2019 Fiscal Year Final Research Report
Analyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay-Sachs disease
| Project/Area Number |
17K08362
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | University of Toyama |
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Principal Investigator |
KATO Atsushi 富山大学, 学術研究部薬学・和漢系, 教授 (60303236)
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| Co-Investigator(Kenkyū-buntansha) |
石井 達 大分大学, 医学部, 客員研究員 (00222935)
広野 修一 北里大学, 薬学部, 教授 (30146328)
足立 伊左雄 富山大学, 学術研究部薬学・和漢系, 教授 (30151070)
名取 良浩 東北医科薬科大学, 薬学部, 助教 (50584455)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| 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 |
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| Outline of Final Research Achievements |
The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favorable cation - π interaction with Trp460. Among them, DMDP amide proved to be the most potent competitive inhibitor with Ki value of 0.041 μM. DMDP amide dose-dependently increased intracellular Hex A activity in the G269S mutant cells and restored Hex A activity up to approximately 43 % of the wild type level; this effect clearly exceeded the border line treatment for Tay-Sachs disease, which is regarded as 10-15 % of wild type level. This is a significantly greater effect than that of pyrimethamine, which is currently in Phase 2 clinical trials. DMDP amide.
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| Free Research Field |
糖質生化学
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| Academic Significance and Societal Importance of the Research Achievements |
Tay-Sachs 病はHex Aの 活性低下に起因する疾患であり、厚生労働省難治性疾患等政策研究事業対象の稀少疾患に指定されている。従来用いられてきた酵素補充療法は、抗体の産生や副作用の問題など克服すべき点が多くあった、本研究では患者自身が持つ不安定な変異酵素を安定化させる化合物を創製し、有効性及び安全性に優れた薬剤の創製を目指した。我々がデザインし合成した化合物は濃度依存的に患者由来G269S変異細胞のHex Aを上昇させ、正常細胞の43%まで酵素活性を回復させた。以上の結果から、本化合物は、最初のTay-Sachs病に対する実用的なシャペロンとして期待される。
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