Activity-Guided Design of HDAC11-Specific Inhibitors.,ACS Chemical Biology

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Activity-Guided Design of HDAC11-Specific Inhibitors.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-07-02 , DOI: 10.1021/acschembio.9b00292
Se In Son ₁ , Ji Cao ₁ , Cheng-Liang Zhu ₁ , Seth P Miller ₁ , Hening Lin _{1,

2}

Affiliation

Mammalian histone deacetylases (HDACs) are a class of enzymes that play important roles in biological pathways. Existing HDAC inhibitors target multiple HDACs without much selectivity. Inhibitors that target one particular HDAC will be useful for investigating the biological functions of HDACs and for developing better therapeutics. Here, we report the development of HDAC11-specific inhibitors using an activity-guided rational design approach. The enzymatic activity and biological function of HDAC11 have been little known, but recent reports suggest that it has efficient defatty-acylation activity and that inhibiting it could be useful for treating a variety of human diseases, including viral infection, multiple sclerosis, and metabolic diseases. Our best inhibitor, SIS17, is active in cells and inhibited the demyristoylation of a known HDAC11 substrate, serine hydroxymethyl transferase 2, without inhibiting other HDACs. The activity-guided design may also be useful for the development of isoform-specific inhibitors for other classes of enzymes.

中文翻译：

HDAC11特异性抑制剂的活性指导设计。

哺乳动物组蛋白脱乙酰基酶（HDACs）是一类在生物途径中起重要作用的酶。现有的HDAC抑制剂在没有太多选择性的情况下靶向多个HDAC。靶向一种特定HDAC的抑制剂将有助于研究HDAC的生物学功能和开发更好的治疗剂。在这里，我们报告了使用活动指导的合理设计方法开发HDAC11特异性抑制剂。HDAC11的酶活性和生物学功能鲜为人知，但最近的报道表明它具有有效的去脂酰化活性，并且抑制它可以用于治疗多种人类疾病，包括病毒感染，多发性硬化症和代谢性疾病。我们最好的抑制剂SIS17 在细胞中具有活性，并抑制已知的HDAC11底物丝氨酸羟甲基转移酶2的去甲酰化，而不抑制其他HDAC。活性指导设计也可用于开发其他类型酶的同工型特异性抑制剂。

更新日期：2019-07-02

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