Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy.
Bumped kinase inhibitors (BKIs) of Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) are leading candidates for treatment of cryptosporidiosis-associated diarrhea. Potential cardiotoxicity related to anti-human ether-à-go-go potassium channel (hERG) activity of the first-generation anti-Cryptosporidium BKIs triggered further testing for efficacy. A luminescence assay adapted for high-throughput screening was used to measure inhibitory activities of BKIs against C. parvum in vitro. Furthermore, neonatal and interferon γ knockout mouse models of C. parvum infection identified BKIs with in vivo activity. Additional iterative experiments for optimum dosing and selecting BKIs with minimum levels of hERG activity and frequencies of other safety liabilities included those that investigated mammalian cell cytotoxicity, C. parvum proliferation inhibition in vitro, anti-human Src inhibition, hERG activity, in vivo pharmacokinetic data, and efficacy in other mouse models. Findings of this study suggest that fecal concentrations greater than parasite inhibitory concentrations correlate best with effective therapy in the mouse model of cryptosporidiosis, but a more refined model for efficacy is needed.
Division of Allergy & Infectious Disease, Center for Emerging & Reemerging Infectious Disease (CERID), University of Washington, Seattle, Washington 98109, USA.
Matthew A
MA
Hulverson
Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, USA
Sumiti
S
Vinayak
Division of Allergy & Infectious Disease, Center for Emerging & Reemerging Infectious Disease (CERID), University of Washington, Seattle, Washington 98109, USA.
Ryan
R
Choi
School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
Deborah A
DA
Schaefer
Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston.
Alejandro
A
Castellanos-Gonzalez
Rama S R
RSR
Vidadala
Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, USA
Carrie F
CF
Brooks
Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, USA
Gillian T
GT
Herbert
School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
Dana P
DP
Betzer
Division of Allergy & Infectious Disease, Center for Emerging & Reemerging Infectious Disease (CERID), University of Washington, Seattle, Washington 98109, USA.
Grant R
GR
Whitman
Hayley N
HN
Sparks
Division of Allergy & Infectious Disease, Center for Emerging & Reemerging Infectious Disease (CERID), University of Washington, Seattle, Washington 98109, USA.
Samuel L M
SLM
Arnold
Division of Allergy & Infectious Disease, Center for Emerging & Reemerging Infectious Disease (CERID), University of Washington, Seattle, Washington 98109, USA.
Kasey L
KL
Rivas
Division of Allergy & Infectious Disease, Center for Emerging & Reemerging Infectious Disease (CERID), University of Washington, Seattle, Washington 98109, USA.
Lynn K
LK
Barrett
Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston.
A Clinton
AC
White
Chemistry & Biochemistry, University of Washington, Seattle.
Dustin J
DJ
Maly
School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
Michael W
MW
Riggs
Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, USA|Department of Cellular Biology, University of Georgia, Athens.
Boris
B
Striepen
Division of Allergy & Infectious Disease, Center for Emerging & Reemerging Infectious Disease (CERID), University of Washington, Seattle, Washington 98109, USA.
Wesley C
WC
Van Voorhis
Division of Allergy & Infectious Disease, Center for Emerging & Reemerging Infectious Disease (CERID), University of Washington, Seattle, Washington 98109, USA.
Kayode K
KK
Ojo
D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage*; D003457:Cryptosporidiosis / Q000188:drug therapy*; D016785:Cryptosporidium parvum / Q000187:drug effects*; D003967:Diarrhea / Q000188:drug therapy; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*
D000981:Antiprotozoal Agents; D047428:Protein Kinase Inhibitors
Cryptosporidiosis treatment; bumped kinase inhibitors.; calcium-dependent protein kinase 1