# Discovery of new molecular phenotypes for anti-schistosomal drug screening

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $220,838

## Abstract

PROJECT SUMMARY: Parasitic Schistosoma blood flukes cause the neglected topical disease
schistosomiasis. This disease infects >200 million people but is clinically treated by monotherapy with just one
broad spectrum drug, praziquantel (PZQ). The vast scope of the disease and the prospect of PZQ resistance
highlight the need for alternative therapies. Indeed, PZQ treatment failure has been reported in the field and
resistance can be selected in the lab, indicating that standing genetic variation for resistance already exists.
However, drug discovery efforts are hampered by our poor understanding of how existing anti-schistosomal
drugs work. Many of these older compounds were discovered >40 years ago using in vivo animal screens. The
long-term goal is to identify druggable targets / lead compounds to treat schistosomiasis. The overall objective
of this application is to resolve the molecular changes in schistosome biology that underpin the efficacy of
existing anti-schistosomal compounds, moving beyond superficial descriptors of worm morphology towards
quantitative endpoints that can be assayed for new leads. The central hypothesis is that anthelmintics evoke
molecular changes that are more productive screening endpoints than superficial phenotypes. The rationale for
this project is that current schistosomiasis drug discovery efforts often focus on in vitro assays for changes in
movement or morphology, which are poor predictors of efficacy in vivo. Some anti-schistosomal drugs do
cause changes in worm movement / morphology, but others are efficacious in vivo with no effect on movement
in vitro, and still other drugs impair movement in vitro but are ineffective in vivo. Better predictors of anti-
parasitic action are needed to develop more productive assays. We will pursue two specific aims: (1) Profiling
the activity of 10 chemically diverse anti-schistosomal drugs using a panel of molecular assays and (2)
Identifying transcriptional signatures of anthelmintics with distinct mechanisms of action. The first aim will
resolve mechanistic similarities and differences between these 10 anthelmintics by systematically assessing
cellular and molecular changes in worms exposed to drug in vivo. These outcomes will serve as endpoints for
the development of quantitative assays for future screens. The second aim will compare the transcriptional
responses of parasites to each drug, providing an unbiased readout of global changes to schistosome biology
and allowing drugs to be binned according to putative mechanisms of action. Insight into the comparative
mechanisms of anti-schistosomal compounds will allow us to rationally select alternative drugs in the event of
PZQ treatment failure. This information will also inform drug-combination strategies to prevent the emergence
of drug resistance. The research proposed in this application is significant because it will provide new assays
for future drug discovery efforts that are better predictors of in vivo anti-paras...

## Key facts

- **NIH application ID:** 10039280
- **Project number:** 1R21AI153545-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** John D Chan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $220,838
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10039280

## Citation

> US National Institutes of Health, RePORTER application 10039280, Discovery of new molecular phenotypes for anti-schistosomal drug screening (1R21AI153545-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10039280. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*