现有药物伏立诺他通过靶向寄生虫组蛋白去乙酰化酶成为治疗隐孢子虫病的新先导药物。
The Existing Drug Vorinostat as a New Lead Against Cryptosporidiosis by Targeting the Parasite Histone Deacetylases.
机构信息
Key Laboratory for Zoonoses Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun, China.
Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station.
出版信息
J Infect Dis. 2018 Mar 13;217(7):1110-1117. doi: 10.1093/infdis/jix689.
BACKGROUND
Cryptosporidiosis affects all human populations, but can be much more severe or life-threatening in children and individuals with weak or weakened immune systems. However, current options to treat cryptosporidiosis are limited.
METHODS
An in vitro phenotypic screening assay was employed to screen 1200 existing drugs for their anticryptosporidial activity and to determine the inhibitory kinetics of top hits. Selected top hits were further evaluated in mice. The action of the lead compound vorinostat on the parasite histone deacetylase (HDAC) was biochemically validated.
RESULTS
Fifteen compounds exhibited anticryptosporidial activity at nanomolar level in vitro. Among them, the histone deacetylase (HDAC) inhibitor vorinostat retained outstanding efficacy in vitro (half maximal effective concentration, EC50 = 203 nM) and in an interleukin 12 knockout mouse model (50% inhibition dose = 7.5 mg/kg). Vorinostat was effective on various parasite developmental stages and could irreversibly kill the parasite. Vorinostat was highly effective against the parasite native HDAC enzymes (half maximal inhibitory concentration, IC50 = 90.0 nM) and a recombinant Cryptosporidium parvum HDAC (the inhibitor constant, Ki = 123.0 nM).
CONCLUSIONS
These findings suggest the potential for repurposing of vorinostat to treat cryptosporidiosis, and imply that the parasite HDAC can be explored for developing more selective anticryptosporidial therapeutics.
背景
隐孢子虫病影响所有人群，但在儿童和免疫系统较弱或受损的个体中可能更为严重或危及生命。然而，目前治疗隐孢子虫病的选择有限。
方法
采用体外表型筛选试验，对 1200 种现有药物进行抗隐孢子虫活性筛选，并确定最佳药物的抑制动力学。对选定的最佳药物在小鼠中进行进一步评估。对先导化合物伏立诺他对寄生虫组蛋白去乙酰化酶（HDAC）的作用进行了生化验证。
结果
15 种化合物在体外以纳摩尔水平表现出抗隐孢子虫活性。其中，组蛋白去乙酰化酶（HDAC）抑制剂伏立诺他在体外（半数有效浓度，EC50 = 203 nM）和白细胞介素 12 敲除小鼠模型中（50%抑制剂量 = 7.5 mg/kg）保留了优异的疗效。伏立诺他在各种寄生虫发育阶段都有效，并且可以不可逆地杀死寄生虫。伏立诺他对寄生虫天然 HDAC 酶（半最大抑制浓度，IC50 = 90.0 nM）和重组微小隐孢子虫 HDAC（抑制剂常数，Ki = 123.0 nM）具有高度活性。
结论
这些发现表明可以重新利用伏立诺他来治疗隐孢子虫病，并且暗示寄生虫 HDAC 可以用于开发更具选择性的抗隐孢子虫治疗药物。
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