Novel Bumped Kinase Inhibitors Are Safe and Effective Therapeutics in the Calf Clinical Model for Cryptosporidiosis
Novel Bumped Kinase Inhibitors Are Safe and Effective Therapeutics in the Calf Clinical Model for Cryptosporidiosis
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DOI：
10.1093/infdis/jiw488
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发表时间：
2016-12-15
影响因子：
6.4
通讯作者：
Riggs, Michael W.
中科院分区：
文献类型：
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作者：
Schaefer, Deborah A.;Betzer, Dana P.;Riggs, Michael W.
隐孢子虫病由顶端复门寄生虫小隐孢子虫引起，是一种腹泻病，给全球人类和牲畜带来了巨大的死亡率和发病率负担。目前还没有针对这种疾病持续有效的寄生虫特异性药物。寄生虫钙依赖性蛋白激酶 (CDPK) 特异性的突变激酶抑制剂 (BKI) 已被证明可以减少几种具有医学和兽医重要性的寄生虫的感染，包括弓形虫、恶性疟原虫和微小弯曲菌。在本研究中，在新生小鼠模型中筛选了 BKI 对抗微小念珠菌感染的功效。然后选择三种 BKI 在隐孢子虫病小牛模型中进行安全性和临床疗效评估。几乎所有临床和寄生虫学评分参数（包括腹泻严重程度、卵囊脱落和整体健康状况）均观察到显着的 BKI 治疗效果。这些结果为 BKI 作为人类隐孢子虫病动物模型中的治疗药物先导物提供了概念证明。
Cryptosporidiosis, caused by the apicomplexan parasite Cryptosporidium parvum, is a diarrheal disease that has produced a large global burden in mortality and morbidity in humans and livestock. There are currently no consistently effective parasite-specific pharmaceuticals available for this disease. Bumped kinase inhibitors (BKIs) specific for parasite calcium-dependent protein kinases (CDPKs) have been shown to reduce infection in several parasites having medical and veterinary importance, including Toxoplasma gondii, Plasmodium falciparum, and C. parvum. In the present study, BKIs were screened for efficacy against C. parvum infection in the neonatal mouse model. Three BKIs were then selected for safety and clinical efficacy evaluation in the calf model for cryptosporidiosis. Significant BKI treatment effects were observed for virtually all clinical and parasitological scoring parameters, including diarrhea severity, oocyst shedding, and overall health. These results provide proof of concept for BKIs as therapeutic drug leads in an animal model for human cryptosporidiosis.