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Calf Clinical Model of Cryptosporidiosis for Efficacy Evaluation of Therapeutics.用于治疗药物疗效评估的隐孢子虫病小牛临床模型。
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本文引用的文献

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Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.开发一种口服可用且能穿透中枢神经系统（CNS）的弓形虫钙依赖性蛋白激酶1（TgCDPK1）抑制剂，其对人醚孔相关基因（hERG）的活性最小，用于治疗弓形虫病。
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Bumped kinase inhibitor prohibits egression in Babesia bovis.碰撞激酶抑制剂可阻止牛巴贝斯虫出芽。
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SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of CDPK1.5-氨基吡唑-4-甲酰胺类似物作为CDPK1强效和选择性抑制剂的构效关系研究
ACS Med Chem Lett. 2015 Oct 22;6(12):1184-1189. doi: 10.1021/acsmedchemlett.5b00319. eCollection 2015 Dec 10.
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Genetic modification of the diarrhoeal pathogen Cryptosporidium parvum.腹泻病原体微小隐孢子虫的基因改造。
Nature. 2015 Jul 23;523(7561):477-80. doi: 10.1038/nature14651. Epub 2015 Jul 15.
5
A novel CDPK1 inhibitor--a potential treatment for cryptosporidiosis in calves?一种新型的CDPK1抑制剂——犊牛隐孢子虫病的潜在治疗方法？
Parasitol Res. 2015 Jan;114(1):335-6. doi: 10.1007/s00436-014-4228-7. Epub 2014 Nov 15.
6
A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium.隐孢子虫的全球负担、新型诊断方法、治疗方法及疫苗靶点综述
Lancet Infect Dis. 2015 Jan;15(1):85-94. doi: 10.1016/S1473-3099(14)70772-8. Epub 2014 Sep 29.
7
The gatekeeper residue and beyond: homologous calcium-dependent protein kinases as drug development targets for veterinarian Apicomplexa parasites.守门人残基及其他：同源钙依赖性蛋白激酶作为兽医治疗顶复门寄生虫的药物开发靶点。
Parasitology. 2014 Sep;141(11):1499-1509. doi: 10.1017/S0031182014000857. Epub 2014 Jun 13.
8
Bumped kinase inhibitor 1294 treats established Toxoplasma gondii infection.撞击激酶抑制剂1294可治疗已有的弓形虫感染。
Antimicrob Agents Chemother. 2014 Jun;58(6):3547-9. doi: 10.1128/AAC.01823-13. Epub 2014 Mar 31.
9
Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes.开发强效且选择性的恶性疟原虫钙依赖性蛋白激酶4（PfCDPK4）抑制剂，以阻断疟疾向蚊子的传播。
Eur J Med Chem. 2014 Mar 3;74:562-73. doi: 10.1016/j.ejmech.2013.12.048. Epub 2014 Jan 11.
10
Potent and selective inhibitors of CDPK1 from and based on a 5-aminopyrazole-4-carboxamide scaffold.基于5-氨基吡唑-4-甲酰胺支架的来自[具体来源1]和[具体来源2]的CDPK1的强效和选择性抑制剂。
ACS Med Chem Lett. 2014 Jan 9;5(1):40-44. doi: 10.1021/ml400315s.

新型碰撞激酶抑制剂在犊牛隐孢子虫病临床模型中是安全有效的治疗药物。

Novel Bumped Kinase Inhibitors Are Safe and Effective Therapeutics in the Calf Clinical Model for Cryptosporidiosis.

作者信息

Schaefer Deborah A, Betzer Dana P, Smith Kylie D, Millman Zachary G, Michalski Hannah C, Menchaca Sarah E, Zambriski Jennifer A, Ojo Kayode K, Hulverson Matthew A, Arnold Samuel L M, Rivas Kasey L, Vidadala Rama S R, Huang Wenlin, Barrett Lynn K, Maly Dustin J, Fan Erkang, Van Voorhis Wesley C, Riggs Michael W

机构信息

School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.

Paul G. Allen School for Global Animal Health, College of Veterinary Medicine, Washington State University, Pullman.

出版信息

J Infect Dis. 2016 Dec 15;214(12):1856-1864. doi: 10.1093/infdis/jiw488. Epub 2016 Oct 17.

DOI:10.1093/infdis/jiw488
PMID:27923949
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5142098/
Abstract

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.

摘要

隐孢子虫病由顶复门寄生虫微小隐孢子虫引起，是一种腹泻疾病，在全球范围内给人类和牲畜带来了巨大的死亡和发病负担。目前尚无针对该疾病的始终有效的寄生虫特异性药物。已证明，针对寄生虫钙依赖性蛋白激酶（CDPKs）的碰撞激酶抑制剂（BKIs）可减少包括刚地弓形虫、恶性疟原虫和微小隐孢子虫在内的几种具有医学和兽医学重要性的寄生虫的感染。在本研究中，在新生小鼠模型中筛选了BKIs对微小隐孢子虫感染的疗效。然后选择了三种BKIs在犊牛隐孢子虫病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、卵囊排出和整体健康状况，均观察到BKIs治疗的显著效果。这些结果为BKIs作为人类隐孢子虫病动物模型中的治疗药物先导提供了概念验证。