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Creation of a Synthetic Ligand for Mitochondrial DNA Sequence Recognition and Promoter-Specific Transcription Suppression

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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
§ Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan
Cite this: J. Am. Chem. Soc. 2017, 139, 25, 8444–8447
Publication Date (Web):June 14, 2017
https://doi.org/10.1021/jacs.7b05230
Copyright © 2017 American Chemical Society

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    Abstract

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    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.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b05230.

    • Experimental procedures, characterization data for 14, primer list for qPCR experiments, and representative denaturation profiles in the Tm analyses, including Figures S1 and S2 and Table S1 (PDF)

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