Challenges to the remaining issues of therapeutically valuable pseudo-natural peptides and products

• Project/Area Number: 20H05618
• Research Category: Grant-in-Aid for Specially Promoted Research
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: The University of Tokyo
• Principal Investigator: 菅 裕明 東京大学, 大学院理学系研究科(理学部), 教授 (00361668)
• Co-Investigator(Kenkyū-buntansha): 仙石 徹 横浜市立大学, 医学部, 准教授 (60576312)
• Project Period (FY): 2020-07-30 – 2025-03-31
• Project Status: Granted (Fiscal Year 2024)
• Budget Amount: ¥631,540,000 (Direct Cost: ¥485,800,000、Indirect Cost: ¥145,740,000); Fiscal Year 2024: ¥130,000,000 (Direct Cost: ¥100,000,000、Indirect Cost: ¥30,000,000); Fiscal Year 2023: ¥130,000,000 (Direct Cost: ¥100,000,000、Indirect Cost: ¥30,000,000); Fiscal Year 2022: ¥130,000,000 (Direct Cost: ¥100,000,000、Indirect Cost: ¥30,000,000); Fiscal Year 2021: ¥130,000,000 (Direct Cost: ¥100,000,000、Indirect Cost: ¥30,000,000); Fiscal Year 2020: ¥111,540,000 (Direct Cost: ¥85,800,000、Indirect Cost: ¥25,740,000)
• Keywords: 特殊ペプチド / 擬天然物 / 薬剤探索 / コロナウイルス / コロナウィルス

Outline of Research at the Start

本特別推進研究計画では、これまで申請者が研究室を主宰してきた約20年にわたる「特殊ペプチド創薬」研究に区切りを付けるべく、やり残された挑戦的な研究に絞り目標を定め、それらを集大成させる。
（１）細胞膜透過を有する特殊ペプチドの構造膜透過性相関検討による探索基盤の確立（２）環β-、環γ-、不飽和環アミノ酸含有特殊ペプチドライブラリーの翻訳合成と生理活性種探索（３）翻訳後酵素修飾された擬天然物ライブラリーの創製と生理活性種探索（４）特殊ペプチドおよび擬天然物の細胞膜透過性と小腸吸収性の研究
上記の研究目標に沿って基礎および応用研究を進め、これまで解決できなかった命題に挑戦する。

Outline of Annual Research Achievements

本特別推進研究計画の申請者は、一貫してCuriosity-Driven-ResearchとTechnology-Driven-Researchの両輪で研究を推進し、非タンパク質性アミノ酸を望みのtRNAにアシル化することを可能にしたリボザイム（フレキシザイム）の開発、フレキシザイムと再構成無細胞翻訳系（FITシステム）を組み合わせた遺伝暗号リプログラミング技術の革新とそれを活用した特殊ペプチドの翻訳合成、特殊ペプチドの翻訳合成と試験管内（mRNA）ディスプレイを組み合わせたRaPIDシステムにより生理活性中分子化合物の超迅速探索、を達成してきた。これまで様々な細胞内標的に対して特殊ペプチドを獲得してきたが、最近になりいくつかの特殊ペプチドに細胞膜透過性があることがわかった。しかし、その構造膜透過性相関に関しては十分な理解が進んでいない。また、ペプチド鎖への導入すら困難と言われてきたβアミノ酸やγアミノ酸に関しても、この数年で創出した人工tRNAを用いることにより、ようやく連続導入も可能であることを示した。しかし、これらの特殊アミノ酸を含む特殊ペプチドのライブラリー化や活性種探索はまだ初期段階にあり、そのポテンシャルの検討は十分できていない。また、天然物には遺伝暗号リプログラミングでは直接導入ができない化学構造を持っている分子も多く、それらを人工的に導入しライブラリーを構築する技術や探索の実証には十分至っていない。さらに、中分子薬剤に最も期待されている細胞膜透過性、さらには経口性につながる小腸吸収性をもつ化合物を確実に獲得する基盤技術としては未完成といえる。これらの残された課題を解決し突破することが、本研究の主題である。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

これまでに、環βアミノ酸および環γアミノ酸を含む特殊環状ペプチドライブラリーの構築②に成功し、標的タンパク質に高い特異性と阻害活性をもつ特殊環状ペプチドの同定に成功した（Nature Chemistry 2024、BCSJ in press、JACS in revision）。ペプトイド・ペプチドハイブリッド型ライブラリーの構築も試み、がん関連細胞内標的に対して探索を行い、細胞膜透過性を定量的に観測できるCAPAアッセイによりそれらが膜透透過性をもつことが確認された。この技術をさらに横展開し、COVID関連標的タンパク質を阻害する同型分子も発見し、細胞内でも機能することを解明した。そのX線構造解析にも成功したことにより、①のシミュレーションへの足がかかりを掴むことができた。さらに、ジピリジン化合物で環状化した擬天然物ペプチドが、通常の環化方法であるアセチル環化型ペプチドよりも優位な膜透過性をもつことを発見した（ACS Bio Med Chem Au 2023）。翻訳後酵素修飾された擬天然物ライブラリーの創製③については、トリプトファンプレニル化酵素KgpFのゲノムマイニングで発見したLimFの研究においては、LimFがヒスチジン側鎖のC2位にゲラニル化する酵素であることを論文発表した（Nature Catalysis 2022、特許申請済）ことに加え、その改変によりLimFの基質特異性をゲラニル基からファルネシル基に変換することにも成功した。また、ラクタゾール生合成系の試験管内再構成にも成功し、そのライブラリーから癌疾患関連酵素に対するキナーゼ活性を有する擬ラクタゾール化合物を発見することができ、さらに同様のアプローチで新たに２つの酵素を標的とした阻害剤の発見にもつながった。

Strategy for Future Research Activity

特殊ペプチドおよび擬天然物の細胞膜透過性の研究④において、細胞膜透過性を測定するスタンダード法になりつつあるCAPAアッセイ法を研究室内で確立でき、既にこのアッセイ法を用いた活性種の検証が進んでおり、実際に細胞膜透過性をもつ特殊ペプチドの同定ができている。この研究目標についても初期目標はほぼ達成できたと考えており、この技術を活用した高活性膜透過特殊ペプチドおよび擬天然物の開発を加速させてきており、今後もデータの蓄積を続ける。一方で、細胞膜透過を有する特殊ペプチドの構造膜透過性相関検討①による探索基盤の確立も進み、理論武装としてスイスETHZのSereina Riniker教授との共同研究も学生を３ヶ月派遣して順調に進んでいる。今後④における中分子膜透過性物質の数を更に増やすことで、理論的な研究への展開を昨年度同様に今年度も加速させていく。最終年度である当該年度には、方法論が確立できると確信している。

Assessment Rating

Interim Assessment Comments (Rating)

A: In light of the aim of introducing the research area into the research categories, the expected progress has been made in research.

Research Products

• [Int'l Joint Research] Technion-Israel Institute of Technology(イスラエル)
• [Int'l Joint Research] Univresity of California San Francisco(米国)
• [Int'l Joint Research] ETH Zurich(スイス)
• [Int'l Joint Research] Johns Hopkins University(米国)
• [Int'l Joint Research] NIH(米国)
• [Int'l Joint Research] Technion-Israel Institute of Technology(イスラエル)
• [Int'l Joint Research] University of California San Francisco(米国)
• [Int'l Joint Research] ETH Zurich(スイス)
• [Int'l Joint Research] Johns Hopkins University(米国)
• [Int'l Joint Research] NIH(米国)
• [Int'l Joint Research] Technion-Israel Institute of Technology(イスラエル)
• [Int'l Joint Research] University of California San Francisco/Johns Hopkins University/NIH(米国)
• [Int'l Joint Research] ETH Zurich(スイス)
• [Int'l Joint Research] Technion-Israel Institute of Technology(イスラエル)
• [Int'l Joint Research] ETH Zurich(スイス)
• [Int'l Joint Research] University of California San Francisco(米国)
• [Int'l Joint Research] Johns Hopkins University(米国)
• [Journal Article] Combining Chemical Protein Synthesis and Random Nonstandard Peptides Integrated Discovery for Modulating Biological Processes (2023)
  • Author(s): Saha Abhishek、Suga Hiroaki、Brik Ashraf
  • Journal Title: Accounts of Chemical Research Volume: 56 Issue: 14 Pages: 1953-1965
  • DOI: 10.1021/acs.accounts.3c00178
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In vitro selection of macrocyclic peptide inhibitors containing cyclic γ2,4-amino acids targeting the SARS-CoV-2 main protease (2023)
  • Author(s): Takashi Miura, Tika Malla, David Owen, Anthony Tumber, Lennart Brewitz, Michael McDonough, Eidarus Salah, Naohiro Terasaka, Takayuki Katoh, Petra Lukacik, Claire Strain-Damerell, Halina Mikolajek, Martin Walsh, Akane Kawamura, Christopher Schofield, Hiroaki Suga
  • Journal Title: Nature Chemistry Volume: 15 Issue: 7 Pages: 998-1005
  • DOI: 10.1038/s41557-023-01205-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural basis of tRNAPro acceptor stem recognition by a bacterial <i>trans</i>-editing domain (2023)
  • Author(s): Ma Xiao、Bakhtina Marina、Shulgina Irina、Cantara William A、Kuzmishin?Nagy Alexandra?B、Goto Yuki、Suga Hiroaki、Foster Mark P、Musier-Forsyth Karin
  • Journal Title: Nucleic Acids Research Volume: 51 Issue: 8 Pages: 3988-3999
  • DOI: 10.1093/nar/gkad192
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] MET-activating ubiquitin multimers. (2023)
  • Author(s): Kawakami N, Sato H, Terasaka N, Matsumoto K, Suga H.
  • Journal Title: Angewandte Chemie, International Edition Volume: 62 Issue: 36
  • DOI: 10.1002/anie.202307157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Translation initiation with exotic amino acids using EF-P-responsive artificial initiator tRNA (2023)
  • Author(s): Katoh Takayuki、Suga Hiroaki
  • Journal Title: Nucleic Acids Research Volume: 51 Issue: 15 Pages: 8169-8180
  • DOI: 10.1093/nar/gkad496
  • Peer Reviewed / Open Access
• [Journal Article] Discovery and characterization of cyclic peptides selective for the C-terminal bromodomains of BET family proteins (2023)
  • Author(s): Franck Charlotte、Patel Karishma、Walport Louise J.、Christie Mary、Norman Alexander、Passioura Toby、Suga Hiroaki、Payne Richard J.、Mackay Joel P.
  • Journal Title: Structure Volume: 31 Issue: 8 Pages: 912-923.e4
  • DOI: 10.1016/j.str.2023.05.009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Discovery, biochemical characterization, and bioengineering of cyanobactin prenyltransferases (2023)
  • Author(s): Zhang Yuchen、Goto Yuki、Suga Hiroaki
  • Journal Title: Trends in Biochemical Sciences Volume: 48 Issue: 4 Pages: 360-374
  • DOI: 10.1016/j.tibs.2022.11.002
  • Peer Reviewed
• [Journal Article] Two-Chain Mature Hepatocyte Growth Factor-Specific Positron Emission Tomography Imaging in Tumors Using 64Cu-Labeled HiP-8, a Nonstandard Macrocyclic Peptide Probe (2023)
  • Author(s): Shota Warashina , Hiroki Sato, Maki Zouda, Maiko Takahashi, Yasuhiro Wada, Toby Passioura, Hiroaki Suga, Yasuyoshi Watanabe, Kunio Matsumoto, Hidefumi Mukai
  • Journal Title: Molecular Pharmaceutics Volume: 20(4) Issue: 4 Pages: 2029-2038
  • DOI: 10.1021/acs.molpharmaceut.2c01020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A RaPID Macrocyclic Peptide That Inhibits the Formation of α‐Synuclein Amyloid Fibrils (2023)
  • Author(s): Ikenoue Tatsuya、Oono Miki、So Masatomo、Yamakado Hodaka、Arata Toshiaki、Takahashi Ryosuke、Kawata Yasushi、Suga Hiroaki
  • Journal Title: ChemBioChem Volume: 24 Issue: 12
  • DOI: 10.1002/cbic.202300320
  • Peer Reviewed
• [Journal Article] Ribosomal Synthesis of Peptides Bearing Noncanonical Backbone Structures via Chemical Posttranslational Modifications (2023)
  • Author(s): Goto Yuki、Suga Hiroaki
  • Journal Title: Methods Mol Biol Volume: － Pages: 255-266
  • DOI: 10.1007/978-1-0716-3214-7_13
  • ISBN: 9781071632130, 9781071632147
  • Peer Reviewed
• [Journal Article] Potent De Novo Macrocyclic Peptides That Inhibit O‐GlcNAc Transferase through an Allosteric Mechanism (2022)
  • Author(s): Alteen Matthew G.、Peacock Hayden、Meek Richard W.、Busmann Jil A.、Zhu Sha、Davies Gideon J.、Suga Hiroaki、Vocadlo David J.
  • Journal Title: Angewandte Chemie International Edition Volume: 62 Issue: 5
  • DOI: 10.1002/anie.202215671
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Post-translational backbone-acyl shift yields natural product-like peptides bearing hydroxyhydrocarbon units (2022)
  • Author(s): Kuroda Tomohiro、Huang Yichao、Nishio Soichiro、Goto Yuki、Suga Hiroaki
  • Journal Title: Nature Chemistry Volume: 14 Issue: 12 Pages: 1413-1420
  • DOI: 10.1038/s41557-022-01065-1
  • Peer Reviewed / Open Access
• [Journal Article] Designing receptor agonists with enhanced pharmacokinetics by grafting macrocyclic peptides into fragment crystallizable regions (2022)
  • Author(s): Sakai Katsuya、Sugano-Nakamura Nozomi、Mihara Emiko、Rojas-Chaverra Nichole Marcela、Watanabe Sayako、Sato Hiroki、Imamura Ryu、Voon Dominic Chih-Cheng、Sakai Itsuki、Yamasaki Chihiro、Tateno Chise、Shibata Mikihiro、Suga Hiroaki、Takagi Junichi、Matsumoto Kunio
  • Journal Title: Nature Biomedical Engineering Volume: 7 Issue: 2 Pages: 164-176
  • DOI: 10.1038/s41551-022-00955-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] De Novo Discovery of Thiopeptide Pseudo-natural Products Acting as Potent and Selective TNIK Kinase Inhibitors (2022)
  • Author(s): Vinogradov Alexander A.、Zhang Yue、Hamada Keisuke、Chang Jun Shi、Okada Chikako、Nishimura Hirotaka、Terasaka Naohiro、Goto Yuki、Ogata Kazuhiro、Sengoku Toru、Onaka Hiroyasu、Suga Hiroaki
  • Journal Title: Journal of the American Chemical Society Volume: 144 Issue: 44 Pages: 20332-20341
  • DOI: 10.1021/jacs.2c07937
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Solid-Phase-Based Synthesis of Lactazole-Like Thiopeptides (2022)
  • Author(s): Zhang Yue、Vinogradov Alexander A.、Chang Jun Shi、Goto Yuki、Suga Hiroaki
  • Journal Title: Organic Letters Volume: 24 Issue: 43 Pages: 7894-7899
  • DOI: 10.1021/acs.orglett.2c02870
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Selective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt DNA damage repair (2022)
  • Author(s): Vamisetti Ganga B.、Saha Abhishek、Huang Yichao J.、Vanjari Rajeshwer、Mann Guy、Gutbrod Julia、Ayoub Nabieh、Suga Hiroaki、Brik Ashraf
  • Journal Title: Nature Communications Volume: 13 Issue: 1
  • DOI: 10.1038/s41467-022-33808-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] State-selective modulation of heterotrimeric Gαs signaling with macrocyclic peptides (2022)
  • Author(s): Dai Shizhong A.、Hu Qi、Gao Rong、Blythe Emily E.、Touhara Kouki K.、Peacock Hayden、Zhang Ziyang、von Zastrow Mark、Suga Hiroaki、Shokat Kevan M.
  • Journal Title: Cell Volume: 185 Issue: 21 Pages: 3950-3965.e25
  • DOI: 10.1016/j.cell.2022.09.019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In Vitro Selection of Macrocyclic α/β3-Peptides against Human EGFR (2022)
  • Author(s): Wakabayashi Risa、Kawai Marina、Katoh Takayuki、Suga Hiroaki
  • Journal Title: Journal of the American Chemical Society Volume: 144 Issue: 40 Pages: 18504-18510
  • DOI: 10.1021/jacs.2c07624
  • Peer Reviewed
• [Journal Article] LimF is a versatile prenyltransferase for histidine-C-geranylation on diverse non-natural substrates (2022)
  • Author(s): Zhang Yuchen、Hamada Keisuke、Nguyen Dinh Thanh、Inoue Sumika、Satake Masayuki、Kobayashi Shunsuke、Okada Chikako、Ogata Kazuhiro、Okada Masahiro、Sengoku Toru、Goto Yuki、Suga Hiroaki
  • Journal Title: Nature Catalysis Volume: 5 Issue: 8 Pages: 682-693
  • DOI: 10.1038/s41929-022-00822-2
  • Peer Reviewed / Open Access
• [Journal Article] De novo Fc-based receptor dimerizers differentially modulate PlexinB1 function (2022)
  • Author(s): Sugano-Nakamura Nozomi、Matoba Kyoko、Hirose Mika、Bashiruddin Nasir K.、Matsunaga Yukiko、Yamashita Keitaro、Hirata Kunio、Yamamoto Masaki、Arimori Takao、Suga Hiroaki、Takagi Junichi
  • Journal Title: Structure Volume: 30 Issue: 10 Pages: 1411-1423.e4
  • DOI: 10.1016/j.str.2022.07.008
  • Peer Reviewed
• [Journal Article] Inner residues of macrothiolactone in autoinducer peptides I/IV circumvent spontaneous <i>S</i>-to-<i>O</i> acyl transfer to the upstream serine residue (2022)
  • Author(s): Nagano Masanobu、Ishida Satoshi、Suga Hiroaki
  • Journal Title: RSC Chemical Biology Volume: 3 Issue: 3 Pages: 295-300
  • DOI: 10.1039/d1cb00225b
  • Peer Reviewed / Open Access
• [Journal Article] Phosphine addition to dehydroalanine for peptide modification (2022)
  • Author(s): Liu Minglong、Sovrovic Miha、Suga Hiroaki、Jongkees Seino A. K.
  • Journal Title: Organic &amp; Biomolecular Chemistry Volume: 20 Issue: 15 Pages: 3081-3085
  • DOI: 10.1039/d2ob00410k
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In Vitro Genetic Code Reprogramming for the Expansion of Usable Noncanonical Amino Acids (2022)
  • Author(s): Katoh Takayuki、Suga Hiroaki
  • Journal Title: Annual Review of Biochemistry Volume: 91 Issue: 1 Pages: 221-243
  • DOI: 10.1146/annurev-biochem-040320-103817
  • Peer Reviewed
• [Journal Article] A context-dependent and disordered ubiquitin-binding motif (2022)
  • Author(s): Dreier Jesper E.、Prestel Andreas、Martins Joao M.、Brondum Sebastian S.、Nielsen Olaf、Garbers Anna E.、Suga Hiroaki、Boomsma Wouter、Rogers Joseph M.、Hartmann-Petersen Rasmus、Kragelund Birthe B.
  • Journal Title: Cellular and Molecular Life Sciences Volume: 79 Issue: 9
  • DOI: 10.1007/s00018-022-04486-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Accurate Models of Substrate Preferences of Post-Translational Modification Enzymes from a Combination of mRNA Display and Deep Learning (2022)
  • Author(s): Vinogradov Alexander A.、Chang Jun Shi、Onaka Hiroyasu、Goto Yuki、Suga Hiroaki
  • Journal Title: ACS Central Science Volume: 8 Issue: 6 Pages: 814-824
  • DOI: 10.1021/acscentsci.2c00223
  • Peer Reviewed / Open Access
• [Journal Article] Drop-off-reinitiation triggered by EF-G-driven mistranslocation and its alleviation by EF-P (2022)
  • Author(s): Tajima Kenya、Katoh Takayuki、Suga Hiroaki
  • Journal Title: Nucleic Acids Research Volume: 50 Issue: 5 Pages: 2736-2753
  • DOI: 10.1093/nar/gkac068
  • Peer Reviewed / Open Access
• [Journal Article] Potent macrocycle inhibitors of the human SAGA deubiquitinating module (2022)
  • Author(s): Morgan Michael、Ikenoue Tatsuya、Suga Hiroaki、Wolberger Cynthia
  • Journal Title: Cell Chemical Biology Volume: 29 Issue: 4 Pages: 544-554.e4
  • DOI: 10.1016/j.chembiol.2021.12.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In Vitro Selection of Foldamer-Like Macrocyclic Peptides Containing 2-Aminobenzoic Acid and 3-Aminothiophene-2-Carboxylic Acid (2022)
  • Author(s): Katoh Takayuki、Suga Hiroaki
  • Journal Title: Journal of the American Chemical Society Volume: 144 Issue: 5 Pages: 2069-2072
  • DOI: 10.1021/jacs.1c12133
  • Peer Reviewed
• [Journal Article] The Development of a Fluorescence‐Based Competitive Assay Enabled the Discovery of Dimeric Cyclic Peptide Modulators of Ubiquitin Chains (2021)
  • Author(s): Vamisetti Ganga B.、Meledin Roman、Nawatha Mickal、Suga Hiroaki、Brik Ashraf
  • Journal Title: Angewandte Chemie International Edition Volume: 60 Issue: 13 Pages: 7018-7023
  • DOI: 10.1002/anie.202013392
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Discovery of De Novo Macrocyclic Peptides by Messenger RNA Display (2021)
  • Author(s): Peacock Hayden、Suga Hiroaki
  • Journal Title: Trends in Pharmacological Sciences Volume: 42 Issue: 5 Pages: 385-397
  • DOI: 10.1016/j.tips.2021.02.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Targeting of extracellular protein?protein interactions with macrocyclic peptides (2021)
  • Author(s): Taguchi Shota、Suga Hiroaki
  • Journal Title: Current Opinion in Chemical Biology Volume: 62 Pages: 82-89
  • DOI: 10.1016/j.cbpa.2021.02.013
  • Peer Reviewed
• [Journal Article] Structure?activity relationship of ipglycermide binding to phosphoglycerate mutases (2021)
  • Author(s): Wiedmann Mareike、Dranchak Patricia K.、Aitha Mahesh、Queme Bryan、Collmus Christopher D.、Kashipathy Maithri M.、Kanter Liza、Lamy Laurence、Rogers Joseph M.、Tao Dingyin、Battaile Kevin P.、Rai Ganesha、Lovell Scott、Suga Hiroaki、Inglese James
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100628-100628
  • DOI: 10.1016/j.jbc.2021.100628
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In Vitro Selection of Macrocyclic <scp>d</scp>/<scp>l</scp>-Hybrid Peptides against Human EGFR (2021)
  • Author(s): Imanishi Sayaka、Katoh Takayuki、Yin Yizhen、Yamada Mituhiro、Kawai Marina、Suga Hiroaki
  • Journal Title: Journal of the American Chemical Society Volume: 143 Issue: 15 Pages: 5680-5684
  • DOI: 10.1021/jacs.1c02593
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] One-Pot <i>In Vitro</i> Ribosomal Synthesis of Macrocyclic Depsipeptides (2021)
  • Author(s): Nagano Masanobu、Huang Yichao、Obexer Richard、Suga Hiroaki
  • Journal Title: Journal of the American Chemical Society Volume: 143 Issue: 12 Pages: 4741-4750
  • DOI: 10.1021/jacs.1c00466
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lasso-grafting of macrocyclic peptide pharmacophores yields multi-functional proteins (2021)
  • Author(s): Mihara E, Watanabe S, Bashiruddin N, Nakamura N, Matoba K, Maini R, Yin Y, Sakai K, Arimori T, Matsumoto K, Suga H, and Takagi J.
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 1543-1543
  • DOI: 10.1038/s41467-021-21875-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Posttranslational chemical installation of azoles into translated peptides (2021)
  • Author(s): Tsutsumi Haruka、Kuroda Tomohiro、Kimura Hiroyuki、Goto Yuki、Suga Hiroaki
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 696-696
  • DOI: 10.1038/s41467-021-20992-0
  • Peer Reviewed / Open Access
• [Journal Article] <i>In vivo</i> modulation of ubiquitin chains by <i>N</i>-methylated non-proteinogenic cyclic peptides (2021)
  • Author(s): Rogers Joseph M.、Nawatha Mickal、Lemma Betsegaw、Vamisetti Ganga B.、Livneh Ido、Barash Uri、Vlodavsky Israel、Ciechanover Aaron、Fushman David、Suga Hiroaki、Brik Ashraf
  • Journal Title: RSC Chemical Biology Volume: 2 Issue: 2 Pages: 513-522
  • DOI: 10.1039/d0cb00179a
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Accurate Broadcasting of Substrate Fitness for Lactazole Biosynthetic Pathway from Reactivity-Profiling mRNA Display (2020)
  • Author(s): Vinogradov Alexander A.、Nagai Emiko、Chang Jun Shi、Narumi Kakeru、Onaka Hiroyasu、Goto Yuki、Suga Hiroaki
  • Journal Title: Journal of the American Chemical Society Volume: 142 Issue: 48 Pages: 20329-20334
  • DOI: 10.1021/jacs.0c10374
  • Peer Reviewed
• [Journal Article] Cyclic peptides can engage a single binding pocket through highly divergent modes (2020)
  • Author(s): Patel Karishma、Walport Louise J.、Walshe James L.、Solomon Paul D.、Low Jason K. K.、Tran Daniel H.、Mouradian Kevork S.、Silva Ana P. G.、Wilkinson-White Lorna、Norman Alexander、Franck Charlotte、Matthews Jacqueline M.、Guss J. Mitchell、Payne Richard J.、Passioura Toby、Suga Hiroaki、Mackay Joel P.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Issue: 43 Pages: 26728-26738
  • DOI: 10.1073/pnas.2003086117
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Discovery of quorum quenchers targeting the membrane-embedded sensor domain of theStaphylococcus aureusreceptor histidine kinase, AgrC (2020)
  • Author(s): Xie Qian、Wiedmann Mareike M.、Zhao Aishan、Pagan Ivelisse R.、Novick Richard P.、Suga Hiroaki、Muir Tom W.
  • Journal Title: Chemical Communications Volume: 56 Issue: 76 Pages: 11223-11226
  • DOI: 10.1039/d0cc04873a
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ribosomal Elongation of Aminobenzoic Acid Derivatives (2020)
  • Author(s): Katoh Takayuki、Suga Hiroaki
  • Journal Title: Journal of the American Chemical Society Volume: 142 Issue: 39 Pages: 16518-16522
  • DOI: 10.1021/jacs.0c05765
  • Peer Reviewed
• [Journal Article] GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf (2020)
  • Author(s): Zhang Ziyang、Gao Rong、Hu Qi、Peacock Hayden、Peacock D. Matthew、Dai Shizhong、Shokat Kevan M.、Suga Hiroaki
  • Journal Title: ACS Central Science Volume: 6 Issue: 10 Pages: 1753-1761
  • DOI: 10.1021/acscentsci.0c00514
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ribosomal synthesis and de novo discovery of bioactive foldamer peptides containing cyclic β-amino acids (2020)
  • Author(s): Katoh Takayuki、Sengoku Toru、Hirata Kunio、Ogata Kazuhiro、Suga Hiroaki
  • Journal Title: Nature Chemistry Volume: 12 Issue: 11 Pages: 1081-1088
  • DOI: 10.1038/s41557-020-0525-1
  • Peer Reviewed
• [Journal Article] Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation (2020)
  • Author(s): Bashiruddin Nasir K.、Hayashi Mikihito、Nagano Masanobu、Wu Yan、Matsunaga Yukiko、Takagi Junichi、Nakashima Tomoki、Suga Hiroaki
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Issue: 49 Pages: 31070-31077
  • DOI: 10.1073/pnas.2012266117
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Promiscuous Enzymes Cooperate at the Substrate Level En Route to Lactazole A (2020)
  • Author(s): Vinogradov Alexander A.、Shimomura Morito、Kano Naokazu、Goto Yuki、Onaka Hiroyasu、Suga Hiroaki
  • Journal Title: Journal of the American Chemical Society Volume: 142 Issue: 32 Pages: 13886-13897
  • DOI: 10.1021/jacs.0c05541
  • Peer Reviewed
• [Journal Article] Introduction to Thiopeptides: Biological Activity, Biosynthesis, and Strategies for Functional Reprogramming (2020)
  • Author(s): Vinogradov Alexander A.、Suga Hiroaki
  • Journal Title: Cell Chemical Biology Volume: 27 Issue: 8 Pages: 1032-1051
  • DOI: 10.1016/j.chembiol.2020.07.003
  • Peer Reviewed
• [Journal Article] Macrocyclic Peptide-Mediated Blockade of the CD47-SIRPα Interaction as a Potential Cancer Immunotherapy (2020)
  • Author(s): Hazama Daisuke、Yin Yizhen、Murata Yoji、Matsuda Makoto、Okamoto Takeshi、Tanaka Daisuke、Terasaka Naohiro、Zhao Jinxuan、Sakamoto Mariko、Kakuchi Yuka、Saito Yasuyuki、Kotani Takenori、Nishimura Yoshihiro、Nakagawa Atsushi、Suga Hiroaki、Matozaki Takashi
  • Journal Title: Cell Chemical Biology Volume: 27 Issue: 9 Pages: 1181-1191.e7
  • DOI: 10.1016/j.chembiol.2020.06.008
  • Peer Reviewed / Open Access
• [Journal Article] Minimal lactazole scaffold for in vitro thiopeptide bioengineering (2020)
  • Author(s): Vinogradov Alexander A.、Shimomura Morito、Goto Yuki、Ozaki Taro、Asamizu Shumpei、Sugai Yoshinori、Suga Hiroaki、Onaka Hiroyasu
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 2272-2272
  • DOI: 10.1038/s41467-020-16145-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Discovery of Potent Cyclic Sulfopeptide Chemokine Inhibitors via Reprogrammed Genetic Code mRNA Display (2020)
  • Author(s): Johansen-Leete Jason、Passioura Toby、Foster Simon R.、Bhusal Ram Prasad、Ford Daniel J.、Liu Minglong、Jongkees Seino A. K.、Suga Hiroaki、Stone Martin J.、Payne Richard J.
  • Journal Title: Journal of the American Chemical Society Volume: 142 Issue: 20 Pages: 9141-9146
  • DOI: 10.1021/jacs.0c03152
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Design, Synthesis, and Conformation?Activity Study of Unnatural Bridged Bicyclic Depsipeptides as Highly Potent Hypoxia Inducible Factor-1 Inhibitors and Antitumor Agents (2020)
  • Author(s): Koike Kota、Nagano Masanobu、Ebihara Masahiro、Hirayama Tasuku、Tsuji Mieko、Suga Hiroaki、Nagasawa Hideko
  • Journal Title: Journal of Medicinal Chemistry Volume: 63 Issue: 8 Pages: 4022-4046
  • DOI: 10.1021/acs.jmedchem.9b02039
  • Peer Reviewed
• [Journal Article] Initiating ribosomal peptide synthesis with exotic building blocks (2020)
  • Author(s): Tsiamantas Christos、Rogers Joseph M.、Suga Hiroaki
  • Journal Title: Chemical Communications Volume: 56 Issue: 31 Pages: 4265-4272
  • DOI: 10.1039/d0cc01291b
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Macrocyclic peptides that inhibit Wnt signallingviainteraction with Wnt3a (2020)
  • Author(s): Otero-Ramirez Manuel E.、Matoba Kyoko、Mihara Emiko、Passioura Toby、Takagi Junichi、Suga Hiroaki
  • Journal Title: RSC Chemical Biology Volume: 1 Issue: 1 Pages: 26-34
  • DOI: 10.1039/d0cb00016g
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An aminoacylation ribozyme evolved from a natural tRNA-sensing T-box riboswitch (2020)
  • Author(s): Ishida Satoshi、Terasaka Naohiro、Katoh Takayuki、Suga Hiroaki
  • Journal Title: Nature Chemical Biology Volume: 16 Issue: 6 Pages: 702-709
  • DOI: 10.1038/s41589-020-0500-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ribosomal Elongation of Cyclic γ-Amino Acids using a Reprogrammed Genetic Code (2020)
  • Author(s): Katoh Takayuki、Suga Hiroaki
  • Journal Title: Journal of the American Chemical Society Volume: 142 Issue: 11 Pages: 4965-4969
  • DOI: 10.1021/jacs.9b12280
  • Peer Reviewed
• [Journal Article] Exploring the Post-translational Enzymology of PaaA by mRNA Display (2020)
  • Author(s): Fleming, S. R., Himes, P. M., Ghodge, S. V., Goto, Y., Suga, H., Bowers, A. A.
  • Journal Title: J Am Chem Soc Volume: 142 Issue: 11 Pages: 5024-5028
  • DOI: 10.1021/jacs.0c01576
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Affinity Maturation of Macrocyclic Peptide Modulators of Lys48‐Linked Diubiquitin by a Twofold Strategy (2020)
  • Author(s): Huang Yichao、Nawatha Mickal、Livneh Ido、Rogers Joseph M.、Sun Hao、Singh Sumeet K.、Ciechanover Aaron、Brik Ashraf、Suga Hiroaki
  • Journal Title: Chemistry A European Journal Volume: 26 Issue: 36 Pages: 8022-8027
  • DOI: 10.1002/chem.202000273
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ribosomal Incorporation of Aromatic Oligoamides as Peptide Sidechain Appendages (2020)
  • Author(s): Tsiamantas Christos、Kwon Sunbum、Rogers Joseph M.、Douat Cline、Huc Ivan、Suga Hiroaki
  • Journal Title: Angewandte Chemie International Edition Volume: 59 Issue: 12 Pages: 4860-4864
  • DOI: 10.1002/anie.201914654
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chemoenzymatic Posttranslational Modification Reactions for the Synthesis of Ψ[CH 2 NH]‐Containing Peptides (2020)
  • Author(s): Kato Yasuharu、Kuroda Tomohiro、Huang Yichao、Ohta Risa、Goto Yuki、Suga Hiroaki
  • Journal Title: Angewandte Chemie International Edition Volume: 59 Issue: 2 Pages: 684-688
  • DOI: 10.1002/anie.201910894
  • Peer Reviewed
• [Presentation] 基礎研究からイノベーションへ (2024)
  • Author(s): 菅 裕明
  • Organizer: 2024新春特別フォーラム
  • Invited
• [Presentation] Libraries and Display Selection for Macrocycles with Better Membrane Permeability (2023)
  • Author(s): Hiroaki Suga
  • Organizer: 18ｔｈ Drug Discovery Chemistry
  • Int'l Joint Research
• [Presentation] 特殊環状ペプチド創薬からネオバイオロジクス創薬へ (2023)
  • Author(s): Hiroaki Suga
  • Organizer: 第96回日本整形外科学会学術総会
  • Int'l Joint Research / Invited
• [Presentation] 『基礎研究から創薬イノベーションへ ―特殊ペプチド創薬・ネオバイオロジクス創薬―』 (2023)
  • Author(s): 菅 裕明
  • Organizer: 高知工科 大学 高知県立大学 高知工業高等専門学校 高知大学医工連携交流会 with 高知大学 MEDi センターキックオフ講演会 招待講演
  • Invited
• [Presentation] De novo discovery of pseud-natural peptides and products (2023)
  • Author(s): Hiroaki Suga
  • Organizer: 49th IUPAC World Chemistry Congress
  • Invited
• [Presentation] De novo discovery of pseudo-natural peptides, products, and beyond (2023)
  • Author(s): Hiroaki Suga
  • Organizer: 16th German Peptide Symposium
  • Int'l Joint Research / Invited
• [Presentation] 特殊ペプチド創薬から擬天然物創薬、ネオバイオロジクス創薬 (2023)
  • Author(s): 菅 裕明
  • Organizer: 第40回メディシナルケミストリーシンポジウム
  • Invited
• [Presentation] Display of pseud-natural peptides and products (2022)
  • Author(s): 菅 裕明
  • Organizer: Chemical Biology & Physiology 21|22（Drug Discovery）
  • Int'l Joint Research / Invited
• [Presentation] The Next Generation RaPID System (2022)
  • Author(s): 菅 裕明
  • Organizer: 27th American Peptide Symposium
  • Int'l Joint Research
• [Presentation] The next generation RaPID system (2022)
  • Author(s): 菅 裕明
  • Organizer: Peptide Therapeutics Forum 2022
  • Int'l Joint Research / Invited
• [Presentation] The Next Generation of RaPID System (2022)
  • Author(s): 菅 裕明
  • Organizer: The １７thAnnual Peptide Therapeutics Symposium
  • Int'l Joint Research / Invited
• [Presentation] "RaPID Development of Pseudo-Natural Peptides/Products and Neobiologics" (2022)
  • Author(s): 菅 裕明
  • Organizer: T. Y. Shen Seminar in Biological Chemistry
  • Int'l Joint Research / Invited
• [Presentation] Display and RaPID Selection of Pseudo-Natural Peptides and Products (2022)
  • Author(s): 菅 裕明
  • Organizer: Boulder Peptide Symposium 2022
  • Int'l Joint Research / Invited
• [Presentation] The RaPID system that revolutionizes the discovery of de novo peptides and proteins for therapeutics (2022)
  • Author(s): 菅 裕明
  • Organizer: Prelog Lecture 2020
  • Int'l Joint Research / Invited
• [Presentation] Displayable Pseudo-Natural Peptides and Products (2021)
  • Author(s): Hiroaki Suga
  • Organizer: The 18th Akabori Conference
  • Invited
• [Presentation] Revolutionizing the discovery processes of macrocyclic peptide therapeutics: A show case of anti-PlexinB1 peptides (2020)
  • Author(s): Hiroaki Suga
  • Organizer: 14th International Conference on Protein Phosphatase Japan Bone Academy 2020
  • Int'l Joint Research / Invited
• [Presentation] The power of RaPID system for de novo macrocycles discovery (2020)
  • Author(s): Hiroaki Suga
  • Organizer: Target 2035 A prove for every protein Kick-off webinar series Asia/Pacific session
  • Int'l Joint Research / Invited
• [Presentation] From Basic Science to Innovation -From genetic code reprogramming to peptide therapeutics (2020)
  • Author(s): Hiroaki Suga
  • Organizer: MIRAI 2.0 Japanese-Swedish Joint Kick-off/Scientific Webinar
  • Int'l Joint Research / Invited
• [Presentation] The next generation of RaPID display (2020)
  • Author(s): Hiroaki Suga
  • Organizer: RSC Desktop Seminar
  • Int'l Joint Research / Invited
• [Remarks]
  • URL: https://www.chem.s.u-tokyo.ac.jp/users/bioorg/index.html
• [Patent(Industrial Property Rights)] Ras INHIBITORS AND USES THERE OF (2020)
  • Inventor(s): 東京大学, UCSF
  • Industrial Property Rights Holder: 東京大学, UCSF
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Overseas
• [Patent(Industrial Property Rights)] Discovery of potent inhibitors of Staphylococcus aureus virulence targeting a membrane-embedded sensor domain (2020)
  • Inventor(s): 東京大学, Princeton大学
  • Industrial Property Rights Holder: 東京大学, Princeton大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Overseas