Substitution to hydrophobic linker and formation of host-guest complex enhanced the effect of synthetic transcription factor made of pyrrole-imidazole polyamide.
Substitution to hydrophobic linker and formation of host-guest complex enhanced the effect of synthetic transcription factor made of pyrrole-imidazole polyamide.
复制标题
疏水性接头的取代和主客体复合物的形成增强了由吡咯-咪唑聚酰胺制成的合成转录因子的效果。
DOI：
10.1016/j.bmc.2023.117208
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发表时间：
2023
影响因子：
3.5
通讯作者：
Sugiyama,Hiroshi
中科院分区：
文献类型：
--
作者：
Hatanaka,Junnosuke;Hashiya,Kaori;Bando,Toshikazu;Sugiyama,Hiroshi
共济失调蛋白（FXN）基因第一内含子中的GAA重复扩增抑制FXN的转录，从而诱导弗里德赖希共济失调（FRDA）。吡咯-咪唑聚酰胺（PIPs）是一类以序列选择性靶向双链DNA的寡肽。先前，报道了与PIP缀合的布罗莫结构域抑制剂如JQ 1选择性地增加转录。在这里，我们报告了一种化合物的合成，该化合物可以增加FRDA患者细胞中FXN的转录。该化合物在比先前报道的化合物低（十分之一）的浓度下有效。高浓度的化合物是有毒的，但毒性与主体-客体复合物降低。
GAA repeat expansion in the first intron of the frataxin (FXN) gene represses the transcription ofFXN, and that induces Friedreich’s ataxia (FRDA). Pyrrole−imidazole polyamides (PIPs) are the class of oligopeptide that targets double-stranded DNA with sequence selectivity. Previously, bromodomain inhibitors such as JQ1 conjugated with PIPs were reported to selectively increase transcription. Here, we report the synthesis of a compound that increases the transcription ofFXNin cells derived from an FRDA patient. The compound was effective in lower (one tenth) concentration than the compound that previously reported. High concentration of the compound is toxic, but toxicity was reduced with a host–guest complex.