Novel therapy for neurological disorders by protein-protein interaction inhibitor

2017 Fiscal Year Final Research Report

• Project/Area Number: 16K15317
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Osaka University
• Principal Investigator: SASAKI Tsutomu 大阪大学, 医学系研究科, 講師 (20534879)
• Co-Investigator(Kenkyū-buntansha): 平田 佳之 大阪薬科大学, 薬学部, 助教 (00745854) ; 長岡 康夫 関西大学, 化学生命工学部, 教授 (90243039)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: PPI阻害剤 / p53 / MDM2 / MDMX / 神経細胞 / 血管内皮

Outline of Final Research Achievements

Protein-protein interactions (PPI) are fundamental to cell biological processes and are often dysregulated in various neurological disorders. PPI hence represent a huge class of therapeutic targets and modulation of PPI with small molecules has becoming increasingly important in drug discovery. To screen for novel neuroprotective small-molecule PPI inhibitors in in vitro and in vivo Parkinson’s disease (PD) and stroke. PPI inhibitors, with protective effects against MPP+-induced neuronal death in in vitro model were identified. Furthermore, oral administration of PPI inhibitors before MPTP mitigated MPTP-induced loss of dopaminergic neurons in substantia nigra, compared with saline-treated control mice. Also, PPI inhibitors mitigated ischemic stroke, resulting in enhanced functional outcome. The discovery of these small-molecule p53/negative regulator-interaction inhibitors with neuroprotective properties may pave the way to new therapeutic strategies for PD or stroke treatment.

Free Research Field

神経内科学