| Project/Area Number |
16K07269
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Structural biochemistry
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| Research Institution | Kyoto University |
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Principal Investigator |
Mashima Tsukasa 京都大学, エネルギー理工学研究所, 助教 (20707426)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | NMR / アプタマー / 四重鎖核酸 / プリオン病 / 立体構造 |
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| Outline of Final Research Achievements |
Prion diseases are neurodegenerative disorders caused by the conversion of cellular prion protein to pathological isoform. Previously, we obtained an RNA aptamer, R12, that possesses anti-prion activity. We also revealed that R12 folds into a unique G-quadruplex structure and two R12 molecules form a homodimer. Here, we developed new prion aptamers, R24 and R12-A-R12, based on the structure of R12 homodimer. The assay with prion-infected cells showed that both aptamers exhibited much higher anti-prion activity than R12. Our NMR studies showed that the structure of a single R12-A-R12 molecule resembled that of the R12 homodimer. R24 is supposed to unimolecularly form a similar structure of R12 homodimer because the sequence of R24 is almost the same as that of R12-A-R12. The quadruplex structure of either R24 or R12-A-R12 formed by one molecule could be stable when they are administered to a prion-infected cell culture. This may be the reason they possess high anti-prion activity.
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| Academic Significance and Societal Importance of the Research Achievements |
プリオン病は重篤な神経変性疾患であるが、根治できる治療法がなく、効果的な治療薬の開発が望まれている。今回我々が開発したアプタマーは、ある種の抗体などを除き、これまでの抗プリオン物質の中で最も高い効率でプリオンタンパク質の異常化を抑制する。よって治療薬への応用が期待されるため、社会的意義がある。
核酸、特に四重鎖構造を有する核酸は一塩基を置換・付加しただけで大きくそのトポロジーが変わることがあり、その原理は不明である。本研究では新規アプタマーを設計し、その立体構造が意図した通りであるかを確認し、さらに活性を大きく向上させることに成功したため、学術的にも意義がある。
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