Design, synthesis, and mechanism elucidation of novel covalent PPARgamma agonists that mimic the endogenous ligands
Project/Area Number |
17K13264
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Multi-year Fund |
Research Field |
Chemical biology
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Research Institution | University of Tsukuba |
Principal Investigator |
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Project Period (FY) |
2017-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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Keywords | PPARγ / 共有結合型リガンド / 化合物スクリーニング / フラグメント分子 / 抗炎症活性 / 共有結合性アゴニスト |
Outline of Final Research Achievements |
This study aims to develop a covalent PPARgamma agonist and identify its molecular mechanism. Using ligand-linking strategy, we successfully identified a series of PPARgamma ligands which posses the ability to form covalent bond with PPARgamma. Docking simulation suggested that these ligands might exhibit the binding mode which mimic the endogenous fatty acid metabolites. RNA sequencing analysis and some biochemical experiments revealed that the ligands show anti-inflammatory effect through the modulation of expression of inflammatory-related genes.
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Academic Significance and Societal Importance of the Research Achievements |
核内受容体PPARγは糖や脂質代謝に関わる転写因子の一種であり、リガンドの結合によりその機能が制御される。これまで、PPARγに対して共有結合を形成し、その転写活性を増大させるアゴニスト化合物は、内在性の脂肪酸代謝物を除いて報告例が少なかったが、本研究により、アゴニスト型、非アゴニスト型の共有結合型リガンドを取得することができ、またその抗炎症活性を明らかにした。これらの化合物は、内在性リガンドによるPPARγに対する働きを調べるためのツールとしてだけでなく、抗炎症物質のシーズとして期待される。
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Report
(4 results)
Research Products
(8 results)
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[Journal Article] Inhibition of mRNA Maturation by Compounds Which Have a Flavonoid Skeleton2017
Author(s)
Kurata M, Morimoto M, Kawamura Y, Mursi IFA, Momma K, Takahashi M, Miyamae Y, Kambe T, Nagao N, Narita H, Shibuya Y and Masuda S
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Journal Title
Biochemistry and Molecular Biology
Volume: 2
Issue: 4
Pages: 46-53
DOI
Related Report
Peer Reviewed / Open Access
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