Department of Chemistry, Graduate School of Science, Kyoto University , Sakyo, Kyoto 606-8502, Japan.
Institute for Integrated Cell-Material Science (WPI-iCeMS), Kyoto University , Sakyo, Kyoto 606-8501, Japan.
J Am Chem Soc. 2017 Jun 28;139(25):8444-8447. doi: 10.1021/jacs.7b05230. Epub 2017 Jun 16.
Synthetic ligands capable of recognizing the specific DNA sequences inside human mitochondria and modulating gene transcription are in increasing demand because of the surge in evidence linking mitochondrial genome and diseases. In the work described herein, we created a new type of mitochondria-specific synthetic ligand, termed MITO-PIPs, by conjugating a mitochondria-penetrating peptide with pyrrole-imidazole polyamides (PIPs). The designed MITO-PIPs showed specific localization inside mitochondria in HeLa cells and recognized the target DNA in a sequence-specific manner. Furthermore, MITO-PIPs that inhibit the binding of mitochondrial transcription factor A to the light-strand promoter (LSP) also triggered targeted transcriptional suppression. The tunability of PIPs' properties suggests the potential of the MITO-PIPs as potent modulators of not only mitochondrial gene transcription but also its DNA mutations.
由于越来越多的证据表明线粒体基因组与疾病有关，因此能够识别人类线粒体内部特定 DNA 序列并调节基因转录的合成配体的需求正在不断增加。在本文所述的工作中，我们通过将线粒体穿透肽与吡咯-咪唑聚酰胺（PIPs）缀合，创建了一种新型的线粒体特异性合成配体，称为 MITO-PIPs。设计的 MITO-PIPs 在 HeLa 细胞中在线粒体中表现出特异性定位，并以序列特异性方式识别靶 DNA。此外，抑制线粒体转录因子 A 与轻链启动子（LSP）结合的 MITO-PIPs 也触发了靶向转录抑制。PIPs 性质的可调节性表明，MITO-PIPs 不仅作为线粒体基因转录的有效调节剂，而且作为其 DNA 突变的有效调节剂具有潜力。
