脱甲基酶
化学
肽
赫拉
生物化学
赖氨酸
组蛋白H3
组蛋白
氨基酸
细胞
基因
作者
Yukihiro Itoh,Keisuke Aihara,Paolo Mellini,Takeo Tojo,Yosuke Ota,Hiroki Tsumoto,V. Raja Solomon,Peng Zhan,Miki Suzuki,Daisuke Ogasawara,Akira Shigenaga,Takao Inokuma,Hidehiko Nakagawa,Naoki Miyata,Tamio Mizukami,Akira Otaka,Takayoshi Suzuki
标识
DOI:10.1021/acs.jmedchem.5b01323
摘要
Inhibition of lysine-specific demethylase 1 (LSD1), a flavin-dependent histone demethylase, has recently emerged as a new strategy for treating cancer and other diseases. LSD1 interacts physically with SNAIL1, a member of the SNAIL/SCRATCH family of transcription factors. This study describes the discovery of SNAIL1 peptide-based inactivators of LSD1. We designed and prepared SNAIL1 peptides bearing a propargyl amine, hydrazine, or phenylcyclopropane moiety. Among them, peptide 3, bearing hydrazine, displayed the most potent LSD1-inhibitory activity in enzyme assays. Kinetic study and mass spectrometric analysis indicated that peptide 3 is a mechanism-based LSD1 inhibitor. Furthermore, peptides 37 and 38, which consist of cell-membrane-permeable oligoarginine conjugated with peptide 3, induced a dose-dependent increase of dimethylated Lys4 of histone H3 in HeLa cells, suggesting that they are likely to exhibit LSD1-inhibitory activity intracellularly. In addition, peptide 37 decreased the viability of HeLa cells. We believe this new approach for targeting LSD1 provides a basis for development of potent selective inhibitors and biological probes for LSD1.
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