| 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 |
|
|---|
| Project Period (FY) |
2013-04-01 – 2015-03-31
|
| Project Status |
Completed (Fiscal Year 2014)
|
| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
|
|---|
| 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 / NPC1L1 / 分子プロファイリング / 核内受容体 / 薬理シャペロン / ニーマン・ピック病Ｃ型 / フォールディング異常症 / 蛋白変性症 / マルチテンプレート / コレステロール輸送 / 生理活性物質 / 蛋白質相互作用 / 膜タンパク質 |
|---|
| 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.
|
