ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

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

View Author Information
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
Copyright © 2017 American Chemical Society

    Article Views





    Other access options
    Supporting Info (1)»


    Abstract Image

    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.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    Jump To

    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)

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 37 publications.

    1. Letao Yang, Christopher Rathnam, Takuya Hidaka, Yannan Hou, Brandon Conklin, Ganesh N. Pandian, Hiroshi Sugiyama, Ki-Bum Lee. Nanoparticle-Based Artificial Mitochondrial DNA Transcription Regulator: MitoScript. Nano Letters 2023, 23 (5) , 2046-2055.
    2. Xue Li, Zhaofang Shi, Tiezheng Jia. Potentiometric Determination of Acid Dissociation Constants (pKa) for an Anticancer Pyrrole-Imidazole Polyamide. ACS Medicinal Chemistry Letters 2022, 13 (11) , 1739-1744.
    3. Yutaro Tsubono, Yusuke Kawamoto, Takuya Hidaka, Ganesh N. Pandian, Kaori Hashiya, Toshikazu Bando, Hiroshi Sugiyama. A Near-Infrared Fluorogenic Pyrrole–Imidazole Polyamide Probe for Live-Cell Imaging of Telomeres. Journal of the American Chemical Society 2020, 142 (41) , 17356-17363.
    4. Tinghan Zhao, Xinglei Liu, Sweety Singh, Xiangshan Liu, Yuanwei Zhang, Junko Sawada, Masanobu Komatsu, Kevin D. Belfield. Mitochondria Penetrating Peptide-Conjugated TAMRA for Live-Cell Long-Term Tracking. Bioconjugate Chemistry 2019, 30 (9) , 2312-2316.
    5. Jing Liu, Horacio Cabral, Peng Mi. Nanocarriers address intracellular barriers for efficient drug delivery, overcoming drug resistance, subcellular targeting and controlled release. Advanced Drug Delivery Reviews 2024, 207 , 115239.
    6. Dan Bai, Reihane Ziadlou, Thangavel Vaijayanthi, Subramani Karthikeyan, Shanmugavel Chinnathambi, Anutthaman Parthasarathy, Li Cai, Marie‐Charlotte Brüggen, Hiroshi Sugiyama, Ganesh N. Pandian. Nucleic acid‐based small molecules as targeted transcription therapeutics for immunoregulation. Allergy 2024, 79 (4) , 843-860.
    7. Hiroshi Sugiyama. Follow your interests and use anything for research. Journal of Synthetic Organic Chemistry, Japan 2024, 82 (2) , 190-193.
    8. Thangavel Vaijayanthi, Ganesh N. Pandian, Hiroshi Sugiyama. Pyrrole–Imidazole Polyamides – A Frontrunner in Nucleic Acid‐Based Small Molecule Drugs. Advanced Therapeutics 2023, 6 (7)
    9. Shalini Pradhan, Sinem Apaydin, Jonas Bucevičius, Rūta Gerasimaitė, Georgij Kostiuk, Gražvydas Lukinavičius. Sequence-specific DNA labelling for fluorescence microscopy. Biosensors and Bioelectronics 2023, 230 , 115256.
    10. Ganesh N. Pandian, Shubham Mishra, Hiroshi Sugiyama. Artificial Genetic Switches and DNA Origami: Current Landscape and Prospects as Designer Therapeutics and Visualization Tools. 2023, 1835-1864.
    11. Vinodh J. Sahayasheela, Zutao Yu, Takuya Hidaka, Ganesh N. Pandian, Hiroshi Sugiyama. Mitochondria and G-quadruplex evolution: an intertwined relationship. Trends in Genetics 2023, 39 (1) , 15-30.
    12. Takuya Hidaka, Kaori Hashiya, Toshikazu Bando, Ganesh N. Pandian, Hiroshi Sugiyama. Targeted elimination of mutated mitochondrial DNA by a multi-functional conjugate capable of sequence-specific adenine alkylation. Cell Chemical Biology 2022, 29 (4) , 690-695.e5.
    13. Congcong Zhang, Yufei Xue, Lan Wang, Qiong Wu, Bin Fang, Yu Sheng, Hua Bai, Bo Peng, Naidi Yang, Lin Li. Progress on the Physiological Function of Mitochondrial DNA and Its Specific Detection and Therapy. ChemBioChem 2022, 23 (4)
    14. Ganesh N. Pandian, Shubham Mishra, Hiroshi Sugiyama. Artificial Genetic Switches and DNA Origami: Current Landscape and Prospects as Designer Therapeutics and Visualization Tools. 2022, 1-30.
    15. Takuya Hidaka. Allele-Specific Replication Inhibition of Mitochondrial DNA by MITO-PIP Conjugated with Alkylation Reagent. 2022, 41-65.
    16. Hiroki Nagase, Takayoshi Watanabe, Nobuko Koshikawa, Seigi Yamamoto, Keizo Takenaga, Jason Lin. Mitochondria: Endosymbiont bacteria DNA sequence as a target against cancer. Cancer Science 2021, 112 (12) , 4834-4843.
    17. Takuya Hidaka, Hiroshi Sugiyama. Chemical Approaches to the Development of Artificial Transcription Factors Based on Pyrrole‐Imidazole Polyamides. The Chemical Record 2021, 21 (6) , 1374-1384.
    18. Jingbo Qin, Ningqiang Gong, Zhihuan Liao, Shouwen Zhang, Peter Timashev, Shuaidong Huo, Xing-Jie Liang. Recent progress in mitochondria-targeting-based nanotechnology for cancer treatment. Nanoscale 2021, 13 (15) , 7108-7118.
    19. Takuya Hidaka, Hiroshi Sugiyama, Ganesh N. Pandian. Sequence-Specific Control of Mitochondrial Gene Transcription Using Programmable Synthetic Gene Switches Called MITO-PIPs. 2021, 217-225.
    20. Ganesh N. Pandian, Hiroshi Sugiyama. Designing Biomimicking Synthetic Transcription Factors for Therapeutic Gene Modulation. 2021, 135-161.
    21. Madhu Malinee, Hiroshi Sugiyama. Impact of Reactive Oxygen Species and G-Quadruplexes in Telomeres and Mitochondria. 2021, 249-274.
    22. Mi Zhang, Jing Liang, Shi-Kun Jiang, Ling Xu, Yan-Ling Wu, Annoor Awadasseid, Xiao-Yin Zhao, Xu-Qiong Xiong, Hiroshi Sugiyama, Wen Zhang. Design, synthesis and anti-cancer activity of pyrrole-imidazole polyamides through target-downregulation of c-kit gene expression. European Journal of Medicinal Chemistry 2020, 207 , 112704.
    23. Miao Wang, Lifo Ruan, Tianyu Zheng, Dongqing Wang, Mengxue Zhou, Huiru Lu, Jimin Gao, Jun Chen, Yi Hu. A surface convertible nanoplatform with enhanced mitochondrial targeting for tumor photothermal therapy. Colloids and Surfaces B: Biointerfaces 2020, 189 , 110854.
    24. Toshikazu Bando, Hiroshi Sugiyama. Epigenetic Drug Discovery by Artificial Genetic Switches. Journal of Synthetic Organic Chemistry, Japan 2020, 78 (5) , 476-484.
    25. Zutao YU. Synthetic DNA Binding Assembly: Architecture, Application and Perspectives. 2020, 1-39.
    26. Jean-Christophe Wyss, Rajesh Kumar, Josip Mikulic, Manfred Schneider, Jean-Luc Mary, Johannes D. Aebi, Lucienne Juillerat-Jeanneret, Dela Golshayan. Differential Effects of the Mitochondria-Active Tetrapeptide SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH2) and Its Peptidase-Targeted Prodrugs in Experimental Acute Kidney Injury. Frontiers in Pharmacology 2019, 10
    27. Zutao Yu, Ganesh N. Pandian, Takuya Hidaka, Hiroshi Sugiyama. Therapeutic gene regulation using pyrrole–imidazole polyamides. Advanced Drug Delivery Reviews 2019, 147 , 66-85.
    28. Jia Dong, Danqi Hong, Wenjie Lang, Jintao Huang, Linghui Qian, Qing Zhu, Lin Li, Jingyan Ge. Differently Tagged Probes for Protein Profiling of Mitochondria. ChemBioChem 2019, 20 (9) , 1155-1160.
    29. Khalid Aman, Giacomo Padroni, John A. Parkinson, Thomas Welte, Glenn A. Burley. Structural and Kinetic Profiling of Allosteric Modulation of Duplex DNA Induced by DNA‐Binding Polyamide Analogues. Chemistry – A European Journal 2019, 25 (11) , 2757-2763.
    30. Adeyemi Rahman, Patrick O'Sullivan, Isabel Rozas. Recent developments in compounds acting in the DNA minor groove. MedChemComm 2019, 10 (1) , 26-40.
    31. Yusuke Kawamoto. Introduction: Sequence-Specific DNA Binding Pyrrole–Imidazole Polyamides and Their Applications. 2019, 1-41.
    32. Tinghan Zhao, Sweety Singh, Yuanwei Zhang, Kevin D. Belfield. Novel mitochondria penetrating peptide for live-cell long-term tracking of mitochondria. 2019, OM3D.5.
    33. Thangavel Vaijayanthi, Ganesh N. Pandian, Hiroshi Sugiyama. Chemical Control System of Epigenetics. The Chemical Record 2018, 18 (12) , 1833-1853.
    34. Xiao-Shuang Hou, Huai-Song Wang, Benson Peter Mugaka, Gong-Jun Yang, Ya Ding. Mitochondria: promising organelle targets for cancer diagnosis and treatment. Biomaterials Science 2018, 6 (11) , 2786-2797.
    35. Chunlei Wu, Wei Wang, Lijing Fang, Wu Su. Programmable pyrrole-imidazole polyamides: A potent tool for DNA targeting. Chinese Chemical Letters 2018, 29 (7) , 1105-1112.
    36. Yusuke Kawamoto, Toshikazu Bando, Hiroshi Sugiyama. Sequence-specific DNA binding Pyrrole–imidazole polyamides and their applications. Bioorganic & Medicinal Chemistry 2018, 26 (8) , 1393-1411.
    37. Giacomo Padroni, John A Parkinson, Keith R Fox, Glenn A Burley. Structural basis of DNA duplex distortion induced by thiazole-containing hairpin polyamides. Nucleic Acids Research 2018, 46 (1) , 42-53.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect