Development of chimeric peptide ligands using a macrocyclic scaffold found in natural products

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K22243
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 37:Biomolecular chemistry and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: GOTO Yuki 東京大学, 大学院理学系研究科(理学部), 准教授 (70570604)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Keywords: ペプチド / RiPP / 擬天然物 / チオペプチド

Outline of Final Research Achievements

Medium-sized macrocyclic peptides with nonproteinogenic building blocks have been revisited as a promising therapeutic modality. We previously established an in vitro selection method for artificial cyclic peptide ligands and have succeeded in developing a wide variety of artificial peptide agents. However, there are still many issues to be solved for the practical use of artificial cyclic peptides as drugs, such as pharmacokinetics, stability against peptidases, and permeability through cell membranes. In this study, we conceived the idea of combining artificial cyclic peptide sequences obtained by the in vitro selection technology with the ring-closing skeleton found in thiopeptides, a family of naturally occurring bioactive peptides. Based on this strategy, we have developed chimeric cyclic peptides that are expected to have better physical properties as pharmaceuticals.

Free Research Field

ケミカルバイオロジー・生体機能関連化学・ペプチド化学

Academic Significance and Societal Importance of the Research Achievements

多くの水素結合部位を有するポリアミド主鎖から成るペプチド分子は本質的に水和状態が安定であり、疎水場である細胞膜を通過できるものは稀である。そのためペプチドを細胞内で働く薬剤として活用するには、余分な細胞内移行シグナル配列を用いたり、高度な細胞内デリバリーシステムの利用が必要であることが多いのが現状である。本研究では、「人工ペプチド配列と天然物の閉環骨格を組み合わせる」というごくシンプルな戦略で、良好な膜透過性が期待できる新たなクラスのペプチド薬剤の設計の道を拓いた。それゆえ、このキメラペプチドの設計戦略は、将来的に細胞内を標的とする中分子医薬品を開発する上での標準戦略となる可能性を秘めている。