Mechanism of lentztrehalose-induced autophagy; its application for the treatment of neurodegenerative diseases

• Project/Area Number: 15K08013
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Natural medicines
• Research Institution: Microbial Chemistry Research Foundation
• Principal Investigator: WADA Shun-ichi 公益財団法人微生物化学研究会, 微生物化学研究所, 研究員 (40450233)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: レンツトレハロース / トレハロース / 神経変性疾患 / アルツハイマー病 / オートファジー

Outline of Final Research Achievements

Dozens of new trehalose-type autophagy inducers were discovered or synthesized. Among them, TRH-X was estimated as mass-producible and suitable as the material to synthesize further derivative compounds. Some of the TRH-X derivatives showed higher autophagy inducing activities than trehalose and other analogues. They would be the promising drug candidates for the treatment of neurodegenerative diseases to dissolve the aggregation of abnormal proteins in the neuronal cells.
The curative effect of trehalose in Alzheimer’s disease was evaluated using a model mouse. Trehalose administrated mice in the early stage of the disease showed significantly better recognitive function and reduced amyloid plaque. The development and application of the new trehalose analogue compound for the treatment of Alzheimer’s disease are expected.

Research Products

• [Journal Article] Structures and biological activities of novel 4’-acetylated analogs of chrysomycins A and B. (2017)
  • Author(s): Wada, S., Sawa, R., Iwanami, F., Nsgayoshi, M., Kubota, Y., Iijima, K., Hayashi, C., Shibuya, Y., Hatano, M., Igarashi, M., Kawada, M.
  • Journal Title: J. Antibiot. Volume: 70 Issue: 11 Pages: 1078-1082
  • DOI: 10.1038/ja.2017.99
  • Peer Reviewed
• [Journal Article] Valgamicin C, a novel cyclic depsipeptide containing the unusual amino acid cleonine, and related valgamicins A, T and V produced by Amycolatopsis sp. ML1-hF4 (2017)
  • Author(s): Hashizume Hideki、Iijima Kiyoko、Yamashita Kazuma、Kimura Tomoyuki、Wada Shun-ichi、Sawa Ryuichi、Igarashi Masayuki
  • Journal Title: The Journal of Antibiotics Volume: 71 Issue: 1 Pages: 129-134
  • DOI: 10.1038/ja.2017.135
  • Peer Reviewed
• [Journal Article] Novel approaches for identification of anti-tumor drugs and new bioactive compounds (2017)
  • Author(s): Kawada Manabu、Atsumi Sonoko、Wada Shun-ichi、Sakamoto Shuichi
  • Journal Title: The Journal of Antibiotics Volume: 71 Issue: 1 Pages: 39-44
  • DOI: 10.1038/ja.2017.97
  • Peer Reviewed
• [Journal Article] ATP Depletion Assay Led to the Isolation of New 36-Membered Polyol Macrolides Deplelides A and B from Streptomyces sp. MM581-NF15 (2017)
  • Author(s): Toshifumi Takeuchi , Masaki Hatano, Maya Umekita, Chigusa Hayashi, Shun-ichi Wada, Miho Nagayoshi, Ryuichi Sawa, Yumiko Kubota, Manabu Kawada, Masayuki Igarashi, Masakatsu Shibasaki
  • Journal Title: Organic Letters Volume: 19 Issue: 16 Pages: 4207-7210
  • DOI: 10.1021/acs.orglett.7b01807
  • Peer Reviewed
• [Journal Article] Stability and Bioavailability of Lentztrehaloses A, B, and C as Replacements for Trehalose. (2016)
  • Author(s): Wada S, Sawa R, Ohba S, Hayashi C, Umekita M, Shibuya Y, Iijima K, Iwanami F, Igarashi M.
  • Journal Title: J Agric Food Chem. Volume: 64 Issue: 38 Pages: 7121-7126
  • DOI: 10.1021/acs.jafc.6b02782
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel autophagy inducers lentztrehaloses A, B and C. (2015)
  • Author(s): Wada S, Kubota Y, Sawa R, Umekita M, Hatano M, Ohba S, Hayashi C, Igarashi M, Nomoto A.
  • Journal Title: J Antibiot Volume: 68 Issue: 8 Pages: 521-529
  • DOI: 10.1038/ja.2015.23
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synthesis and Determination of Absolute Configuration of Lentztrehalose A (2015)
  • Author(s): Zhang M, Wada S, Amemiya F, Watanabe T, Shibasaki M.
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 63 Issue: 11 Pages: 961-966
  • DOI: 10.1248/cpb.c15-00600
  • NAID: 130005105723
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Lentzea 属放線菌由来新規trehalose 類縁体lentztrehalose 類の構造と生物活性 (2017)
  • Author(s): 和田俊一， 澤 竜一， 大庭俊一， 波多野和樹， 染野哲也， 久保田由美子， 梅北まや， 林 千草， 飯島希昌子， 渋谷優子，川田 学，五十嵐雅之
  • Organizer: 日本農芸化学会 2017 年度大会
  • Place of Presentation: 京都女子大学 （京都府京都市）
  • Year and Date: 2017-03-19
• [Presentation] 新規4'-acetyl-chrysomycin A, Bの構造と生物活性 (2017)
  • Author(s): 和田俊一、澤竜一、岩波史樹、永吉美穂、久保田由美子、飯島希昌子、林千草、渋谷優子、波多野和樹、五十嵐雅之、川田学
  • Organizer: 2017年度 日本放線菌学会大会
• [Presentation] 希少放線菌 Amycolatopsis sp. ML1-hF4株の生産する新規化合物 pargamicins A,B,C,Dの構造解析および生物活性 (2017)
  • Author(s): 橋爪秀樹、山下和真、久保田由美子、林千草、和田俊一、原田滋子、澤竜一、五十嵐雅之
  • Organizer: 2017年度 日本放線菌学会大会
• [Presentation] Lentzea 属放線菌由来lentztrehalose 類のtrehalose 改良品としての安定性評価 (2016)
  • Author(s): 和田 俊一, 澤 竜一, 大庭 俊一, 林 千草, 梅北 まや, 渋谷 優子, 飯島 希昌子, 五十嵐 雅之
  • Organizer: 2016 年度 日本放線菌学会大会
  • Place of Presentation: 東京大学農学部（東京都文京区）
  • Year and Date: 2016-09-09
• [Presentation] 希少放線菌 Amycolatopsis sp. ML1-hF4 株の生産する異常アミノ酸 cleonine 含有新規化合物 valgamicin C および新規類縁体の構造および生物活性 (2016)
  • Author(s): 橋爪 秀樹, 山下 和真, 飯島 希昌子, 木村 智之, 渋谷 優子, 和田 俊一, 澤 竜一, 五十嵐 雅之
  • Organizer: 2016 年度 日本放線菌学会大会
  • Place of Presentation: 東京大学農学部（東京都文京区）
  • Year and Date: 2016-09-08
• [Presentation] Lentzea属放線菌由来trehalose類縁体lentztrehalose類の構造と生物活性 (2015)
  • Author(s): 和田 俊一, 澤 竜一, 大庭 俊一, 染野 哲也, 久保田 由美子, 波多野 和樹, 梅北 まや, 張 明, 渡辺 匠, 林 千草, 川田 学, 五十嵐 雅之, 柴﨑 正勝
  • Organizer: 第30回 日本放線菌学会大会
  • Place of Presentation: 富山国際会議場 (富山)
  • Year and Date: 2015-09-08
• [Remarks] 第１生物活性研究部 テーマ概要
  • URL: http://www.bikaken.or.jp/laboratories/oncology/summary.html
• [Patent(Industrial Property Rights)] レンツトレハロースAの製造方法、並びに前記製造方法に有用な化合物及びその製造方法 (2015)
  • Inventor(s): 渡邊匠、和田俊一、五十嵐雅之、張明
  • Industrial Property Rights Holder: 公益財団法人微生物化学研究会
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-06-11