Chemo-enzymatic synthesis of medium-sized molecules regulating transcriptions

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K14790
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
• Research Institution: The University of Tokyo
• Principal Investigator: Ryo Tanifuji 東京大学, 大学院理学系研究科(理学部), 助教 (10866205)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 化学ー酵素合成 / マクロ環 / 中分子 / DNAアルキル化 / DNAータンパク質間相互作用

Outline of Final Research Achievements

This study aimed to design and synthesize a series of mid-sized molecules that regulate nucleic acid-protein interactions by integrating enzymatic transformation and chemical synthesis. Successful cascade enzymatic conversion was achieved by combining enzymatic construction of complex scaffolds with subsequent oxidative modifications.
The structural diversification of the designed macrocyclic mid-sized molecules was also explored. Mid-sized molecules incorporating known ligands for transcription factors and photoaffinity labeling units on the constructed macrocycles were synthesized. The covalent bond formation between the overexpressed and purified transcription factors and the synthesized molecules was examined. Additionally, the proliferation inhibitory activity of the synthesized molecules against cancer cells was systematically evaluated. The results indicated that subtle structural changes in the macrocycles potentially modulated their mechanisms of action.

Free Research Field

天然物化学

Academic Significance and Societal Importance of the Research Achievements

核酸－タンパク質間相互作用の制御は、転写因子を標的とするデコイ核酸に代表されるように、核酸を基盤とした技術が発達している。しかし核酸を標的とする中分子化合物については、如何なる細胞も無差別的に攻撃し得る低い選択性から、精力的な開発が実施されていない。他方で、少数であるがDNAや近傍の核内タンパク質に作用する化合物のADC薬剤がFDAにより認可されている。特定の細胞への低・中分子の選択的送達法の開発が進む現状において、核内作用型分子の多様化は、新規薬剤開発に直結する重要な課題と言える。本研究では、核内現象の選択的制御を実現する新規中分子群の創製につながる知見が得られた。