ArticleAntimicrobial agents and chemotherapy2014
Validation of IMP dehydrogenase inhibitors in a mouse model of cryptosporidiosis.
Article in Antimicrobial agents and chemotherapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 76 citations in OpenAlex.
- Structure-Activity Relationship Study of Anti-Cryptosporidium Benzoxaboroles Yields Enhanced Potency and Curative Efficacy.Journal of medicinal chemistry · 2026Article
- High-Content Screening for Cryptosporidium Drug Discovery.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Norditerpene Natural Products from Subterranean Fungi with Anti-Parasitic Activity.Microorganisms · 2025Article
- Molecular pathogenesis of Cryptosporidium and advancements in therapeutic interventions.Parasite (Paris, France) · 2025Review
- Identification of potent and orally efficacious phosphodiesterase inhibitors in Cryptosporidium parvum-infected immunocompromised male mice.Nature communications · 2024Article
- Anti-Cryptosporidial Drug-Discovery Challenges and Existing Therapeutic Avenues: A "One-Health" Concern.Life (Basel, Switzerland) · 2024Review
- Understanding theFrontiers in parasitology · 2024Review
- Specific pathway abundances in the neonatal calf faecal microbiome are associated with susceptibility to Cryptosporidium parvum infection: a metagenomic analysis.Animal microbiome · 2023Article
- Early immune and host cell responses toFrontiers in parasitology · 2023Article
- Effects of fenbendazole on fecal microbiome in BPH/5 mice, a model of hypertension and obesity, a brief report.PloS one · 2023Article
- Compartmentalization and regulation of GTP in control of cellular phenotypes.Trends in molecular medicine · 2022Review
- An update onJournal of parasitic diseases : official organ of the Indian Society for Parasitology · 2022Review
- Effect of Caging onMicroorganisms · 2022Article
- Optimization of the Urea Linker of Triazolopyridazine MMV665917 Results in a New Anticryptosporidial Lead with Improved Potency and Predicted hERG Safety Margin.Journal of medicinal chemistry · 2021Article
- Systemic efficacy onParasitology · 2021Article
- Molecular Basis of P131 Cryptosporidial-IMPDH Selectivity-A Structural, Dynamical and Mechanistic Stance.Cell biochemistry and biophysics · 2021Article
- A probable means to an end: exploring P131 pharmacophoric scaffold to identify potential inhibitors of Cryptosporidium parvum inosine monophosphate dehydrogenase.Journal of molecular modeling · 2021Article
- Changes in the Microbiome ofMicroorganisms · 2020Article
- Repurposing existing drugs: identification of irreversible IMPDH inhibitors by high-throughput screening.Journal of enzyme inhibition and medicinal chemistry · 2019Article
- P-Glycoprotein-Mediated Efflux Reduces the In Vivo Efficacy of a Therapeutic Targeting the Gastrointestinal Parasite Cryptosporidium.The Journal of infectious diseases · 2019Article
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Authors and funding
11 authors at 6 institutions in 1 country.
Funding
Abstract
Cryptosporidium parasites are a major cause of diarrhea and malnutrition in the developing world, a frequent cause of waterborne disease in the developed world, and a potential bioterrorism agent. Currently, available treatment is limited, and Cryptosporidium drug discovery remains largely unsuccessful. As a result, the pharmacokinetic properties required for in vivo efficacy have not been established. We have been engaged in a Cryptosporidium drug discovery program targeting IMP dehydrogenase (CpIMPDH). Here, we report the activity of eight potent and selective inhibitors of CpIMPDH in the interleukin-12 (IL-12) knockout mouse model, which mimics acute human cryptosporidiosis. Two compounds displayed significant antiparasitic activity, validating CpIMPDH as a drug target. The best compound, P131 (250 mg/kg of body weight/day), performed equivalently to paromomycin (2,000 mg/kg/day) when administered in a single dose and better than paromomycin when administered in three daily doses. One compound, A110, appeared to promote Cryptosporidium infection. The pharmacokinetic, uptake, and permeability properties of the eight compounds were measured. P131 had the lowest systemic distribution but accumulated to high concentrations within intestinal cells. A110 had the highest systemic distribution. These observations suggest that systemic distribution is not required, and may be a liability, for in vivo antiparasitic activity. Intriguingly, A110 caused specific alterations in fecal microbiota that were not observed with P131 or vehicle alone. Such changes may explain how A110 promotes parasitemia. Collectively, these observations suggest a blueprint for the development of anticryptosporidial therapy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.