Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy
Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy
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DOI：
10.1093/infdis/jix120
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发表时间：
2017-04-15
影响因子：
6.4
通讯作者：
Ojo, Kayode K.
中科院分区：
文献类型：
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作者：
Hulverson, Matthew A.;Vinayak, Sumiti;Ojo, Kayode K.
微小隐孢子虫钙依赖性蛋白激酶1（CpCDPK 1）的冲击激酶抑制剂（BKI）是治疗隐孢子虫病相关腹泻的主要候选药物。与第一代抗隐孢子虫BKI的抗人ethe-a-go-go钾通道（hERG）活性相关的潜在心脏毒性引发了进一步的疗效试验。采用发光法进行高通量筛选，测定BKI对C. parvum in vitro.此外，新生儿和干扰素。C.小孢子虫感染鉴定了具有体内活性的BKI。用于最佳给药和选择具有最低hERG活性水平和其他安全性责任频率的BKI的其他迭代实验包括研究哺乳动物细胞毒性的实验，C.体外微小细胞增殖抑制、抗人Src抑制、hERG活性、体内药代动力学数据和在其他小鼠模型中的功效。这项研究的结果表明，粪便浓度大于寄生虫抑制浓度与隐孢子虫病小鼠模型中的有效治疗最相关，但需要更精确的疗效模型。
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 ethe-a-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. 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.