Development of a TTR amyloidogenesis inhibitor based on the capture of transthyretin monomers
| Project/Area Number |
16K08193
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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 |
Physical pharmacy
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| Research Institution | University of Toyama |
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Principal Investigator |
Takeshi Yokoyama 富山大学, 大学院医学薬学研究部(薬学), 助教 (50524162)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | トランスサイレチン / アミロイドーシス / ATTR-FAP / ジアセレイン / PPI創薬 / アントラキノン / 構造生物学 / 医薬品化学 / X線結晶構造解析 / 蛋白質 |
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| Outline of Final Research Achievements |
We explored a candidate for a novel transthyretin (TTR) amyloloidogenesis inhibitor that binds to the TTR monomer. We found diacerein, a anti-inflammatory drug, as a candidate of a TTR amyloidogenesis inhibitor by computer-aided screening and screening of in-house compound library. We discovered by biophysical experiments that while diacerein stabilized the TTR tetramer by binding to TTR in a same manner as other TTR amyloidogenesis inhibitors, diacerein inhibited the TTR amyloid fibril formation of TTR by stabilizing the TTR monomer and dimer. Altough further investigation is required, our study indicates diacerein would be a novel TTR amyloidogenesis inhibitor.
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| Academic Significance and Societal Importance of the Research Achievements |
現在、国内で承認されているATTR-FAPの治療は肝移植またはTTRを安定化するビンダケルに依存している。治療の選択肢を広げるために、新しい作用機序のアミロイド線維形成阻害剤の創製が望まれる。本研究ではジアセレインが強い線維阻害作用を示すことを発見し、ビンダケルとは異なる作用機序であることが示唆された。ジアセレインは新規のアミロイド線維形成阻害剤、あるいはその鋳型化合物となりうる。
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Report
(4 results)
Research Products
(23 results)
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[Journal Article] Transthyretin Amyloid Fibril Disrupting Activities of Extracts and Fractions from Juglans mandshurica Maxim. var. cordiformis (Makino) Kitam.2019
Author(s)
Chaudhary N., Sasaki, R., Shuto, T., Watanabe, M., Kawahara, T., Suico, M.A., Yokoyama, T., Mizuguchi, M., Kai, H., Devkota, H.
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Journal Title
Molecules
Volume: 24
Issue: 3
Pages: 500-500
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Virtual and high-throughput screenings identify novel TTR stabilizers for hereditary ATTR amyloidosis2018
Author(s)
5) Keisuke Chosa, Yukiko Teranishi, Ryoko Sasaki, Shun Takaki, Takeshi Yokoyama, Yoshiki Imai, Yuriko Wakita, Takashi Sato, Tsuyoshi Shuto, Mary Ann Suico, Mineyuki Mizuguchi, Hirofumi Kai
Organizer
The XVIth International Symposium on Amyloidosis
Related Report
Int'l Joint Research
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