells that initiate fibrogenic changes underpinning many of the pathologies of
chronic schistosomiasis. Our collaborative team bring together expertise in 5-HT2B receptor structure, TRP
channel biology and blood vessel physiology to execute activities from molecular (receptor structure) to in vivo
pathology (mechanisms regulating parasite infection and liver disease). If successful, our activities will resolve
targets and effectors for ±PZQ that will enable development of better anthelmintic therapies and adjuncts.

## Key facts

- **NIH application ID:** 10370365
- **Project number:** 5R01AI145871-03
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** JONATHAN S MARCHANT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $444,538
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370365

## Citation

> US National Institutes of Health, RePORTER application 10370365, Identification of targets of the antiparasitic drug praziquantel (5R01AI145871-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10370365. Licensed CC0.

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