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一种用于对具有治疗意义的神经系统基因进行靶向转录激活的多靶点小分子。

A Multi-target Small Molecule for Targeted Transcriptional Activation of Therapeutically Significant Nervous System Genes.

作者信息

Wei Yulei, Pandian Ganesh N, Zou Tingting, Taniguchi Junichi, Sato Shinsuke, Kashiwazaki Gengo, Vaijayanthi Thangavel, Hidaka Takuya, Bando Toshikazu, Sugiyama Hiroshi

机构信息

Department of Chemistry Graduate School of Science Kyoto University Kitashirakawa-oiwakecho, Sakyo-ku Kyoto 606-8502 Japan.

Institute for Integrated Cell-Material Sciences (WPI-iCeMS) Kyoto University Yoshida-ushinomiyacho, Sakyo-ku Kyoto 606-8501 Japan.

出版信息

ChemistryOpen. 2016 Nov 30;5(6):517-521. doi: 10.1002/open.201600125. eCollection 2016 Dec.

DOI:10.1002/open.201600125
PMID:28032018
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5167308/
Abstract

An integrated multi-target small molecule capable of altering dynamic epigenetic and transcription programs associated with the brain and nervous system has versatile applications in the regulation of therapeutic and cell-fate genes. Recently, we have been constructing targeted epigenetic ON switches by integrating sequence-specific DNA binding pyrrole-imidazole polyamides with a potent histone deacetylase inhibitor SAHA. Here, we identified a DNA-based epigenetic ON switch termed SAHA-L as the first-ever multi-target small molecule capable of inducing transcription programs associated with the human neural system and brain synapses networks in BJ human foreskin fibroblasts and 201B7-iPS cells. Ingenuity pathway analysis showed that SAHA-L activates the signaling of synaptic receptors like glutamate and γ-aminobutyric acid, which are key components of autism spectrum disorders. The long-term incubation of SAHA-L in 201B7-iPS cells induced morphology changes and promoted a neural progenitor state. Our finding suggests that the tunable SAHA-L could be advanced as a cell-type-independent multi-target small molecule for therapeutic and/or cell-fate gene modulation.

摘要

一种能够改变与大脑和神经系统相关的动态表观遗传和转录程序的整合多靶点小分子，在治疗和细胞命运基因的调控方面具有广泛应用。最近，我们通过将序列特异性DNA结合吡咯-咪唑聚酰胺与强效组蛋白脱乙酰酶抑制剂SAHA整合，构建了靶向表观遗传开启开关。在此，我们鉴定出一种基于DNA的表观遗传开启开关SAHA-L，它是首个能够在BJ人包皮成纤维细胞和201B7诱导多能干细胞中诱导与人类神经系统和脑突触网络相关转录程序的多靶点小分子。 Ingenuity通路分析表明，SAHA-L激活了谷氨酸和γ-氨基丁酸等突触受体的信号传导，而这些受体是自闭症谱系障碍的关键组成部分。SAHA-L在201B7诱导多能干细胞中的长期孵育诱导了形态变化并促进了神经祖细胞状态。我们的发现表明，可调节性的SAHA-L可以作为一种不依赖细胞类型的多靶点小分子，用于治疗和/或细胞命运基因调控。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d1a/5167308/d8e0f3d74447/OPEN-5-517-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d1a/5167308/8e79abbfde37/OPEN-5-517-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d1a/5167308/1b414719626b/OPEN-5-517-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d1a/5167308/0367fe3d089e/OPEN-5-517-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d1a/5167308/d8e0f3d74447/OPEN-5-517-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d1a/5167308/8e79abbfde37/OPEN-5-517-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d1a/5167308/1b414719626b/OPEN-5-517-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d1a/5167308/0367fe3d089e/OPEN-5-517-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4d1a/5167308/d8e0f3d74447/OPEN-5-517-g004.jpg

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Stem Cell Reports. 2016 Apr 12;6(4):539-551. doi: 10.1016/j.stemcr.2016.02.013. Epub 2016 Mar 24.
2
A Synthetic Transcriptional Activator of Genes Associated with the Retina in Human Dermal Fibroblasts.人皮肤成纤维细胞中与视网膜相关基因的合成转录激活因子。
Chembiochem. 2015 Jul 6;16(10):1497-501. doi: 10.1002/cbic.201500140. Epub 2015 May 28.
3
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Nucleic Acids Res. 2017 Sep 19;45(16):9219-9228. doi: 10.1093/nar/gkx693.
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BMC Biol. 2014 Nov 19;12:95. doi: 10.1186/s12915-014-0095-z.
4
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5
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6
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7
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