A new strategy to develop therapeutic agents for neurodegenerative diseases by structural biology

2016 Fiscal Year Final Research Report

• Project/Area Number: 26440079
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biophysics
• Research Institution: Osaka Prefecture University
• Principal Investigator: Onda Maki 大阪府立大学, 理学(系)研究科(研究院), 准教授 (60311916)
• Co-Investigator(Renkei-kenkyūsha): MIKAMI Bunzo 京都大学, 農学研究科, 教授 (40135611) ; TADA Toshiji 大阪府立大学, 理学系研究科, 客員研究員 (70275288) ; KINOSHITA Takatoshi 大阪府立大学, 理学系研究科, 准教授 (90405340)
• Research Collaborator: Lomas David A. ロンドン大学, ユニヴァーシティ・カレッジ・ロンドン・医学部呼吸生物学, 教授 ; Miranda Elena ローマ・ラ・サピエンツァ大学, チャールズ・ダーウィン生物学・生物工学研究科, 常任研究員
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: neuroserpin / tPA / inhibitor / drug design / serpin / alzheimer / neurodegeneration / dementia

Outline of Final Research Achievements

Neuroserpin is a promising target for cure of neurodegenerative diseases because the protein inhibits tissue type plasminogen activator (tPA) in the brain and central nervous system. Neuroserpin inhibitor compounds thus, without effects on thrombolysis, can assist to produce plasmin that degrades amyloid fibril in the brain. In this project, crystal structures of a complex of neuroserpin with tPA and a pathogenic mutant of neuroserpin S49P were determined at 4 angstrom resolution and 1.9 angstrom resolution, respectively. Based on these structural data, three compounds that accelerate latent transition of neuroserpin, and two compounds that inhibit binding of neuroserpin with tPA were found. These five compounds were subjected to effect and toxic tests using a neuronal cell culture model of Alzheimer's disease, and based on the results, we successfully found two potential leads for drug design.

Free Research Field

構造生物学