| Project/Area Number |
16350063
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Polymer chemistry
|
|---|
| Research Institution | Chiba University (2006)
Nagoya University (2004-2005) |
|---|
Principal Investigator |
NISHIDA Yoshihiro Chiba University, Graduate School of Horticulture, Professor, 園芸学部, 教授 (80183896)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MIURA Yoshiko Japan Advanced Institute of Science And Technology in Hokuriku (JAIST, Hokuriku), Institute of Biomaterial Science, Associate Professor, マテリアルサイエンス研究科, 助教授 (00335069)
HORIUCHI Motohiro Hokkaido University, Graduate School of Veterinary Medicine, 獣医学研究科, 教授 (30219216)
UZAWA Hirotaka National Institute of Advanced Industrial Science and Technology (AIST), Research Center of Advanced Bionics, Team Leader, バイオニクス研究センター, チーム長 (60356566)
小林 一清 名古屋大学, 工学研究科, 教授 (10023483)
|
|---|
| Project Period (FY) |
2004 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2006: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2005: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2004: ¥6,500,000 (Direct Cost: ¥6,500,000)
|
|---|
| Keywords | glycosaminoglycans / module synthesis / sulfated sugars / prion / oligosaccharide / glycomics / BSE / heparan sulfate / 糖鎖医薬 / ライブラリー合成 / 糖鎖モジュール化法 / アルツハイマー / 光反応性プローブ / モジュール化 / 糖鎖ライブラリー |
|---|
| Research Abstract |
Sulfated glycosaminoglycans (GAGs) and their analogues such as pentosan polysulfate (PPS), dextran sulfate (DS), and heparin inhibit abnormal isoform of prion protein (PrP^<Sc>) formation in prion-infected cells and prolong the incubation time of scrapie-infected animals. Sulfation of GAGs is not completely regulated and possible sulfation sites are randomly sulfated. This property impedes an elucidation of fundamental structures of GAGs that are involved in diverse biological events on cell surfaces. To address the structure-activity relationship of GAGs in the inhibition of PrP^<Sc> formation, we assembled a series of glycosaminoglycans analogues by applying our synthetic strategy based on the concept of carbohydrate modules. Among the synthetic glycosides and their copolymers thus derived and examined, monomeric 4-sulfo-N-acetyl-glucosamine (4SGN), and two copolymers, poly-4SGN and poly-6-sulfo-N-acetyl-glucosamine (6SGN), inhibited PrP^<Sc> formation with 50% effective dose lower than 20 μg/ml. The inhibitory effect became more evident in consecutive treatment. They reduced the expression of cellular prion protein but did not affect cell growth. Structural comparison suggested that coincidence of N-acetyl group at C-2 with sulfate group at C-4 or C-6 might be involved in the inhibition of PrP^<Sc> formation. However, neither monomeric nor dimeric 6SGN, but poly-6SGN showed the inhibitory effect, suggesting the importance of polyvalent configuration in the effect of 6SGN. These results indicate that the artificially sulfated glycosides and their polymers are useful not only for the analysis of structure-activity relationship of GAGs but also for the improvement of new therapeutic compounds for prion diseases.
|
