Development of molecular technologies for target protein degradation

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15251
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Osaka University
• Principal Investigator: Takada Yuri 大阪大学, 産業科学研究所, 助教 (20902357)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 有機化学 / ペプチド / タンパク質分解誘導剤 / PROTAC / 構造活性相関 / タンパク質間相互作用 / 創薬 / 固相合成

Outline of Final Research Achievements

This study aims to establish molecular technologies for the efficient and broadly applicable development of peptide-based proteolysis-targeting chimeras (PROTACs) through peptide stapling strategies. We focused on lysine-specific demethylase 1 (LSD1) as the target protein and conducted research on developing peptide-based PROTACs. We designed and synthesized novel LSD1 ligand peptides incorporating non-natural amino acids, as well as various cross-linking chains used for peptide stapling. By conjugating these components, we prepared multiple stapled peptides. The synthesized stapled peptides were suggested to possess LSD1 degradation-inducing activity.

Free Research Field

有機化学、創薬化学

Academic Significance and Societal Importance of the Research Achievements

タンパク質分解誘導薬(PROTAC)の創製には、標的タンパク質の適切なリガンドが必要であり、各リガンドの最適化、リンカーとのリガンドの結合部位の精査、リンカーの長さや種類の最適化等非常に多くの条件検討が必要であるため、簡便に設計・合成可能かつ幅広い標的に適用可能なPROTACの開発基盤技術が強く求められる。
本研究では、ペプチドのステープル化戦略を活用し、リシン特異的脱メチル化酵素1(LSD1)を標的タンパク質としたペプチド性PROTAC候補化合物を創製した。本戦略は、ペプチド性PROTACの創製を簡略化し、高い汎用性が期待される。