NIH grant: Optimization of orally efficacious pyrazolopyrimidines for treating cryptosporidiosis (1R01AI195718-01A1)

retained text

NIH grant 1R01AI195718-01A1: Optimization of orally efficacious pyrazolopyrimidines for treating cryptosporidiosis
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: CHRISTOPHER D HUSTON. Award: $777365.
Start: 2026-08-01T00:00:00.
PROJECT SUMMARY
Cryptosporidium parasites are NIAID biodefense priority pathogens that infect the intestinal epithelium and cause
cryptosporidiosis in humans and livestock. They are amongst the most important causes of life-threatening
diarrhea in infants worldwide and cause incurable diarrhea in immunosuppressed patients. Unfortunately,
nitazoxanide, the only approved drug, has limited efficacy in children and is equivalent to a placebo in AIDS
patients. The long-term goal of this research is to develop improved drugs to treat cryptosporidiosis. This project
focuses on a new series of pyrazolopyrimidine benzoxaboroles (PP-BB) that were identified during a bioisostere
replacement survey of a pyrazolopyrimidine (PP) benzoic acid lead that targets the parasite phosphodiesterase
(PDE) CpPDE1. The new PP-BBs possess many characteristics of the ideal anticryptosporidial target product
profile, since they are potent against both C. hominis and C. parvum, highly selective for parasites vs. host cells,
rapidly eliminate C. parvum in rate-of-action time-kill assays, and the current lead possesses outstanding efficacy
without relapse at one week follow up in an immunocompromised C. parvum-infected mouse model. The current
lead is a racemic mixture with one enantiomer >400x more potent than the other. Furthermore, the lead is active
against the related model apicomplexan parasite Toxoplasma gondii and its enantiomers mirror the potency
selectivity pattern seen against C. parvum, suggesting a conserved apicomplexan target. The specific aims
focus on further improving the therapeutic index (Aim 1) while identifying and optimizing compound
characteristics needed to achieve the high intestinal concentrations required to maximize in vivo efficacy (Aim
2) and resolving the physiologically relevant PP-BB target(s) (Aim 3), since the PP-BBs may still target CpPDE1
but optimization may have shifted activity to include a second target. Aims 1 and 2 are supported by a rigorous
milestone-based testing cascade that retains key prior innovations for compound prioritization. Aim 1 will use
iterative medicinal chemistry to optimize anti-Cryptosporidium potency, selectivity versus human PDEs, and
PK/ADME properties to yield potent, optimized PP-BBs. Aim 2 will systematically determine physicochemical
parameters correlated with in vivo efficacy, enabling selection of optimized PP-BBs and nomination of 1-2 orally
efficacious preclinical candidates. Aim 3 (target identification) will circumvent technical limitations inherent to C.
parvum by combining unbiased target identification using thermal proteome profiling in T. gondii with follow up
CRISPR-mediated C. parvum genetic studies. Collectively, success will accelerate anti-Cryptosporidium drug
development by yielding 1-2 pre-clinical candidates that are optimized for safety and in vivo efficacy, and a novel
genetically validated drug target. Given the dire need for new cryptosporidiosis drugs, the public health impact
of success would be extremely significant.

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