title: Novel Bumped Kinase Inhibitors Are Safe and Effective Therapeutics in the Calf Clinical Model for Cryptosporidiosis.
abstract: Cryptosporidiosis, caused by the apicomplexan parasite Cryptosporidium parvum, is a diarrheal disease that has produced a large global burden in mortality and morbidity in humans and livestock. There are currently no consistently effective parasite-specific pharmaceuticals available for this disease. Bumped kinase inhibitors (BKIs) specific for parasite calcium-dependent protein kinases (CDPKs) have been shown to reduce infection in several parasites having medical and veterinary importance, including Toxoplasma gondii, Plasmodium falciparum, and C. parvum In the present study, BKIs were screened for efficacy against C. parvum infection in the neonatal mouse model. Three BKIs were then selected for safety and clinical efficacy evaluation in the calf model for cryptosporidiosis. Significant BKI treatment effects were observed for virtually all clinical and parasitological scoring parameters, including diarrhea severity, oocyst shedding, and overall health. These results provide proof of concept for BKIs as therapeutic drug leads in an animal model for human cryptosporidiosis.
authors.affiliation: School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Schaefer
authors.affiliation: School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
authors.forename: Dana P
authors.initials: DP
authors.lastname: Betzer
authors.affiliation: School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
authors.forename: Kylie D
authors.initials: KD
authors.lastname: Smith
authors.affiliation: School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
authors.forename: Zachary G
authors.initials: ZG
authors.lastname: Millman
authors.affiliation: School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Michalski
authors.affiliation: School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Menchaca
authors.affiliation: Paul G. Allen School for Global Animal Health, College of Veterinary Medicine, Washington State University, Pullman.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Zambriski
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease.
authors.forename: Kayode K
authors.initials: KK
authors.lastname: Ojo
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hulverson
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease.
authors.forename: Samuel L M
authors.initials: SL
authors.lastname: Arnold
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease.
authors.forename: Kasey L
authors.initials: KL
authors.lastname: Rivas
authors.affiliation: Department of Chemistry.
authors.forename: Rama S R
authors.initials: RS
authors.lastname: Vidadala
authors.affiliation: Department of Biochemistry, University of Washington, Seattle.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease.
authors.forename: Lynn K
authors.initials: LK
authors.lastname: Barrett
authors.affiliation: Department of Chemistry.|Department of Biochemistry, University of Washington, Seattle.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
authors.affiliation: Department of Biochemistry, University of Washington, Seattle.
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease.
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.affiliation: School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Riggs
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002417:Cattle; D002418:Cattle Diseases / Q000188:drug therapy*; D003457:Cryptosporidiosis / Q000188:drug therapy*; D016785:Cryptosporidium parvum / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000981:Antiprotozoal Agents; D047428:Protein Kinase Inhibitors
keywords: CpCDPK-1; Cryptosporidium; animal model; bumped kinase inhibitor; clinical evaluation; cryptosporidiosis; oocyst shedding; therapeutic