Unexpected small molecules as novel SIRT2 suicide inhibitors
Unexpected small molecules as novel SIRT2 suicide inhibitors
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意想不到的小分子作为新型 SIRT2 自杀抑制剂
DOI：
10.1016/j.bmc.2020.115353
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发表时间：
2020-03-15
影响因子：
3.5
通讯作者：
He, Bin
中科院分区：
文献类型：
--
作者：
Chen, Xiaoxue;Zou, Yefang;He, Bin
基于我们偶然发现的中间体酯 (1a) 组装了一系列沉默调节蛋白抑制剂候选物。经过筛选和评估，鉴定出几种SIRT2选择性抑制剂，可以抑制SIRT2的所有脱乙酰化、脱脂酰化和脱苯甲酰化。在这些抑制剂中，化合物1e是最好的SIRT2选择性抑制剂。抑制机制的初步研究表明，化合物1e可能是一种不可逆的自杀抑制剂。由于几乎所有报道的沉默调节蛋白抑制剂都是非共价的，因此仍然需要开发沉默调节蛋白共价抑制剂。这些发现将有助于进一步开发 SIRT2 选择性抑制剂和自杀抑制剂。
A series of sirtuin inhibitor candidates were assembled based on an intermediate ester (1a) our accidently discovered. After screening and evaluation, several SIRT2 selective inhibitors were identified, which can inhibit all the deacetylation, defatty-acylation and debenzoylation of SIRT2. Among these inhibitors, compound 1e was the best SIRT2 selective inhibitors. The primary study on the inhibitory mechanism indicated that compound 1e may be a suicide inhibitor acting as an irreversible way. Given almost all reported sirtuin inhibitors are non-covalent, sirtuin covalent inhibitors are still need to be developed. These findings will facilitate for further development of SIRT2 selective and suicide inhibitors.