# Discovery and development of novel schistosomicidal agents

> **NIH NIH R41** · ACHEMINALL CORPORATION · 2024 · $300,000

## 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. Although very successful, this initial study was
focused largely on aspects other than optimization of oral bioavailability of TGR inhibitors, impeding their further
development. We hypothesize that it will be possible to optimize our novel TGR inhibitors for oral administration
while maintaining efficacy comparable to that for compound 2 administered IP, an objective for this feasibility
study. To achieve this objective, we propose: to optimize novel TGR inhibitors using cutting-edge structure- and
ligand-based computer-aided design, medicinal chemistry, and pharmacokinetics approaches for oral availability
while also improving potency, selectivity, solubility, and safety. Select compounds will be assessed for 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 of novel orally bioavailable TGR inhibitors with demonstrated activity in animal models is ...

## Key facts

- **NIH application ID:** 10921896
- **Project number:** 1R41AI184237-01
- **Recipient organization:** ACHEMINALL CORPORATION
- **Principal Investigator:** Pavel Petukhov
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $300,000
- **Award type:** 1
- **Project period:** 2024-06-21 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10921896

## Citation

> US National Institutes of Health, RePORTER application 10921896, Discovery and development of novel schistosomicidal agents (1R41AI184237-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10921896. Licensed CC0.

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