Development of prenylated peptides interacting with intracellular targets

• Project/Area Number: 20H02866
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
• Research Institution: Kyoto University (2023); The University of Tokyo
• Principal Investigator: Goto Yuki 京都大学, 理学研究科, 教授 (70570604)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2023: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2022: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2021: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 中分子ペプチド / プレニル化ペプチド / 擬天然物 / 生物活性分子

Outline of Research at the Start

次世代型の創薬候補分子として、中分子サイズの環状ペプチドが近年注目されている。しかしながら、親水性の高いアミド結合を主鎖にもつペプチドは、一般的に細胞膜を通過できないため、細胞内移行配列に頼らずに細胞内標的を阻害する人工ペプチド薬剤の開発原理は、現時点では存在しない。そこで、本研究では、天然物ペプチドにみられ、高い細胞膜親和性が期待されるプレニル化骨格を活用することで、任意の生物活性を示す人工プレニル化ペプチドを創製するシステムの樹立を最終目標として掲げる。

Outline of Final Research Achievements

The aim of this project was to establish a system for the development of artificial prenylated peptides with desired binding ability by utilizing prenyl modifications found in natural product peptides. Specifically, more than 25 putative peptide prenyltransferases have been identified, and among these, we succeeded in discovering and identifying five new groups of prenyltransferases that perform unprecedented modes of prenylation (Goal A), and in constructing more diverse artificial prenylated residues through prenylation of artificial amino acid derivatives (Goal B). Furthermore, we established an in vitro selection system for artificial PMPs ligands using these prenylating enzymes (Goal C) and succeeded in developing artificial prenylated peptide agents that inhibit specific target proteins and can internalize into cells (Goal D).

Academic Significance and Societal Importance of the Research Achievements

次世代型の創薬候補分子として、中分子サイズの環状ペプチドが近年注目されている。しかしながら、親水性の高いアミド結合を主鎖にもつペプチドは、一般的 に細胞膜を通過できないため、細胞内移行配列に頼らずに細胞内標的を阻害する人工ペプチド薬剤の開発原理は、残念ながら現時点では存在しない。本研究成果は、細胞内標的を阻害する人工ペプチド薬剤開発の基盤技術となりうる。

Research Products

• [Int'l Joint Research] Princeton University/Univ. of North Carolina at Chapel Hill(米国)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [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] New developments in RiPP discovery, enzymology and engineering (2021)
  • Author(s): Montalban-Lopez, M., et al.
  • Journal Title: Nat. Prod. Rep. Volume: 38 Issue: 1 Pages: 130-239
  • DOI: 10.1039/d0np00027b
  • 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] 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] 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] A Macrocyclic Peptide Library with a Structurally Constrained Cyclopropane‐containing Building Block Leads to Thiol‐independent Inhibitors of Phosphoglycerate Mutase (2020)
  • Author(s): Okuma Rika、Kuwahara Tomoki、Yoshikane Takafumi、Watanabe Mizuki、Dranchak Patricia、Inglese James、Shuto Satoshi、Goto Yuki、Suga Hiroaki
  • Journal Title: Chemistry - An Asian Journal Volume: 15 Issue: 17 Pages: 2631-2636
  • DOI: 10.1002/asia.202000700
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Human trans-editing enzyme displays tRNA acceptor-stem specificity and relaxed amino acid selectivity (2020)
  • Author(s): Vargas-Rodriguez, O., Bakhtina, M., McGowan, D., Abid, J., Goto, Y., Suga, H., Musier-Forsyth, K.
  • Journal Title: J. Biol. Chem. Volume: 295 Issue: 48 Pages: 16180-16190
  • DOI: 10.1074/jbc.ra120.015981
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Artificial in vitro biosynthesis for backbone-modified peptides (2020)
  • Author(s): Yuki Goto
  • Organizer: 7th FIP Pharmaceutical Sciences World Congress (PSWC2020 Virtual)
• [Presentation] Artificial in vitro biosynthesis for backbone-modified peptides (2020)
  • Author(s): Yuki Goto
  • Organizer: 6th International Symposium on Middle Molecular Strategy (ISMMS-6)