Development of new BACE1 inhibitors : an approach for downsizing molecules

• Project/Area Number: 22790119
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Drug development chemistry
• Research Institution: Kogakuin University (2011); Kyoto Prefectural University of Medicine (2010)
• Principal Investigator: KAKIZAWA Taeko 工学院大学, 工学部, 講師 (60445963)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: アルツハイマー病 / BACE1阻害剤

Research Abstract

The enzyme BACE1 is a major target for developing drugs for the treatment of Alzheimer's disease, because it catalyzes the production of amyloid β peptide. We designed and synthesized several low-molecular-weight tetrapeptidic BACE1 inhibitors with high potency from KMI-927.

Research Products

• [Journal Article] Development of L40I HTLV-I protease inhibition assay using novel fluorogenic and chromogenic substrate. (2011)
  • Author(s): Henri-Obadja Kumada, Jeffrey-Tri Nguyen, Keiji Nishiyama, Taeko Kakizawa, Yasuhiro Arii, Koushi Hidaka, Tooru Kimura, Yoshio Hayashi, Yoshiaki Kiso
  • Journal Title: J. Peptide Science Volume: 17(8) Issue: 8 Pages: 569-575
  • DOI: 10.1002/psc.1375
  • Peer Reviewed
• [Journal Article] The E22SS-type mutant of amyloid SS peptide (ASS) adopts distinct selfassembly mechanisms from wild- type ASS. (2011)
  • Author(s): Youhei Sohma, Hui Wang, Atsuhiko Taniguchi, Yuta Hirayama, Taeko Kakizawa, Hidehito Mukai, Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem. Volume: 19 Issue: 12 Pages: 3787-3792
  • DOI: 10.1016/j.bmc.2011.04.056
  • Peer Reviewed
• [Journal Article] Evaluation of superior BACE1 cleavage sequences containing unnatural amino acids (2011)
  • Author(s): T. Kakizawa, A. Sanjoh, A. Kobayashi, Y. Hattori, K. Teruya, and K. Akaji
  • Journal Title: Bioorganic and Medicinal Chemistry Volume: 19 Issue: 9 Pages: 2785-2789
  • DOI: 10.1016/j.bmc.2011.03.056
  • Peer Reviewed
• [Journal Article] Dehydrocoupling reactions of secondary and primary amine-borane adducts catalyzed by half-sandwich carbonyl complexes, [CpMn(CO)_3], [(η^6-C_6H_6) Cr(CO)_3], and [CpV(CO)_4] (2011)
  • Author(s): T. Kakizawa, Y. Kawano, K. Naganeyama, and M. Shimoi
  • Journal Title: Chemistry Letters Volume: 40 Issue: 2 Pages: 171-173
  • DOI: 10.1246/cl.2011.171
  • NAID: 10027814770
  • Peer Reviewed
• [Journal Article] Evaluation of superior BACE1 cleavage sequences containing unnatural amino acids (2011)
  • Author(s): Taeko Kakizawa
  • Journal Title: Bioorganic and medicinal chemistry Volume: VOL.19 Pages: 2785-2789
  • Peer Reviewed
• [Journal Article] Dehydrocoupling reactions of secondary and primary amine-borane adducts catalyzed by half-sandwich carbonyl complexes, [CpMn(CO)_3], [(η^6-C_6H_6)Cr(CO)_3], and [CpV(CO)_4] (2011)
  • Author(s): Taeko Kakizawa
  • Journal Title: Chemistry letters Volume: VOL.40 Pages: 171-173
  • NAID: 10027814770
  • Peer Reviewed
• [Journal Article] Tetrapeptides, as small-sized peptidic inhibitors; synthesis and their inhibitory activity against (2010)
  • Author(s): Taeko Kakizawa, Koushi Hidaka, Daisuke Hamada, Ryoji Yamaguchi, Tsuyoshi Uemura, Hitomi Kitamura, Harichandra D. Tagad, Takashi Hamada, Zyta Ziora, Yoshio Hamada, Tooru Kimura, Yoshiaki Kiso
  • Journal Title: BACE1. J. Peptide Science Volume: 16 Issue: 6 Pages: 257-262
  • DOI: 10.1002/psc.1238
  • Peer Reviewed
• [Journal Article] Tetrapeptides, as small-sized peptidic inhibitors ; synthesis and their inhibitory activity against BACE1 (2010)
  • Author(s): Taeko Kakizawa
  • Journal Title: Journal of peptide science Volume: VOL.16 Pages: 257-262
  • Peer Reviewed
• [Presentation] LC-MSを用いたペプチドライブラリーからのBACE 1基質特異性のスクリーニング (2010)
  • Author(s): 柿澤多惠子・服部恭尚・照屋健太・三城明・赤路健一
  • Organizer: 第6回3大学連携研究フォーラム
  • Place of Presentation: 京都府立大学
  • Year and Date: 2010-12-07
• [Presentation] Design and Preparation of the Tetrapeptides as Low Molecular Sized BACE1 Inhibitors (2010)
  • Author(s): Taeko Kakizawa・Koushi Hidaka・Daisuke Hamada・Ryoji Yamaguchi・Tsuyoshi Uemura・Hitomi Kitamura・Harichandra D. Tagad・Takeshi Hamada・Zyta Ziora・Yoshio Hamada・Tooru Kimura・Yoshiaki Kiso
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: Kyoto, Japan
• [Presentation] Click Peptide : Application to E22Δ-type Mutant of Amyloid β Peptide (2010)
  • Author(s): Hui Wang・Youhei Sohma・Atsuhiko Taniguchi・Yuta Hirayama・Taeko Kakizawa・Hidehito Mukai・Yoshiaki Kiso
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: Kyoto, Japan
• [Presentation] Evaluation of substrate specificities for BACE1 using synthetic peptide libraries (2010)
  • Author(s): Taeko Kakizawa・Yasunao Hattori・Kenta Teruya・Akira Sanjoh・Kenichi Akaji
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: Kyoto, Japan
• [Presentation] ペプチドライブラリーを用いたBACE 1基質特異性の検討 (2010)
  • Author(s): 柿澤多惠子・服部恭尚・照屋健太・三城明・赤路健一
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都テルサ
• [Presentation] Design and preparation of the tetrapeptides as low molecular sized BACE1 inhibitors (2010)
  • Author(s): Taeko Kakizawa
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: 京都国際会館
• [Presentation] Evaluation of substrate specificities for BALE 1 using synthetic peptide libraries (2010)
  • Author(s): Taeko Kakizawa
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: 京都国際会館
• [Presentation] Click peptide : application to E22Δ-type mutant of amyloid β peptide (2010)
  • Author(s): Hui Wang
  • Organizer: 5th International Peptide Symposium
  • Place of Presentation: 京都国際会館
• [Remarks] 国際会議のプロシーディング等(1) T. Kakizawa, K. Hidaka, D. Hamada, R. Yamaguchi, T. Uemura, H. Kitamura, H. D. Tagad, T. Hamada, Z. Ziora, Y. Hamada, T. Kimura, and Y. Kiso, Japanese Peptide Society,「Design and Preparation of the Tetrapeptides as Low Molecular Sized BACE1 Inhibitors」Peptide Science 2010, ed. N. Fujii and Y. Kiso, p.252(2011).
• [Remarks] (2) H. Wang, Y. Sohma, A. Taniguchi, Y. Hirayama, T. Kakizawa, H. Mukai, and Y. Kiso, Japanese Peptide Society,「Click Peptide : Application to E22Δ-type Mutant of Amyloid β Peptide」Peptide Science 2010, ed. N. Fujii and Y. Kiso, p.221(2011).
• [Remarks] (3) T. Kakizawa, Y. Hattori, K. Teruya, A. Sanjoh, and K. Akaji, Japanese Peptide Society,「Evaluation of substrate specificities for BACE1 using synthetic peptide libraries」Peptide Science 2010, ed. N. Fijii and Y. Kiso, p.121(2011).
• [Remarks] (4) H. Wang, T. Kakizawa, A. Taniguchi, T. Mizuguchi, Y. Sohma, H. Mukai, T. Kimura, and Y. Kiso, Japanese Peptide Society,「Investigation of Aβ1.42 Mutants Based on O-Acyl Isopeptide Method ; Synthesis of O-Acyl Isopeptides and in Situ Production of their