Creation of a Synthetic Ligand for Mitochondrial DNA Sequence Recognition and Promoter-Specific Transcription SuppressionClick to copy article linkArticle link copied!
- Takuya Hidaka
- Ganesh N. Pandian
- Junichi Taniguchi
- Tomohiro Nobeyama
- Kaori Hashiya
- Toshikazu Bando
- Hiroshi Sugiyama
Abstract

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.
Cited By
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by ACS Publications if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
This article is cited by 38 publications.
- 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. https://doi.org/10.1021/acs.nanolett.2c03958
- 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. https://doi.org/10.1021/acsmedchemlett.2c00348
- 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. https://doi.org/10.1021/jacs.0c04955
- 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. https://doi.org/10.1021/acs.bioconjchem.9b00465
- 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. https://doi.org/10.1016/j.addr.2024.115239
- 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. https://doi.org/10.1111/all.15959
- Hiroshi Sugiyama. Follow your interests and use anything for research. Journal of Synthetic Organic Chemistry, Japan 2024, 82
(2)
, 190-193. https://doi.org/10.5059/yukigoseikyokaishi.82.190
- Gokhan Burcin Kubat, Ibrahim Turkel, Berkay Ozerklig, Ozbeyen Atalay, Serpil Suvay, Meltem Tuncer, Omer Faruk Taner, Oner Ulger. Mitochondrial transplantation methods. 2024, 199-214. https://doi.org/10.1016/B978-0-443-18858-9.00010-X
- Thangavel Vaijayanthi, Ganesh N. Pandian, Hiroshi Sugiyama. Pyrrole–Imidazole Polyamides – A Frontrunner in Nucleic Acid‐Based Small Molecule Drugs. Advanced Therapeutics 2023, 6
(7)
https://doi.org/10.1002/adtp.202300022
- 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. https://doi.org/10.1016/j.bios.2023.115256
- 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. https://doi.org/10.1007/978-981-19-9776-1_64
- 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. https://doi.org/10.1016/j.tig.2022.10.006
- 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. https://doi.org/10.1016/j.chembiol.2021.08.003
- 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)
https://doi.org/10.1002/cbic.202100474
- 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. https://doi.org/10.1007/978-981-16-1313-5_64-1
- Takuya Hidaka. Allele-Specific Replication Inhibition of Mitochondrial DNA by MITO-PIP Conjugated with Alkylation Reagent. 2022, 41-65. https://doi.org/10.1007/978-981-16-8436-4_3
- 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. https://doi.org/10.1111/cas.15143
- 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. https://doi.org/10.1002/tcr.202000158
- 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. https://doi.org/10.1039/D1NR01068A
- 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. https://doi.org/10.1007/978-1-0716-1262-0_13
- Ganesh N. Pandian, Hiroshi Sugiyama. Designing Biomimicking Synthetic Transcription Factors for Therapeutic Gene Modulation. 2021, 135-161. https://doi.org/10.1007/978-3-030-55924-3_6
- Madhu Malinee, Hiroshi Sugiyama. Impact of Reactive Oxygen Species and G-Quadruplexes in Telomeres and Mitochondria. 2021, 249-274. https://doi.org/10.1007/978-981-16-4457-3_16
- 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. https://doi.org/10.1016/j.ejmech.2020.112704
- 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. https://doi.org/10.1016/j.colsurfb.2020.110854
- Toshikazu Bando, Hiroshi Sugiyama. Epigenetic Drug Discovery by Artificial Genetic Switches. Journal of Synthetic Organic Chemistry, Japan 2020, 78
(5)
, 476-484. https://doi.org/10.5059/yukigoseikyokaishi.78.476
- Zutao YU. Synthetic DNA Binding Assembly: Architecture, Application and Perspectives. 2020, 1-39. https://doi.org/10.1007/978-981-15-4423-1_1
- 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 https://doi.org/10.3389/fphar.2019.01209
- Zutao Yu, Ganesh N. Pandian, Takuya Hidaka, Hiroshi Sugiyama. Therapeutic gene regulation using pyrrole–imidazole polyamides. Advanced Drug Delivery Reviews 2019, 147 , 66-85. https://doi.org/10.1016/j.addr.2019.02.001
- 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. https://doi.org/10.1002/cbic.201800735
- 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. https://doi.org/10.1002/chem.201805338
- Adeyemi Rahman, Patrick O'Sullivan, Isabel Rozas. Recent developments in compounds acting in the DNA minor groove. MedChemComm 2019, 10
(1)
, 26-40. https://doi.org/10.1039/C8MD00425K
- Yusuke Kawamoto. Introduction: Sequence-Specific DNA Binding Pyrrole–Imidazole Polyamides and Their Applications. 2019, 1-41. https://doi.org/10.1007/978-981-13-6912-4_1
- Tinghan Zhao, Sweety Singh, Yuanwei Zhang, Kevin D. Belfield. Novel mitochondria penetrating peptide for live-cell long-term tracking of mitochondria. 2019, OM3D.5. https://doi.org/10.1364/OMP.2019.OM3D.5
- Thangavel Vaijayanthi, Ganesh N. Pandian, Hiroshi Sugiyama. Chemical Control System of Epigenetics. The Chemical Record 2018, 18
(12)
, 1833-1853. https://doi.org/10.1002/tcr.201800067
- 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. https://doi.org/10.1039/C8BM00673C
- 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. https://doi.org/10.1016/j.cclet.2018.05.025
- Yusuke Kawamoto, Toshikazu Bando, Hiroshi Sugiyama. Sequence-specific DNA binding Pyrrole–imidazole polyamides and their applications. Bioorganic & Medicinal Chemistry 2018, 26
(8)
, 1393-1411. https://doi.org/10.1016/j.bmc.2018.01.026
- 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. https://doi.org/10.1093/nar/gkx1211
Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.