Development of cell-penetrating E3 ligase ligand and its application to nanoparticle-based degraders.

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15257
• 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: National Institute of Health Sciences
• Principal Investigator: Yokoo Hidetomo 国立医薬品食品衛生研究所, 有機化学部, 研究員 (80881424)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: タンパク質分解剤 / PROTAC / ユビキチンリガーゼ / ナノ粒子

Outline of Final Research Achievements

PROTAC is a chimeric molecule containing a target protein-ligand and a ubiquitin ligase (E3) ligand linked via a linker, leading to ubiquitination of the target protein and degradation by the proteasome. Such targeted protein degradation is expected to be a new drug modality. However, due to the low cell membrane permeability of PROTAC, a technology to improve its cell membrane permeability is required. In this research, the development of a cell membrane-permeable E3 ligand is important because the E3 ligand is a highly common moiety in PROTACs. In addition, novel membrane-permeable peptides, peptides with non-proteinogenic amino acids that could form particles with nucleic acids, and some PROTACs have been developed.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

本研究により得られた知見は、タンパク質分解医薬品の分子設計や高活性な医薬品候補化合物の開発に有用となり、創薬分野へ貢献しうる。加えて、タンパク質分解医薬品の開発効率化に資する品質、有効性、安全性の確保を目指したレギュラトリーサイエンス分野においても貢献しうる。