特殊ペプチド創薬

2013 Fiscal Year Annual Research Report

• Project/Area Number: 21000005
• Research Institution: The University of Tokyo
• Principal Investigator: 菅 裕明 東京大学, 大学院理学系研究科, 教授 (00361668)
• Project Period (FY): 2009-05-08 – 2014-03-31
• Keywords: ケミカルバイオロジー / ペプチド / RNA / 生理活性物質 / タンパク質合成 / 特殊ペプチド / 創薬

Research Abstract

本研究は、「特殊ペプチド創薬」を目指し、プラットフォーム技術RaPID (Random non-standard Peptide Integrated Discovery)システムの完成とその応用を示すことを目的としている。具体的には、
①両親媒性環状特殊ペプチドの合成技術開発
②リボソームによる炭素・炭素結合形成技術開発によるポリケチド骨格含有特殊ペプチドの合成
③上記特殊ペプチドライブラリーの合成と網羅探索系の融合
④生理活性特殊ペプチドの探索を掲げた。①～③はRaPIDシステムの完成にあたり、④はその応用にあたる。
本研究では、②を除く、他の項目は全て達成した。特筆すべきは、①から発展的に研究を進めたPatD酵素を用いたセリン・スレオニン・システイン側鎖の修飾によるペプチド鎖へのヘテロ環導入に成功し、最近その成果を記した論文がChemistry and Biology誌に掲載されることになった。②については、当初からハイリスク・ハイリターンの計画としていたが、残念ながら計画したとおりの成果は上がっていない。しかし、②のリボソームの研究から発展した成果が出て、最近その成果を記した論文がNature Chemical Biology誌に掲載されることになった。さらに、平成25年度は、④の実績が多数上がり、Nature誌、PNAS誌、JACS誌、ACS Chemical Biology誌等に原著論文を発表した。また、平成24年度から総説の依頼も急増し、平成25年度だけでAnnual Review in Biochemistryをはじめとする研究誌に5報のReviewを書き、本研究の成果への注目度が高まっていることが伺える。

Research Products

• [Journal Article] Protein cocrystallization molecules originating from in vitro selected macrocyclic peptides (2014)
  • Author(s): C.J. Hipolito, N.K. Bashiruddin, H. Suga
  • Journal Title: Current Opinion in Structural Biology Volume: 26 Pages: 24-31
  • DOI: DOI:10.1016/j.sbi.2014.03.001
  • Peer Reviewed
• [Journal Article] Structural Basis for Potent Inhibition of SIRT2 Deacetylase by a Macrocyclic Peptide Inducing Dynamic Structural Change (2014)
  • Author(s): K. Yamagata, Y. Goto, H. Nishimasu, J. Morimoto, R. Ishitani, N. Dohmae, N. Takeda, R. Nagai, I. Komuro, H. Suga, O. Nureki
  • Journal Title: Structure Volume: 22 Pages: 345-352
  • Peer Reviewed
• [Journal Article] Flexizymes-facilitated genetic code reprogramming leading to the discovery of drug-like peptides (2014)
  • Author(s): N. Terasaka, H. Suga
  • Journal Title: Chemistry Letters Volume: 43 Pages: 11-19
  • Peer Reviewed
• [Journal Article] One-pot synthesis of azoline-containing peptides in a cell-free translation system integrated with a posttranslational cyclodehydratase (2014)
  • Author(s): Y. Goto, Y. Ito, Y. Kato, S. Tsunoda, H. Suga*
  • Journal Title: Chemistry and Biology Volume: (in press)(未確定)
  • Peer Reviewed
• [Journal Article] An orthogonal ribosome-tRNAs pair via the engineering of peptidyl transferase center (2014)
  • Author(s): N. Terasaka, G. Hayashil, T. Katoh, and H. Suga
  • Journal Title: Nature Chemical Biology Volume: (in press)(未確定)
  • Peer Reviewed
• [Journal Article] Structural basis for gating mechanisms of a eukaryotic P-glycoprotein homolog (2014)
  • Author(s): A. Kodan, T. Yamaguchi, T. Nakatsu, K. Sakiyama, C. J. Hipolito, A. Fujioka, R. Hirokane, K. Ikeguchi, B. Watanabe, J. Hiratake, Y. Kimura, H. Suga, K. Ueda, H. Kato
  • Journal Title: Pro. Nat. Acad. Sci. Volume: 111(未確定) Pages: 4049-4054
  • Peer Reviewed
• [Journal Article] Selection-based discovery of druglike macrocyclic peptides (2014)
  • Author(s): T. Passioura, T. Katoh, Y. Goto, H. Suga
  • Journal Title: Annual Review in Biochemistry Volume: (in press)(未確定)
  • Peer Reviewed
• [Journal Article] Non-standard peptide expression under the genetic code consisting of reprogrammed dual sense codons (2013)
  • Author(s): Y. Goto, M. Iseki, A. Hitomi, H. Murakami, and H. Suga
  • Journal Title: ACS Chemical Biology Volume: 8 Pages: 266, 719
  • DOI: DOI:10.1021/cb400549p
  • Peer Reviewed
• [Journal Article] A macrocyclic peptide that serves as a cocrystallization ligand and inhibits the function of a MATE family transporter (2013)
  • Author(s): C.J. Hipolito, Y. Tanaka, T. Katoh, O. Nureki, H. Suga
  • Journal Title: Molecules Volume: 18 Pages: 10514-10530
  • DOI: DOI:10.3390/molecules180910514
  • Peer Reviewed
• [Journal Article] Flexizyme-mediated genetic reprogramming as a tool for noncanonical Peptide synthesis and drug discovery (2013)
  • Author(s): T. Passioura, H. Suga
  • Journal Title: Chemistry European Journal Volume: 19 Pages: 6530-6536
  • DOI: DOI:10.1002/chem.201300247
  • Peer Reviewed
• [Journal Article] In Vitro Selection of Multiple Libraries Created by Genetic Code Reprogramming To Discover Macrocyclic Peptides That Antagonize VEGFR2 Activity in Living Cells (2013)
  • Author(s): T. Kawakami, T. Ishizawa, T. Fujino, P.C. Reid, H. Suga, H. Murakami
  • Journal Title: ACS Chemical Biology Volume: 8 Pages: 1205-1514
  • DOI: DOI:10.1021/cb300697h
  • Peer Reviewed
• [Journal Article] Technologies for the synthesis of mRNA-encoding libraries and discovery of bioactive natural product-inspired non-traditional macrocyclic peptides (2013)
  • Author(s): K. Ito, T. Passioura, H. Suga
  • Journal Title: Molecules Volume: 18 Pages: 3502-3528
  • DOI: DOI:10.3390/molecules18033502
  • Peer Reviewed
• [Journal Article] Reevaluation of the D-amino acid compatibility with the elongation event in translation (2013)
  • Author(s): T. Fujino, Y. Goto, H. Suga, H. Murakami
  • Journal Title: Journal of American Chemical Society Volume: 135 Pages: 1830-1837
  • DOI: DOI:10.1021/ja309570x
  • Peer Reviewed
• [Journal Article] Distinct tRNA recognition strategies used by a homologous family of editing domains prevent mistranslation (2013)
  • Author(s): M. Das, O. Vargas-Rodriguez, Y. Goto, H. Suga, K. Museir-Forsyth
  • Journal Title: Nucleic Acids Research Volume: 未確定
  • DOI: 10.1093/nar/gkt1332
  • Peer Reviewed
• [Journal Article] Structural basis for the drug extrusion mechanism by a MATE multidrug transporter (2013)
  • Author(s): Y. Tanaka, C. J. Hipolito, A. D. Maturana, K. Ito, T. Kuroda, T. Higuchi, T. Katoh, H. E. Kato, M. Hattori, K. Kumazaki, T. Tsukazaki, R. Ishitani, H. Suga, O. Nureki
  • Journal Title: Nature Volume: 496 Pages: 247-51
  • DOI: 10.1038/nature12014
  • Peer Reviewed
• [Presentation] 擬天然物の新機能創出分子技術 (2014)
  • Author(s): Hiroaki Suga
  • Organizer: 日本化学会第94春期年会「社会持続的発展のための分子技術」
  • Place of Presentation: 名古屋大学東山キャンパス(名古屋市)
  • Year and Date: 2014-03-29
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2014)
  • Author(s): Hiroaki Suga
  • Organizer: AsiaTIDES, 2. Plenary Lecture
  • Place of Presentation: シェラトン都ホテル東京(東京都港区)
  • Year and Date: 2014-02-25
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: Solvay Conference of "New Chemistry and New Opportunities from the Expanding Protein Universe"
  • Place of Presentation: International Solvay Institute (Brussels, Belgium)
  • Year and Date: 20131015-19
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: "Jokichi Takamine" 130 years of Glasgow-Japan Collaboration
  • Place of Presentation: University of Glasgow (Glasgow, UK)
  • Year and Date: 20130905-06
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: Current Strategy for Delopment of Biopharmaceuticals and Small Molecule Drugs
  • Place of Presentation: 北海道大学(北海道札幌)
  • Year and Date: 20130801-02
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: International Conference on Structural Genomics 2013, Structural Life Science
  • Place of Presentation: 京王プラザホテル(北海道札幌)
  • Year and Date: 20130729-0801
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: Keynote Lecture, Symposium on Chemoselective Reactions for the Synthesis and Application
  • Place of Presentation: Max Planc Institute (Dortmund, Germany)
  • Year and Date: 20130702-05
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: Symposium on Foldamers
  • Place of Presentation: Les Cordeliers Conference Centre (Paris, France)
  • Year and Date: 20130409-12
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: Korean Peptide Protein Society Meeting
  • Place of Presentation: Seoul National University (Seoul, Korea)
  • Year and Date: 2013-11-29
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: Basel Chemical Society Lectureship
  • Place of Presentation: Medicinal Chemistry Navartis Institute (Basel, Switzerland)
  • Year and Date: 2013-10-24
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: RiboClub
  • Place of Presentation: Hotel Cheribourg (Quebec, Canada)
  • Year and Date: 2013-09-22
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: Biochemistry Seminar of University of Colorado, BioFrontier Institute
  • Place of Presentation: Univerity of Colorado (Boulder, USA)
  • Year and Date: 2013-09-11
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: Lilly Distinguished Lecturer at Colorado State University
  • Place of Presentation: Colorado State University (Fort Collins, US)
  • Year and Date: 2013-09-10
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: ACS National Meeting
  • Place of Presentation: Indiana Convention Center (Indianapolis, USA)
  • Year and Date: 2013-09-09
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: American Peptide Symposium 2013
  • Place of Presentation: Hilton Waikoloa Village (Hawaii, USA)
  • Year and Date: 2013-06-23
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: Gordon Research Conference, Bioorganic Chemistry
  • Place of Presentation: Proctor Academy (New Hampshire, USA)
  • Year and Date: 2013-06-13
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: 5th Gratama Workshop
  • Place of Presentation: 東京工業大学大岡山キャンパス(東京都目黒区)
  • Year and Date: 2013-05-30
  • Invited
• [Presentation] Discovery of natural product-like petides accerelated by RaPID system (2013)
  • Author(s): Hiroaki Suga
  • Organizer: RIKEN-Max Planc Joint Symposium
  • Place of Presentation: 理化学研究所和光研究所(埼玉県和光市)
  • Year and Date: 2013-04-16
  • Invited
• [Patent(Industrial Property Rights)] MATE活性阻害ペプチド (2013)
  • Inventor(s): 菅裕明、濡木理、クリストファージェイ ヒポライト、田中良樹
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Number: PCT/JP2013/070779
  • Filing Date: 2013-07-28
  • Overseas
• [Patent(Industrial Property Rights)] 大環状ペプチド、その製造方法、及び大環状ペプチドライブラリを用いるスクリーニング方法 (2013)
  • Inventor(s): 菅裕明
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Rights Type: 特願
  • Industrial Property Number: 2013-174906
  • Filing Date: 2013-08-26
• [Patent(Industrial Property Rights)] c-Metタンパク質アゴニスト (2013)
  • Inventor(s): 菅裕明, 伊藤健一郎
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Rights Type: 特願
  • Industrial Property Number: 2013-214771
  • Filing Date: 2013-10-15
• [Patent(Industrial Property Rights)] 安定化された二次構造を有するペプチド、及びペプチドライブラリー、それらの製造方法 (2011)
  • Inventor(s): 菅裕明、樋口岳
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Rights Type: 特願
  • Industrial Property Number: 2012-546968 (JP) 13/990123 (US) 11845198.8 (EP) 201180058284.4 (CN)
  • Filing Date: 2011-12-05