Structural and functional development studies of ligands for disease progression factors

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H03996
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Hashimoto Yuichi 東京大学, 定量生命科学研究所, 教授 (90164798)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 構造展開 / 薬理シャペロン / 核内受容体 / タンパク質分解誘導

Outline of Final Research Achievements

Bio-active compounds which regulate activity, stability, decomposition, cellular localization, and/or trafficking of various disease-associating proteins were designed and synthesized. Typical achievements are design and synthesis of: (1) agonists/antagonists/down regulators for various nuclear receptors, including nuclear estrogen receptor, (2) inhibitors for epigenetic factors, including bromodomain proteins and HDAC, (3) protein knockdown inducers for neurodegenerative disease associated beta-sheet type self-aggregative polyglutamine proteins, including huntingtin protein/atrophin/ataxins, and (4) pharmacological chaperones which correct abnormal cellular trafficking of disease-associated functional proteins, including mutant Niemann-Pick type C1. Also, pharmacological and physiological ligands which regulate the stability of lipid metabolism rate-limiting enzymes, including squalene mono-oxygenase and HMG-CoA reductase, were analyzed.

Free Research Field

生物有機化学

Academic Significance and Societal Importance of the Research Achievements

現時点で薬物治療法が存在しない神経変性疾患を代表とするを多くのいわゆる難病には、機能性タンパク質の演出型の異常に起因するものが多く、タンパク変性疾患と総称・分類することができる。タンパク変性疾患に対しては、従来の小分子創薬、すなわち、薬物受容体を標的にその機能を直接制御する活性を追求する創薬手法では対応できない。本研究課題では、タンパク変性疾患に対して、その原因因子ないし増悪因子たるタンパク質の演出型（安定性／細胞内局在／凝集性など）の異常を修正する小分子化合物群を設計／創製し、それをもって、未だ治療法なき難病に対して新たな治療戦略が提案可能である。