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Preclinical optimization of a parasiticidal drug for cryptosporidiosis

Investigators
Huston, Christopher; Griggs, David; Meyers, Marvin J
Institutions
University of Vermont
Start date
2019
End date
2024
Objective
PROJECT SUMMARYCryptosporidiosis is amongst the most important causes of life-threatening diarrhea in children globally, causesincurable diarrhea in AIDS and transplant patients, and is the most common cause of waterborne diarrhealoutbreaks in the United States. Almost all human cases of cryptosporidiosis are due to infection of the smallintestinal epithelium with one of two species of Cryptosporidium parasites, C. parvum or C. hominis.Nitazoxanide, the only approved drug, is efficacious in otherwise healthy adults, but unfortunately, has limitedefficacy (~56%) in children and is equivalent to a placebo in AIDS patients. The long-term goal of this researchprogram is to develop improved drugs to treat cryptosporidiosis. In this project, a parasiticidal piperazine-based lead compound with extraordinary in vivo efficacy that was identified by phenotypic screening will beoptimized, and its molecular mechanism of action will be determined. The lead optimization program is guidedby an ideal target product profile and milestones to provide a pre-clinical lead that is likely to be effective in allpatient populations affected by Cryptosporidium and has safety characteristics suitable for treatment of infants,minimal drug-drug interactions, minimal oral dosing requirements, stability in the tropics, and a lowmanufacturing cost. The methods for lead optimization bring together novel in vitro assays and a highlyimmunocompromised mouse model of cryptosporidiosis with well-established pharmacology and medicinalchemistry approaches. For this, cyclic rounds of chemical synthesis will be combined with in vitroCryptosporidium assays, in vitro ADME studies, mouse PK studies, and a chronic mouse model of C. parvuminfection. A piglet model will then be used to test clinical efficacy against C. hominis. The method for drugtarget identification will take advantage of the lead compound's activity against related malaria parasites toidentify mutations associated with drug resistance and candidate drug targets, followed by CRISPR/Cas9validation of mutations in C. parvum and biochemical methods to assess direct protein-drug interactions.Success would yield an optimized clinical candidate that is ready to be advanced to testing in regulatorytoxicology studies, and a validated drug target that will accelerate drug development by enabling target-baseddrug design and target-based screening efforts to identify additional chemotypes. Given the dire need for newcryptosporidiosis drugs, the public health impact of success could be extremely significant.
Funding Source
Nat'l. Inst. of Allergy and Infectious Diseases
Project source
View this project
Project number
1R01AI143951-01
Accession number
143951
Categories
Chemical Contaminants
Bacterial Pathogens