Development of novel cholesterol synthesis modulators that alter stability of cholesterol-biosynthetic enzymes

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K15949
• 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: Ochanomizu University (2021-2022); Tokyo University of Science (2020)
• Principal Investigator: Ohgane Kenji お茶の水女子大学, 基幹研究院, 講師 (30771092)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: コレステロール / タンパク質安定性

Outline of Final Research Achievements

Cholesterol biosynthetic pathway is tightly regulated at both transcriptional and post-translational levels. In this study, we specifically focused on the latter, and sought to identify small molecules that alter stability of cholesterol biosynthesis enzymes, including squalene monooxygenase. Based on our initial hit compounds from a screening that monitor squalene monooxygenase stability, we synthesized oxysterol derivatives, and clarified its structure-activity relationships. Also, during the course of the study, we noted that the catalytic domain of the enzyme is specifically stabilized by its inhibitors, and the stabilization could be sensitively detected by luciferase activity fused to the enzyme. Expecting this could be a useful cell-based screen for squalene monooxygenase inhibitors, we performed characterization of the screen.

Free Research Field

医薬化学

Academic Significance and Societal Importance of the Research Achievements

酵素の機能を阻害する化合物は、これまで阻害剤として数多く医薬応用されてきた。本研究では、機能ではなく酵素自体の量を変化させる化合物について探求をおこない、特にコレステロール合成経路のスクアレンモノオキシゲナーゼに着目して化合物の探索を行なった。本酵素の安定性を低下させるオキシステロールを見出し、そのどのような構造が必要かを明らかにし、高活性化を目指す上での基礎となる情報を得た。また、スクアレンモノオキシゲナーゼの阻害剤を探索する新しい方法として、簡便かつ細胞内での作用を検出できる実験系の開発をおこなった。今後、新たなスクアレンモノオキシゲナーゼ阻害剤の発見につながる可能性がある。