# Identification of the target of meclonazepam in schistosome worms

> **NIH NIH R21** · RUSH UNIVERSITY MEDICAL CENTER · 2021 · $251,200

## Abstract

PROJECT SUMMARY/ABSTRACT
Schistosome parasites infect 200 million people, resulting in significant morbidity and more than 200,000
deaths annually. Schistosomiasis control strategies rely almost exclusively on chemotherapy and tens of
millions of people are treated with the only available drug, praziquantel (PZQ). There are no new drugs in the
clinical pipeline. PZQ cure rates obtained in mass drug administration campaigns are typically less than 50%.
Furthermore, with projected levels of PZQ use it is inevitable that PZQ-resistant parasites will evolve.
Therefore, it is imperative to identify new drug targets and drugs for schistosomiasis treatment.
A number of highly promising compounds with antischistosomal activity have been identified. However, further
advancement of these compounds to drugs is impeded because their targets are unknown. In this regard, the
benzodiazepine derivative meclonazepam (Ro11-3128) had been identified as a lead candidate.
Meclonazepam exhibited potent therapeutic activity against both mature and immature stages of S. mansoni
and S. haematobium in humans. Unfortunately, the drug was later discontinued due to its lack of selectivity
resulting in unacceptable side effects at therapeutic doses. Meclonazepam is an anxiolytic benzodiazepine that
is an allosteric modulator of mammalian gamma-amino butyric acid receptors. No homologues in Schistosoma
worms have been identified in genome databases. The closest matches (glutamate-gated transporters) have
been investigated and were not inhibited by meclonazepam. This indicates that the target of meclonazepam in
schistosomes is not a known benzodiazepine receptor and remains undiscovered.
This revised R21 proposal is designed to test the central hypothesis that meclonazepam kills worms through
interaction with a worm-specific and unknown target. We propose to identify the target of meclonazepam in
Schistosoma parasites using orthogonal and complementary approaches (1) design and synthesis of novel,
drug-like meclonazepam-based photoreactive probes, and (2) biophysical changes in proteins bound to
inhibitors. We anticipate multiple proteins being identified by these analyses. Proteins will be studied further if
(1) they were identified only in species sensitive to meclonazepam and not in those insensitive, (2) they were
identified in worms treated with meclonazepam or active analogs and not in worms treated with inactive
analogs, and (3) meclonazepam competes with probe binding to the protein. Proteins meeting these strict
criteria will be selected for further investigation. Analysis of potential function, recombinant expression and
biochemical analysis, and gene silencing will be used to confirm the targets. Identification of the molecular
target in the worm is the essential first step needed to develop novel therapeutic targets and produce clinically
relevant treatments for schistosomiasis.

## Key facts

- **NIH application ID:** 10218461
- **Project number:** 1R21AI149102-01A1
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Pavel A Petukhov
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $251,200
- **Award type:** 1
- **Project period:** 2021-02-22 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218461

## Citation

> US National Institutes of Health, RePORTER application 10218461, Identification of the target of meclonazepam in schistosome worms (1R21AI149102-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10218461. Licensed CC0.

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