Design and synthesis of iminosugar-based pharmacological chaperone as a structure stabilizing agent for mutation enzyme

2016 Fiscal Year Final Research Report

• Project/Area Number: 26460143
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: University of Toyama
• Principal Investigator: Kato Atsushi 富山大学, 附属病院, 准教授 (60303236)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: リソソーム病 / グリコシダーゼ / イミノ糖 / シャペロン / フォールディング / テイーサックス病

Outline of Final Research Achievements

We performed the computer modelling aided design and synthesis of Hex A inhibitors along with their applicability to Tay-Sachs disease treatment through biological evaluation in both an enzymatic and cellular setting. All 16 stereoisomeric N-methyl proline amides iminosugars have been synthesized from lactone saccessible from the enantiomers of glucuronolactone. All eight enantiomers with a (3R)-hydroxyl configuration are low micromolar to nanomolar inhibitors of a range of Hex A. Furthermore, its stereoisomers bearing a (2S,3R)-trans configuration are significantly more potent inhibitors than those with a (2R,3R)-cis motif. DMDP amide improved the thermostability of Hex A in vitro and increased intracellular Hex A activity by 15-fold in Tay-Sachs G269S fibroblasts after incubation for 5 days. These experimental results suggested that DMDP amide will be a good candidate for treatment of Tay-Sachs disease.

Free Research Field

糖質生化学