Design, synthesis, and mechanism elucidation of novel covalent PPARgamma agonists that mimic the endogenous ligands

• Project/Area Number: 17K13264
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Chemical biology
• Research Institution: University of Tsukuba
• Principal Investigator: MIYAMAE Yusaku 筑波大学, 生命環境系, 准教授 (30610240)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥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)
• 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 / パートナーリガンド

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.

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。

Research Products

• [Journal Article] A Method for Conditional Regulation of Protein Stability in Native or Near-Native Form (2020)
  • Author(s): Miyamae Yusaku、Chen Ling-chun、Utsugi Yuki、Farrants Helen、Wandless Thomas J.
  • Journal Title: Cell Chemical Biology Volume: 27 Issue: 12 Pages: 1573-1581.e3
  • DOI: 10.1016/j.chembiol.2020.09.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Stimulation of insulin secretion by acetylenic fatty acids in insulinoma MIN6 cells through FFAR1 (2020)
  • Author(s): Nishino Katsutoshi、Uesugi Haruka、Hirasawa Akira、Ohtera Anna、Miyamae Yusaku、Neffati Mohamed、Isoda Hiroko、Kambe Taiho、Masuda Seiji、Irie Kazuhiro、Nagao Masaya
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 522 Issue: 1 Pages: 68-73
  • DOI: 10.1016/j.bbrc.2019.11.037
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Importance of the Proximity and Orientation of Ligand-Linkage to the Design of Cinnamate-GW9662 Hybrid Compounds as Covalent PPARγ Agonists (2019)
  • Author(s): Utsugi, Y., Kobuchi, H., Kawamura, Y., Atito, A.S.A., Nagao, M., Isoda, H., Miyamae, Y.
  • Journal Title: Molecules Volume: 24 Issue: 10 Pages: 2019-2019
  • DOI: 10.3390/molecules24102019
  • NAID: 120007133399
  • Peer Reviewed / Open Access
• [Journal Article] Food-Derived Compounds Apigenin and Luteolin Modulate mRNA Splicing of Introns with Weak Splice Sites (2019)
  • Author(s): Kurata Masashi、Fujiwara Naoko、Fujita Ken-ichi、Yamanaka Yasutaka、Seno Shigeto、Kobayashi Hisato、Miyamae Yusaku、Takahashi Nobuyuki、Shibuya Yasuyuki、Masuda Seiji
  • Journal Title: iScience Volume: 22 Pages: 336-352
  • DOI: 10.1016/j.isci.2019.11.033
  • NAID: 120007132694
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of mRNA Maturation by Compounds Which Have a Flavonoid Skeleton (2017)
  • 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
  • Journal Title: Biochemistry and Molecular Biology Volume: 2 Issue: 4 Pages: 46-53
  • DOI: 10.11648/j.bmb.20170204.13
  • Peer Reviewed / Open Access
• [Presentation] 共有結合型PPARγリガンドとその類縁化合物に拠る抗炎症活性の検証 (2021)
  • Author(s): 大前勇馬、礒田博子、宮前友策
  • Organizer: 日本農芸化学会2021年大会
• [Presentation] 生体直交型反応を示す官能基を付加した PPARγ リガンドの合成と活性評価 (2021)
  • Author(s): 安彩伽、大前勇馬、有本光江、加香 孝一郎、礒田博子、深水昭吉、繁森英幸、宮前友策
  • Organizer: 日本農芸化学会2021年大会
• [Presentation] Effect of a covalent PPARγ agonist on inflammatory pathway (2020)
  • Author(s): Yuma Omae, Hiroko Isoda, Yusaku Miyamae
  • Organizer: JAACT2020
  • Int'l Joint Research
• [Presentation] フラグメントユニットの近接性と配向性が異なる共有結合型PPARγリガンドの合成と活性評価 (2020)
  • Author(s): 宇津木優樹; 小渕裕菜; 河村幸雄; 永尾雅哉; 礒田博子; 宮前友策
  • Organizer: 日本農芸化学会2020年度大会
• [Presentation] 脱ユビキチン化酵素の切断活性を利用した細胞内標的タンパク質発現制御法の構築 (2020)
  • Author(s): 宮前 友策; 宇津木優樹; 礒田博子; Ling-Chun Chen; Thomas J. Wandless
  • Organizer: 日本農芸化学会2020年度大会
• [Presentation] リガンド結合ポケットの特性を利用した新規共有結合性PPARγアゴニストの創製と生物活性評価 (2019)
  • Author(s): 宮前友策; 宇津木優樹; 大寺杏奈; 小渕裕菜; 吉田光多郎; 大前勇馬; 神戸大朋; 増田誠司; 河村幸雄; 永尾雅哉; 礒田博子
  • Organizer: 第61回天然有機化合物討論会
• [Presentation] 脱ユビキチン化酵素の切断機構を利用した細胞内標的タンパク質発現制御法の開発 (2019)
  • Author(s): 宮前 友策; 宇津木優樹; 礒田博子; Ling-Chun Chen; Thomas J. Wandless
  • Organizer: 日本ケミカルバイオロジー学会第14回年会
• [Presentation] Identification of a new type of covalent PPARγ agonist using a ligand-linking strategy (2018)
  • Author(s): Yusaku Miyamae, Anna Ohtera, Kotaro Yoshida, Kazuhiro Maejima, Toru Akita, Akira Kakizuka, Kazuhiro Irie, Seiji Masuda, Taiho Kambe, Masaya Nagao
  • Organizer: JAACT2018
  • Int'l Joint Research
• [Presentation] Biological evaluation of cinnamate-GW9662 hybrid compounds as a novel class of covalent PPARγ agonist (2018)
  • Author(s): Yuki Utsugi, Hirona Kobuchi, Yukio Kawamura, Ahmed Salahelden Aboelhamd Atito, Masaya Nagao, Hiroko Isoda, Yusaku Miyamae
  • Organizer: JAACT2018
  • Int'l Joint Research
• [Presentation] 新規共有結合性PPARγアゴニストの構造活性相関及び推定結合様式の解析 (2018)
  • Author(s): 宇津木優樹、小渕裕菜、河村幸雄、Ahmed Salahelden Aboelhamd Atito, 永尾雅哉、礒田博子、宮前友策
  • Organizer: 日本農芸化学会関東支部大会2018年度大会