Chemical biology of trafficking regulation of membrane cholesterol transporter protein

2014 Fiscal Year Final Research Report

• Project/Area Number: 25670052
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: HASHIMOTO Yuichi 東京大学, 分子細胞生物学研究所, 教授 (90164798)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: トラフィッキング / コレステロール / 局在異常 / スクリーニング / ステロイド / フェナンスリジノン

Outline of Final Research Achievements

Niemann-Pick type C1 (NPC) and NPC1-like 1 (NPC1L1) are cholesterol transporter. We discovered NPC and NPC1L1 ligands by using a novel cell-based assay that employs pharmacological chaperone effect as a readout. Those steroid derivatives bound to a site different from both the sterol-binding domain (for NPC1/NPC1L1) and the ezetimibe-binding site (for NPC1L1), implying that they may be a novel class of NPC1L1 inhibitors with a distinct mode of action. Regarding NPC1 ligands, a potent pharmacological chaperon which corrects abnormal trafficking of mutated NPC1 was created. As an extension of structure-activity relationship studies for NPC1L1 ligands, we found non-steroidal NPC1L1 ligands, which may be better candidates for clinical application than steroidal ligands, by using the same assay to screen our focused library of ligands for liver X receptor (LXR), a nuclear receptor that recognizes oxysterols as endogenous ligands.

Free Research Field

医薬化学