Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy.
J Infect Dis
; 215(8): 1275-1284, 2017 04 15.
Article
em En
| MEDLINE
| ID: mdl-28329187
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cryptosporidium parvum
/
Criptosporidiose
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Inibidores de Proteínas Quinases
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Antiprotozoários
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Infect Dis
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos