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

作者：Wei Yulei; Pandian Ganesh N; Zou Tingting; Taniguchi Junichi; Sato Shinsuke; Kashiwazaki Gengo; Vaijayanthi Thangavel; Hidaka Takuya; Bando Toshikazu; Sugiyama Hiroshi^*

来源：ChemistryOpen, 2016, 5(6): 517-521.

DOI：10.1002/open.201600125

• brain and nervous system
• DNA recognition
• multi-target small molecules
• polymerase chain reaction
• synthetic biology

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 g-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.

• 出版日期2016-12