# Development of non-sedative, parasite-selective benzodiazepines to treat the neglected tropical disease schistosomiasis

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN OSHKOSH · 2021 · $165,786

## Abstract

ABSTRACT: The neglected tropical disease schistosomiasis is caused by parasitic blood flukes that infect
>230 million people worldwide. Current treatment is reliant on just one drug, praziquantel (PZQ). PZQ is
ineffective against recently acquired parasites that have not reached sexual maturity. PZQ also does not kill
schistosomes directly. These drawbacks, and the prospect of emerging treatment-resistant parasite strains,
highlight the need for alternative therapies to control schistosomiasis. The long-term goal is to identify
improved anti-schistosomal drugs. Therefore, this proposal will investigate an alternative group of compounds
with proven anti-parasitic activity, benzodiazepines. Benzodiazepine leads are effective at treating
schistosomiasis but have high affinity for the human GABAARs that cause sedation. The overall objective of
this application is to identify derivatives of a schistocidal benzodiazepine, meclonazepam, that retain anti-
parasitic activity and lack affinity for sedation-causing GABAAR sub-types. The central hypothesis is that
that benzodiazepine therapies with decreased engagement of host GABAARs will minimize sedation and retain
schistocidal activity. The rationale for this project is that while host sedation is driven by drug action at the
α1GABAAR, schistosome genomes lack GABAARs entirely. Therefore, GABAARs cannot account for the anti-
parasitic effects of benzodiazepines. Instead, preliminary data indicates that meclonazepam acts on parasite
Ca2+ channels. Since the ‘on-target’ parasite receptor and ‘off-target’ host receptor for this drug are distinct, it
should be possible to develop treatments with improved selectivity. This will be done by pursuing two specific
aims: 1) Develop analogs of meclonazepam with decreased activity at mammalian α1GABAARs. 2) Block
sedation in vivo by admixture of meclonazepam with α1GABAAR antagonists. Under the first aim, we will
synthesize meclonazepam analogs and screen these and other sub-type selective benzodiazepines in binding
assays against mammalian GABAARs. Compounds with decreased GABAAR affinity will then be screened
against schistosomes to identify parasite-selective derivatives. Finally, schistocidal ligands will be screened in
murine model of schistosomiasis to assess efficacy benchmarked relative to meclonazepam. In the second
aim, we will assess the in vivo sedative effects of meclonazepam (as well as hits from Aim 1) and the blockade
of sedation by α1GABAAR-selective antagonists. The rotarod test will be used to determine the sedating dose
of each compound, which will then be administered in mixture with varying ratios of antagonists to determine
an admixture that admixture clears parasites with minimized side effects. The research proposed is significant
because it will advance new schistocidal leads – no drug to treat schistosomiasis has been FDA approved
since 1982. This research is innovative, combining Dr. Chan’s expertise in parasitology with the medicinal
che...

## Key facts

- **NIH application ID:** 10612112
- **Project number:** 5R21AI146540-05
- **Recipient organization:** UNIVERSITY OF WISCONSIN OSHKOSH
- **Principal Investigator:** John D Chan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $165,786
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10612112

## Citation

> US National Institutes of Health, RePORTER application 10612112, Development of non-sedative, parasite-selective benzodiazepines to treat the neglected tropical disease schistosomiasis (5R21AI146540-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10612112. Licensed CC0.

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