Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy. (3rd March 2017)

• Record Type: Journal Article
• Authors: Hulverson, Matthew A.; Vinayak, Sumiti; Choi, Ryan; Schaefer, Deborah A.; Castellanos-Gonzalez, Alejandro; Vidadala, Rama S. R.; Brooks, Carrie F.; Herbert, Gillian T.; Betzer, Dana P.; Whitman, Grant R.; Sparks, Hayley N.; Arnold, Samuel L. M.; Rivas, Kasey L.; Barrett, Lynn K.; White, A. Clinton; Maly, Dustin J.; Riggs, Michael W.; Striepen, Boris; Van Voorhis, Wesley C.; Ojo, Kayode K.
• Is Part Of: Journal of infectious diseases. Volume 215:Number 8(2017:Apr. 15)
• Page Start: 1275
• Page End: 1284
• Publication Date: 2017-03-03
• Subjects: Cryptosporidiosis treatment -- calcium-dependent protein kinase 1 -- bumped kinase inhibitors.; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jix120
• Languages: English
• ISSNs: 0022-1899

Abstract

Summary: This study describes iterative experiments to define bumped-kinase inhibitor properties needed for clinical efficacy. For these compounds, pharmacokinetics analysis of clinical cryptosporidiosis in mice show that fecal drug levels greater than parasite inhibitory concentrations correlate best with effective therapeutic outcomes. Abstract: Bumped kinase inhibitors (BKIs) of Cryptosporidium parvum calcium-dependent protein kinase 1 ( Cp CDPK1) 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.