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j.chembiol.2021.08.003.pdf | 1.32 MB | Adobe PDF | 見る/開く |
タイトル: | Targeted elimination of mutated mitochondrial DNA by a multi-functional conjugate capable of sequence-specific adenine alkylation |
著者: | Hidaka, Takuya Hashiya, Kaori Bando, Toshikazu N., Ganesh Pandian Sugiyama, Hiroshi |
著者名の別形: | 日髙, 拓也 橋谷, かおり 坂東, 俊和 ナマシヴァヤム, ガネシュ・パンディアン 杉山, 弘 |
キーワード: | pyrrole-imidazole polyamide mitochondrial DNA mitochondria DNA alkylation DNA mutation heteroplasmy mitochondrial disease designer small molecule |
発行日: | Apr-2022 |
出版者: | Elsevier BV |
誌名: | Cell Chemical Biology |
巻: | 29 |
号: | 4 |
開始ページ: | 690 |
終了ページ: | 695 |
論文番号: | e5 |
抄録: | Mutations in mitochondrial DNA (mtDNA) cause mitochondrial diseases, characterized by abnormal mitochondrial function. Although eliminating mutated mtDNA has potential to cure mitochondrial diseases, no chemical-based drugs in clinical trials are capable of selective modulation of mtDNA mutations. Here, we construct a class of compounds encompassing pyrrole-imidazole polyamides (PIPs), mitochondria-penetrating peptide, and chlorambucil, an adenine-specific DNA-alkylating reagent. The sequence-selective DNA binding of PIPs allows chlorambucil to alkylate mutant adenine more efficiently than other sites in mtDNA. In vitro DNA alkylation assay shows that our compound 8950A-Chb(Cl/OH) targeting a nonpathogenic point mutation in HeLa S3 cells (m.8950G>A) can specifically alkylate the mutant adenine. Furthermore, the compound reduces the mtDNA possessing the target mutation in cultured HeLa S3 cells. The programmability of PIPs to target different sequences could allow this class of compounds to be developed as designer drugs targeting pathogenic mutations associated with mitochondrial diseases in future studies. |
記述: | ミトコンドリアの変異DNAを減らす化合物の開発. 京都大学プレスリリース. 2021-08-27. Deleting DNA to treat mitochondrial diseases. 京都大学プレスリリース. 2021-08-27. |
著作権等: | © 2021. This manuscript version is made available under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International license. The full-text file will be made open to the public on 21 April 2023 in accordance with publisher's 'Terms and Conditions for Self-Archiving'. This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 |
URI: | http://hdl.handle.net/2433/275663 |
DOI(出版社版): | 10.1016/j.chembiol.2021.08.003 |
PubMed ID: | 34450110 |
関連リンク: | https://www.icems.kyoto-u.ac.jp/news/4421/ https://www.icems.kyoto-u.ac.jp/en/news/4422/ |
出現コレクション: | 学術雑誌掲載論文等 |
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