1. A Novel Calcium-Dependent Kinase Inhibitor, Bumped Kinase Inhibitor 1517, Cures Cryptosporidiosis in Immunosuppressed Mice
- Author
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Kayode K. Ojo, Kasey Rivas, Samantha Nava, Alejandro Castellanos-Gonzalez, Erkang Fan, Zhongsheng Zhang, Hayley Sparks, Wenlin Huang, Wesley C. Van Voorhis, Lynn K. Barrett, Arthur Clinton White, and Matthew A. Hulverson
- Subjects
0301 basic medicine ,030106 microbiology ,Antiprotozoal Agents ,Cryptosporidiosis ,Mice, SCID ,Microbiology ,03 medical and health sciences ,Immunocompromised Host ,Major Articles and Brief Reports ,Parasitic Sensitivity Tests ,Calcium flux ,parasitic diseases ,Immunology and Allergy ,Gene silencing ,Animals ,Protein Kinase Inhibitors ,chemistry.chemical_classification ,Cryptosporidium parvum ,biology ,Kinase ,Chemistry ,Calcium-Binding Proteins ,Cryptosporidium ,biology.organism_classification ,Virology ,In vitro ,Chronic infection ,Disease Models, Animal ,030104 developmental biology ,Infectious Diseases ,Enzyme ,Treatment Outcome - 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.
- Published
- 2016