Keap Calm, and Carry on Covalently
Keap Calm, and Carry on Covalently
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DOI：
10.1021/jm400224q
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发表时间：
2013-10-10
影响因子：
7.3
通讯作者：
Moody, Christopher J.
中科院分区：
文献类型：
--
作者：
Wilson, Anthony J.;Kerns, Jeffrey K.;Moody, Christopher J.
Nrf2-Keap1系统在细胞防御氧化应激中起着重要作用。暴露于亲电试剂后，富含半胱氨酸的蛋白Keap1被共价修饰，正是这种修饰允许Nrf2的积累和随后的核易位，并诱导超过100个保护基因的转录。这一机制可用于慢性肾病（CKD）、慢性阻塞性肺病（COPD）、哮喘和多发性硬化症（MS）和帕金森病等神经退行性疾病的药物发现方法，利用亲电试剂修饰Keap1，这些化合物通常在药物发现项目中被认为是有用的。本观点讨论了基于强效亲电试剂的潜在治疗方法的发展，如异硫氰酸酯和Michael受体，它们与毒性事件无关，实际上可以启动一系列有益的保护途径。
The Nrf2-Keap1 system plays a major role in cellular defense against oxidative stress. Upon exposure to electrophiles, the cysteine-rich protein Keap1 is covalently modified, and it is this modification of Keap1 that allows the accumulation and subsequent nuclear translocation of Nrf2 where it induces the transcription of over 100 protective genes. This mechanism can be exploited in drug discovery approaches to diseases such as chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), asthma, and neuro-degenerative diseases like multiple sclerosis (MS) and Parkinson's, utilizing the modification of Keap1 by electrophiles, compounds that would not normally be considered useful in drug discovery programs. This Perspective discusses the development of potential therapies based on potent electrophiles, such as isothiocyanates and Michael acceptors, that, far from being associated with toxic events, can actually initiate a range of beneficial protective pathways.