Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy
Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy
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DOI：
10.1038/s42003-020-0826-3
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发表时间：
2020-03-05
影响因子：
5.9
通讯作者：
Hasnain, S. Samar
中科院分区：
文献类型：
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作者：
Chantadul, Varunya;Wright, Gareth S. A.;Hasnain, S. Samar
编码超氧化物歧化酶-1 （SOD1）的基因突变是第一个被发现导致运动神经元疾病（MND）的遗传因素。这些突变导致SOD1二聚体稳定性受损，其中最严重和最常见的突变之一Ala4Val （A4V）表现出单体化和聚集的倾向，导致神经元死亡。我们发现临床上使用的依布selen和相关类似物仅与Cys111结合时可促进A4V SOD1的热稳定性。我们在C6S突变背景下开发了一种基于A4V SOD1差异扫描荧光的检测方法，可有效评估化合物的适用性。晶体学数据表明，这些化合物的硒原子在二聚体界面的Cys111处与A4V SOD1共价结合，从而产生稳定。这与依布selen的靶向扩展的化学适应性及其靶向SOD1药理伴侣活性一起，为使用依布selen作为模板的基于结构的MND治疗提供了显着的希望。Chantadul等人使用x射线晶体学和差示扫描荧光分析表明，当使用点突变去除第二游离半胱氨酸时，艾布selen及其类似物增加了WT和A4V突变体SOD1的热稳定性。因此，依布selen可以作为基于结构的ALS治疗药物开发的模板。
Mutations to the gene encoding superoxide dismutase-1 (SOD1) were the first genetic elements discovered that cause motor neuron disease (MND). These mutations result in compromised SOD1 dimer stability, with one of the severest and most common mutations Ala4Val (A4V) displaying a propensity to monomerise and aggregate leading to neuronal death. We show that the clinically used ebselen and related analogues promote thermal stability of A4V SOD1 when binding to Cys111 only. We have developed a A4V SOD1 differential scanning fluorescence-based assay on a C6S mutation background that is effective in assessing suitability of compounds. Crystallographic data show that the selenium atom of these compounds binds covalently to A4V SOD1 at Cys111 at the dimer interface, resulting in stabilisation. This together with chemical amenability for hit expansion of ebselen and its on-target SOD1 pharmacological chaperone activity holds remarkable promise for structure-based therapeutics for MND using ebselen as a template.Chantadul et al. uses x-ray crystallography and differential scanning fluorescence-based assay to show that ebselen and its analogues increase thermostability of both WT and A4V mutant SOD1 when second free cysteine is removed using a point mutation. Hence, ebselen can be used as a template for structure based drug development of ALS therapeutics.