# Development of novel TGR inhibitors for the treatment of schistosomiasis

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $800,624

## 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. With projected levels of PZQ use, it is inevitable that PZQ-resistant parasites will evolve. Therefore, it
is imperative to find new drug targets and drugs for schistosomiasis treatment, our long-term objective. We
identified a highly promising drug target: the worm selenocysteine-containing enzyme thioredoxin glutathione
reductase (TGR). We established that TGR is a central and essential mediator of antioxidant defenses in the
worm. The antioxidant defenses of vertebrates are diversified to three enzymes, glutathione reductase,
thioredoxin reductase, and glutaredoxin, whereas schistosomes rely solely on TGR. TGR is a chokepoint and its
inhibition leads to rapid worm death in all developmental stages. In contrast, PZQ has poor activity against
juvenile worms, often resulting in partial cures. TGR is a defined molecular target, active as a recombinant
protein, and we have established biochemical assays amenable to rapid compound screening, SAR, and
optimization. We initiated several HTS of large compound libraries, which identified TGR inhibitors that have
been used to obtain both liganded and ligand-free crystal structures of TGR, allowing a structure-based approach
to hit optimization. These studies have elucidated an inhibitory mechanism that is completely novel for this family
of proteins, allowing the development of non-covalent inhibitors. We hypothesize that it will be possible to
optimize our novel TGR inhibitors for potency for TGR inhibition and selectivity against human glutathione
reductase and thioredoxin reductase enzymes in vitro and schistosomicidal efficacy in vivo, our short-term
objectives. Our aims are to optimize novel TGR inhibitors using cutting-edge structure- and ligand-based
computer-aided design and medicinal chemistry to improve potency, selectivity, solubility, toxicity, and
bioavailability. This will be complemented by X-ray crystallography and cryo-electron microscopy. Medicinal
chemistry will be informed by enzymatic analysis of TGR and orthologous human enzymes, metabolic stability,
in vitro cell toxicity, and activity against ex vivo worms. Finally, select compounds will be assessed for PK/PD
properties and efficacy against schistosome infections in mice. To accomplish these aims, we assembled a team
of experts in schistosome biochemistry and drug discovery, medicinal chemistry, computer-aided molecular
design, chemical and structural biology of TGR. The varied and synergistic expertise of the team will facilitate
overcoming critical barriers to development of schistosomicidal therapeutics. While additional preclinical studies
would be needed, discovery o...

## Key facts

- **NIH application ID:** 10879953
- **Project number:** 1R01AI177493-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** FRANCESCO ANGELUCCI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $800,624
- **Award type:** 1
- **Project period:** 2024-07-05 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879953

## Citation

> US National Institutes of Health, RePORTER application 10879953, Development of novel TGR inhibitors for the treatment of schistosomiasis (1R01AI177493-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10879953. Licensed CC0.

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