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siRNA potency enhancement via chemical modifications of nucleotide bases at the 5′-end of the siRNA guide strand

Small interfering RNAs (siRNAs) can be utilized not only as functional biological research tools but also as therapeutic agents. For the clinical use of siRNA as drugs, various chemical modifications have been used to improve the activity of siRNA drugs, and further chemical modifications are expect...

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Autores principales: Shinohara, Fumikazu, Oashi, Taiji, Harumoto, Toshimasa, Nishikawa, Tomoyuki, Takayama, Yuki, Miyagi, Hikaru, Takahashi, Yuichi, Nakajima, Takahiro, Sawada, Takashi, Koda, Yasuo, Makino, Asana, Sato, Atsuko, Hamaguchi, Kaori, Suzuki, Michihiko, Yamamoto, Junichiro, Tomari, Yukihide, Saito, Jun-Ichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812868/
https://www.ncbi.nlm.nih.gov/pubmed/33177188
http://dx.doi.org/10.1261/rna.073783.119
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author Shinohara, Fumikazu
Oashi, Taiji
Harumoto, Toshimasa
Nishikawa, Tomoyuki
Takayama, Yuki
Miyagi, Hikaru
Takahashi, Yuichi
Nakajima, Takahiro
Sawada, Takashi
Koda, Yasuo
Makino, Asana
Sato, Atsuko
Hamaguchi, Kaori
Suzuki, Michihiko
Yamamoto, Junichiro
Tomari, Yukihide
Saito, Jun-Ichi
author_facet Shinohara, Fumikazu
Oashi, Taiji
Harumoto, Toshimasa
Nishikawa, Tomoyuki
Takayama, Yuki
Miyagi, Hikaru
Takahashi, Yuichi
Nakajima, Takahiro
Sawada, Takashi
Koda, Yasuo
Makino, Asana
Sato, Atsuko
Hamaguchi, Kaori
Suzuki, Michihiko
Yamamoto, Junichiro
Tomari, Yukihide
Saito, Jun-Ichi
author_sort Shinohara, Fumikazu
collection PubMed
description Small interfering RNAs (siRNAs) can be utilized not only as functional biological research tools but also as therapeutic agents. For the clinical use of siRNA as drugs, various chemical modifications have been used to improve the activity of siRNA drugs, and further chemical modifications are expected to improve the utility of siRNA therapeutics. As the 5′ nucleobase of the guide strand affects the interaction between an siRNA and AGO2 and target cleavage activity, structural optimization of this specific position may be a useful strategy for improving siRNA activity. Here, using the in silico model of the complex between human AGO2 MID domain and nucleoside monophosphates, we screened and synthesized an original adenine-derived analog, 6-(3-(2-carboxyethyl)phenyl)purine (6-mCEPh-purine), that fits better than the natural nucleotide bases into the MID domain of AGO2. Introduction of the 6-mCEPh-purine analog at the 5′-end of the siRNA guide strand significantly enhanced target knockdown activity in both cultured cell lines and in vivo animal models. Our findings can help expand strategies for rationally optimizing siRNA activity via chemical modifications of nucleotide bases.
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spelling pubmed-78128682022-02-01 siRNA potency enhancement via chemical modifications of nucleotide bases at the 5′-end of the siRNA guide strand Shinohara, Fumikazu Oashi, Taiji Harumoto, Toshimasa Nishikawa, Tomoyuki Takayama, Yuki Miyagi, Hikaru Takahashi, Yuichi Nakajima, Takahiro Sawada, Takashi Koda, Yasuo Makino, Asana Sato, Atsuko Hamaguchi, Kaori Suzuki, Michihiko Yamamoto, Junichiro Tomari, Yukihide Saito, Jun-Ichi RNA Article Small interfering RNAs (siRNAs) can be utilized not only as functional biological research tools but also as therapeutic agents. For the clinical use of siRNA as drugs, various chemical modifications have been used to improve the activity of siRNA drugs, and further chemical modifications are expected to improve the utility of siRNA therapeutics. As the 5′ nucleobase of the guide strand affects the interaction between an siRNA and AGO2 and target cleavage activity, structural optimization of this specific position may be a useful strategy for improving siRNA activity. Here, using the in silico model of the complex between human AGO2 MID domain and nucleoside monophosphates, we screened and synthesized an original adenine-derived analog, 6-(3-(2-carboxyethyl)phenyl)purine (6-mCEPh-purine), that fits better than the natural nucleotide bases into the MID domain of AGO2. Introduction of the 6-mCEPh-purine analog at the 5′-end of the siRNA guide strand significantly enhanced target knockdown activity in both cultured cell lines and in vivo animal models. Our findings can help expand strategies for rationally optimizing siRNA activity via chemical modifications of nucleotide bases. Cold Spring Harbor Laboratory Press 2021-02 /pmc/articles/PMC7812868/ /pubmed/33177188 http://dx.doi.org/10.1261/rna.073783.119 Text en © 2021 Shinohara et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Article
Shinohara, Fumikazu
Oashi, Taiji
Harumoto, Toshimasa
Nishikawa, Tomoyuki
Takayama, Yuki
Miyagi, Hikaru
Takahashi, Yuichi
Nakajima, Takahiro
Sawada, Takashi
Koda, Yasuo
Makino, Asana
Sato, Atsuko
Hamaguchi, Kaori
Suzuki, Michihiko
Yamamoto, Junichiro
Tomari, Yukihide
Saito, Jun-Ichi
siRNA potency enhancement via chemical modifications of nucleotide bases at the 5′-end of the siRNA guide strand
title siRNA potency enhancement via chemical modifications of nucleotide bases at the 5′-end of the siRNA guide strand
title_full siRNA potency enhancement via chemical modifications of nucleotide bases at the 5′-end of the siRNA guide strand
title_fullStr siRNA potency enhancement via chemical modifications of nucleotide bases at the 5′-end of the siRNA guide strand
title_full_unstemmed siRNA potency enhancement via chemical modifications of nucleotide bases at the 5′-end of the siRNA guide strand
title_short siRNA potency enhancement via chemical modifications of nucleotide bases at the 5′-end of the siRNA guide strand
title_sort sirna potency enhancement via chemical modifications of nucleotide bases at the 5′-end of the sirna guide strand
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812868/
https://www.ncbi.nlm.nih.gov/pubmed/33177188
http://dx.doi.org/10.1261/rna.073783.119
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