# IMPDH inhibitors for the treatment of Cryptosporidium infections

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2020 · $746,322

## Abstract

PROJECT SUMMARY/ABSTRACT
Cryptosporidium species, such as C. parvum, are protozoan parasites that present a significant health threat to
young children and immunocompromised adults. These organisms are potential bio-terrorism agents that could
incapacitate large populations, as well. Current treatment options for Cryptosporidium infections are limited.
Commonly used anti-parasitic drugs are ineffective, the only FDA-approved drug is poorly efficacious, and
vaccines are unavailable. Cryptosporidium species rely on inosine 5’-monophosphate dehydrogenase
(IMPDH), as revealed by genomic analysis, for producing guanine nucleotides and, hence, survival. The
parasite likely obtained its IMPDH gene from ε-proteobacterium, so C. parvum IMPDH (CpIMPDH) is highly
diverged from the human orthologs. Consequently, selective CpIMPDH inhibitors may provide an effective
strategy for the treatment of cryptosporidiosis with minimum toxicity to patients. To date, we have identified
several structurally distinct classes of CpIMPDH inhibitors that have demonstrated excellent enzymatic
potency, selectivity over human IMPDH, anti-parasitic activity in a cell culture model and, for one compound
series, in vivo efficacy in an acute cryptosporidiosis mouse model. The overall goals of this study are to further
refine CpIMPDH inhibitors to achieve efficacy in both acute and chronic mouse models of cryptosporidiosis to
support the hypothesis that selective CpIMPDH inhibition is a viable treatment strategy for C. parvum
infections, provide guidance for the research community with respect to optimal compound properties for in
vivo efficacy and selection of pre-clinical candidates for further development. These goals will be achieved by
pursuing three specific aims: 1) design and in vitro evaluation of CpIMPDH inhibitors in assays of CpIMPDH
inhibitory potency and selectivity, a C. parvum cell culture infection model and ADME properties (including
solubility, intestinal microsomal stability, cellular uptake, efflux, toxicity, and UGT-mediated glucuronidation); 2)
assess the in vivo pharmacokinetic and acute toxicity properties of CpIMPDH inhibitors, including in vivo
models of absorption and tissue distribution in both normal and C. parvum infected mice; 3) evaluate optimized
CpIMPDH inhibitors in acute and chronic animal models of cryptosporidiosis assessing efficacy via imaging of
fluorescent parasites, fecal oocyst excretion and gastrointestinal gross and histopathology. In addition, the
impact of CpIMPDH inhibitors on commensal bacteria populations will be examined to more fully evaluate
pharmacodynamics. This project will also develop a strategy for enterohepatic recycling in order to maximize
gastrointestinal concentrations, while reducing systemic exposure and toxicity risk.
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## Key facts

- **NIH application ID:** 9934115
- **Project number:** 5R01AI125362-05
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** Gregory D Cuny
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $746,322
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934115

## Citation

> US National Institutes of Health, RePORTER application 9934115, IMPDH inhibitors for the treatment of Cryptosporidium infections (5R01AI125362-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934115. Licensed CC0.

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