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Title: Development and structural determination of an anti-PrPC aptamer that blocks pathological conformational conversion of prion protein
Authors: Mashima, Tsukasa
Lee, Joon-Hwa
Kamatari, Yuji O.
Hayashi, Tomohiko
Nagata, Takashi  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-3733-2709 (unconfirmed)
Nishikawa, Fumiko
Nishikawa, Satoshi
Kinoshita, Masahiro
Kuwata, Kazuo
Katahira, Masato  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0003-0336-7660 (unconfirmed)
Author's alias: 真嶋, 司
鎌足, 雄司
林, 智彦
永田, 崇
西川, 富美子
西川, 諭
木下, 正弘
桑田, 一夫
片平, 正人
Keywords: Nucleic acids
Prions
RNA
Solution-state NMR
Issue Date: 18-Mar-2020
Publisher: Springer Nature
Journal title: Scientific Reports
Volume: 10
Thesis number: 4934
Abstract: Prion diseases comprise a fatal neuropathy caused by the conversion of prion protein from a cellular (PrPC) to a pathological (PrPSc) isoform. Previously, we obtained an RNA aptamer, r(GGAGGAGGAGGA) (R12), that folds into a unique G-quadruplex. The R12 homodimer binds to a PrPC molecule, inhibiting PrPC-to-PrPSc conversion. Here, we developed a new RNA aptamer, r(GGAGGAGGAGGAGGAGGAGGAGGA) (R24), where two R12s are tandemly connected. The 50% inhibitory concentration for the formation of PrPSc (IC50) of R24 in scrapie-infected cell lines was ca. 100 nM, i.e., much lower than that of R12 by two orders. Except for some antibodies, R24 exhibited the lowest recorded IC50 and the highest anti-prion activity. We also developed a related aptamer, r(GGAGGAGGAGGA-A-GGAGGAGGAGGA) (R12-A-R12), IC50 being ca. 500 nM. The structure of a single R12-A-R12 molecule determined by NMR resembled that of the R12 homodimer. The quadruplex structure of either R24 or R12-A-R12 is unimolecular, and therefore the structure could be stably formed when they are administered to a prion-infected cell culture. This may be the reason they can exert high anti-prion activity.
Description: 狂牛病を引き起こすプリオン蛋白質の異常化を抑制するRNA分子の開発 --アルツハイマー病の治療への応用の可能性も--. 京都大学プレスリリース. 2020-03-19.
Rights: © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
URI: http://hdl.handle.net/2433/246239
DOI(Published Version): 10.1038/s41598-020-61966-4
PubMed ID: 32188933
Related Link: https://www.kyoto-u.ac.jp/ja/research-news/2020-03-19
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