Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy.

Abstract

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.

• Authors: Matthew A Hulverson, Sumiti Vinayak, Ryan Choi, Deborah A Schaefer, Alejandro Castellanos-Gonzalez, Rama S R Vidadala, Carrie F Brooks, Gillian T Herbert, Dana P Betzer, Grant R Whitman, Hayley N Sparks, Samuel L M Arnold, Kasey L Rivas, Lynn K Barrett, A Clinton White Jr, Dustin J Maly, Michael W Riggs, Boris Striepen, Wesley C Van Voorhis, Kayode K Ojo
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 215 Issue 8 Pg. 1275-1284 (04 15 2017) ISSN: 1537-6613 [Electronic] United States
• PMID: 28329187 (Publication Type: Journal Article)
• Copyright: © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

Chemical References

• Antiprotozoal Agents
• Protein Kinase Inhibitors

Topics

• Administration, Oral
• Animals
• Antiprotozoal Agents (administration & dosage)
• Cryptosporidiosis (drug therapy)
• Cryptosporidium parvum (drug effects)
• Diarrhea (drug therapy)
• Disease Models, Animal
• Female
• Mice
• Mice, Knockout
• Mice, SCID
• Protein Kinase Inhibitors (administration & dosage)