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Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides
http://hdl.handle.net/10069/00041010
http://hdl.handle.net/10069/000410107475b7ab-0896-474b-88e1-423737c348e1
名前 / ファイル | ライセンス | アクション |
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Pharmaceutics13_817.pdf (2.1 MB)
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Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2021-11-08 | |||||
タイトル | ||||||
タイトル | Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides | |||||
言語 | ||||||
言語 | eng | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | tiny LNA | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | miR-122 | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | GalNAc | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | Ligand-targeted drug delivery system | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | antisense oligonucleotide | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
著者 |
Yamamoto, Tsuyoshi
× Yamamoto, Tsuyoshi× Mukai, Yahiro× Wada, Fumito× Terada, Chisato× Kayaba, Yukina× Oh, Kaho× Yamayoshi, Asako× Obika, Satoshi× Harada–Shiba, Mariko |
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抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | The development of clinically relevant anti-microRNA antisense oligonucleotides (anti-miRNA ASOs) remains a major challenge. One promising configuration of anti-miRNA ASOs called “tiny LNA (tiny Locked Nucleic Acid)” is an unusually small (~8-mer), highly chemically modified anti-miRNA ASO with high activity and specificity. Within this platform, we achieved a great enhancement of the in vivo activity of miRNA-122-targeting tiny LNA by developing a series of N-acetylgalactosamine (GalNAc)-conjugated tiny LNAs. Specifically, the median effective dose (ED50) of the most potent construct, tL-5G3, was estimated to be ~12 nmol/kg, which is ~300–500 times more potent than the original unconjugated tiny LNA. Through in vivo/ex vivo imaging studies, we have confirmed that the major advantage of GalNAc over tiny LNAs can be ascribed to the improvement of their originally poor pharmacokinetics. We also showed that the GalNAc ligand should be introduced into its 5′ terminus rather than its 3′ end via a biolabile phosphodiester bond. This result suggests that tiny LNA can unexpectedly be recognized by endogenous nucleases and is required to be digested to liberate the parent tiny LNA at an appropriate time in the body. We believe that our strategy will pave the way for the clinical application of miRNA-targeting small ASO therapy. | |||||
書誌情報 |
Pharmaceutics 巻 13, 号 6, p. art. no. 817, 発行日 2021-05-31 |
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出版者 | ||||||
出版者 | MDPI | |||||
EISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 1999-4923 | |||||
DOI | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | DOI | |||||
関連識別子 | 10.3390/pharmaceutics13060817 | |||||
権利 | ||||||
権利情報 | © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). | |||||
著者版フラグ | ||||||
出版タイプ | VoR | |||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
引用 | ||||||
内容記述タイプ | Other | |||||
内容記述 | Pharmaceutics, 13(6), art. no. 817; 2021 |