Discovery of NRBP1-Ubiquitin Ligase Inhibitors for the Creation of Novel Alzheimer's Disease Therapeutics

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06769
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Kochi University
• Principal Investigator: Yasukawa Takashi 高知大学, 教育研究部医療学系基礎医学部門, 講師 (60291936)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: アルツハイマー病 / ユビキチンリガーゼ / NRBP1

Outline of Final Research Achievements

For the discovery of compounds that inhibit the interaction between NRBP1 and BRI2, screening was conducted using natural product, small molecule, and middle molecule libraries. Although an increase in the amount of BRI2 processing products and inhibition of amyloid β (Aβ) aggregation were observed with some of the middle molecule compounds, no compounds were found to have sufficient potency of action to induce an increase in endogenous BRI2 and inhibition of Aβ production. Two hit compounds were obtained that induced an increase in endogenous BRI2 and suppression of Aβ production, but both were natural compounds with complex structures, making it difficult to obtain analogues through synthetic expansion. Therefore, the search for lead compounds based on these two compounds had to be abandoned.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

学術的意義：NRBP1-BRI2間の相互作用を特異的に阻害する化合物のスクリーニングによって2種類のヒット化合物が得られたことから、当該化合物の存在が確認された。さらに、神経系培養細胞レベルで、ヒット化合物の添加によって内在性BRI2の増加とAβ産生の抑制が誘導されることから、NRBP1がアルツハイマー病（AD）治療薬の標的として妥当であることが示された。
社会的意義：BRI2の機能を活性化するNRBP1-BRI2間の相互作用を特異的に阻害する化合物が新規AD治療薬の開発につながる可能性を示した。