Studies on synthesis of inhibitors of sulfotransferases in mucopolysaccharide biosynthesis and application of the inhibitors to substrate deprivation therapy for mucopolysaccharidoses
| Project/Area Number |
14370761
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | Microbial Chemistry Research Foundation |
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Principal Investigator |
NISHIMURA Yoshio Microbial Chemistry Research Center, Associate Director, 微生物化学研究センター, 副センター長 (80164599)
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| Co-Investigator(Kenkyū-buntansha) |
ADACHI Hayamitsu Microbial Chemistry Research Center, Drug Development Unit, Head, 微生物化学研究センター・探索研究推進ユニット, ユニット長 (00250051)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | mucopolysaccharidose / Hunter disease / substrate deprivation therapy / iduronate 2-O-sufatase / siastatin B / iduronate 2-O-sulfotransferase / glycosaminoglycan / 1-N-iminosugar / Iduronate 2-o-sulfatase欠損 / Iduronate 2-o-sulfotransferase / Sanfilipo病 / 2-O-sulfatase欠損 / N-sulfatase欠損 / N-surfatase欠損 |
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| Research Abstract |
gem-Diamine 1-N-iminosugars related to L-iduronic acid and D-glucosamine were investigated to inhibit iduronate 2-O-sulfotransferase (2-O-ST) and N-deacetylase/N-sulfotransferase (NDST) for the GAG-chain biosynthesis in Hunter and Sanfilipo syndrome, respectively. Within the three years, about 60 compounds were synthesized and evaluated as inhibitors of 2-O-ST and NDST using an in vitro enzyme assay. Two iminosugars containing guanidine groups acted as potent inhibitors of 2-O-ST. Two inhibitors were subsequently tested in vivo as inhibitors of glycosaminoglycan biosynthesis using (i) biotinylated FGF-2 (ii) total ^<35>SO_4-labeling of the glycosaminoglycan chains and (iii) ^3H-GlcN-labeling of the glycosaminoglycan chains followed by disaccharide analysis. However, none of the active in vitro compounds were inhibitors of GAG biosynthesis in vivo. Both compounds were also found non-toxic to CHO-K1 cells. The lack of activity most likely reflects poor uptake by cells due to the positively charged guanidine moiety. These biological studies may require introduction of substituents and/or removal blocking groups to increase the permeability of the compounds to cell membranes.
This is the first evidence that gem-diamine 1-N-iminosugars act as inhibitors of an enzyme involved in heparan sulfate synthesis. This suggests that the combination of substrate deprivation therapy and enzyme replacement therapy would also be anticipated.
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Report
(4 results)
Research Products
(10 results)
