title: A Novel Calcium-Dependent Kinase Inhibitor, Bumped Kinase Inhibitor 1517, Cures Cryptosporidiosis in Immunosuppressed Mice.
abstract: Cryptosporidium is recognized as one of the main causes of childhood diarrhea worldwide. However, the current treatment for cryptosporidiosis is suboptimal. Calcium flux is essential for entry in apicomplexan parasites. Calcium-dependent protein kinases (CDPKs) are distinct from protein kinases of mammals, and the CDPK1 of the apicomplexan Cryptosporidium lack side chains that typically block a hydrophobic pocket in protein kinases. We exploited this to develop bumped kinase inhibitors (BKIs) that selectively target CDPK1. We have shown that several BKIs of Cryptosporidium CDPK1 potently reduce enzymatic activity and decrease parasite numbers when tested in vitro. In the present work, we studied the anticryptosporidial activity of BKI-1517, a novel BKI. The half maximal effective concentration for Cryptosporidium parvum in HCT-8 cells was determined to be approximately 50 nM. Silencing experiments of CDPK1 suggest that BKI-1517 acts on CDPK1 as its primary target. In a mouse model of chronic infection, 5 of 6 SCID/beige mice (83.3%) were cured after treatment with a single daily dose of 120 mg/kg BKI-1517. No side effects were observed. These data support advancing BKI-1517 as a lead compound for drug development for cryptosporidiosis.
authors.affiliation: Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Castellanos-Gonzalez
authors.affiliation: Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston.
authors.forename: Hayley
authors.initials: H
authors.lastname: Sparks
authors.affiliation: Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston.
authors.forename: Samantha
authors.initials: S
authors.lastname: Nava
authors.affiliation: Allergy and Infectious Diseases Division, Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.affiliation: Allergy and Infectious Diseases Division, Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle.
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Allergy and Infectious Diseases Division, Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle.
authors.forename: Kasey
authors.initials: K
authors.lastname: Rivas
authors.affiliation: Allergy and Infectious Diseases Division, Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hulverson
authors.affiliation: Allergy and Infectious Diseases Division, Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle.
authors.forename: Lynn K
authors.initials: LK
authors.lastname: Barrett
authors.affiliation: Allergy and Infectious Diseases Division, Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle.
authors.forename: Kayode K
authors.initials: KK
authors.lastname: Ojo
authors.affiliation: Allergy and Infectious Diseases Division, Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle.
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
authors.affiliation: Allergy and Infectious Diseases Division, Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle.
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.affiliation: Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston.
authors.forename: Arthur Clinton
authors.initials: AC
authors.lastname: White
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000302:isolation & purification; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors; D003457:Cryptosporidiosis / Q000188:drug therapy*; D016785:Cryptosporidium parvum / Q000187:drug effects; D004195:Disease Models, Animal; D016867:Immunocompromised Host; D016513:Mice, SCID; D021261:Parasitic Sensitivity Tests; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000302:isolation & purification; D016896:Treatment Outcome
chemical_list: D000981:Antiprotozoal Agents; D002135:Calcium-Binding Proteins; D047428:Protein Kinase Inhibitors
keywords: BKI; CDPK; CDPK1; cryptosporidiosis; cryptosporidium; kinase inhibitors; siRNA